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Effects of Prenatal Stress on Corticosteroid Receptors and Monoamine Concentrations in Limbic Areas of Suckling Piglets (Sus scrofa) at Different Ages
Abstract
The present study was conducted in order to reveal the effects of prenatal stress on the central stress regulation in domestic pigs by measuring changes in corticosteroid receptor binding and monoamine concentrations in different limbic brain regions. Pregnant sows were subjected to a restraint stress for 5 min daily during the last 5 weeks of gestation. Maternal stress resulted in a significantly higher number of glucocorticoid receptors in the hippocampus, but decreased glucocorticoid receptors in the hypothalamus of the offspring at the first postnatal day. No alterations of hippocampal mineralocorticoid receptors were found. There was also no significant effect of prenatal stress on the brain monoamine concentrations. Prenatally stressed piglets showed lower basal plasma cortisol and increased corticosteroid binding globulin concentrations at the third postnatal day indicating decreased free cortisol concentrations after birth. Morbidity and mortality during the suckling period were significantly increased in prenatally stressed litters, as shown by a higher frequency of diseased and died piglets per litter. In conclusion, the results indicate that in pigs restraint stress during late gestation affects the ontogeny of the foetal neuroendocrine feedback system with consequences for the regulation of the hypothalamo-pituitary-adrenal function and the vitality of the offspring.
... The stage of gestation during which a stressor occurs is also an important factor to consider (82)(83)(84)(85)(86), because various systems of the developing embryo/foetus are vulnerable to stress at different times throughout prenatal development (83). For example, early gestation (day 10 to day 17) is a critical period for pig embryo establishment and development. ...
... Various studies show the potential effects of prenatal stress on swine offspring, whether physiological or psychological (behaviour/personality). Specific physiological effects reported to date include altered development of the HPA axis (76), and associated decreased (86), or increased levels of basal circulating cortisol (171). Increased offspring hippocampal glucocorticoid receptors, decreased serum immunoglobulin G concentrations, and decreased lymphocyte proliferation (86) are also reported. ...
... Various studies show the potential effects of prenatal stress on swine offspring, whether physiological or psychological (behaviour/personality). Specific physiological effects reported to date include altered development of the HPA axis (76), and associated decreased (86), or increased levels of basal circulating cortisol (171). Increased offspring hippocampal glucocorticoid receptors, decreased serum immunoglobulin G concentrations, and decreased lymphocyte proliferation (86) are also reported. Such effects can result in reduced immunity, higher susceptibility to disease, and greater mortality among prenatally stressed piglets (17). ...
Chronic stress has a detrimental effect on sow welfare and productivity, as well as on the welfare and resilience of their piglets, mediated prenatally. Despite this, the specific risk factors for chronic stress in pregnant sows are understudied. Group-housed pregnant sows continuously face numerous challenges associated with aspects of the physical (group type and size, flooring, feeding system) and social (stocking density, mixing strategy) environment. There are many well-known potent stressors for pigs that likely contribute to chronic, physiological stress, including overcrowding, hot temperatures, feed restriction, inability to forage, uncomfortable floors, and poor handling. Some of these stressors also contribute to the development of production diseases such as lameness, which in turn are also likely causes of chronic stress because of the associated pain and difficulty accessing resources. The aim of this review is to discuss potential risk factors for chronic stress in pregnant sows such as space allowance, group size and type (stable/dynamic), feeding level, lameness, pen design, feed system, enrichment and rooting material, floor type, the quality of stockmanship, environmental conditions, and individual sow factors. The mechanisms of action of both chronic and prenatal stress, as well as the effects of the latter on offspring are also discussed. Gaps in existing research and recommendations for future work are outlined.
... Therefore, because a marked increase in glucocorticoids, norepinephrine, and epinephrine has been observed in livestock species during times of HS [32][33][34], it is possible that the offspring HPA-axis may be altered due to maternal HS-exposure. Although the mechanism(s) of action are currently unknown in swine, changes in corticosteroid binding globulin availability in the plasma [10,12,35], and altered glucocorticoid receptor expression in the hypothalamus and hippocampus have been described in pigs and may be due to in utero cortisol exposure [10,35]. Furthermore, previous studies have described an increased cortisol response in IUHS pigs exposed to novel postnatal stressors [24]. ...
... Therefore, because a marked increase in glucocorticoids, norepinephrine, and epinephrine has been observed in livestock species during times of HS [32][33][34], it is possible that the offspring HPA-axis may be altered due to maternal HS-exposure. Although the mechanism(s) of action are currently unknown in swine, changes in corticosteroid binding globulin availability in the plasma [10,12,35], and altered glucocorticoid receptor expression in the hypothalamus and hippocampus have been described in pigs and may be due to in utero cortisol exposure [10,35]. Furthermore, previous studies have described an increased cortisol response in IUHS pigs exposed to novel postnatal stressors [24]. ...
... Despite this however, IUHS piglets in the present study had an overall reduction in circulating cortisol concentrations compared to IUTN piglets, largely due to a more pronounced decrease in cortisol concentrations following weaning and transport. Although this result was unexpected, decreased postnatal cortisol concentrations associated with in utero stress have been previously reported in piglets [10,14,36] and it is possible that IUHS down regulated the HPA-axis feedback set point resulting in decreased postnatal cortisol release in response to a stressor. Alternatively, the decrease in circulating cortisol for IUHS compared to IUTN pigs could indicate that their physiological stress response to weaning and transport was reduced because decreased circulating cortisol levels are a general indicator of reduced stress in pigs [37]. ...
The study objective was to determine whether in utero heat stress (IUHS) affects piglet physiology and behavior following common production practices. A total of 12 gilts were confirmed pregnant and allocated to either heat stress (HS; n = 6) or thermoneutral (TN; n = 6) conditions on day 30–60 of gestation. At weaning (22.5 ± 2.3 days of age), 1 boar and 1 barrow of median weight were selected from each litter and transported for approximately 7 h. Piglets were then blocked into pens (n = 2/pen) by in utero treatment (IUHS (n = 12) or in utero thermoneutral (IUTN, n = 12)) and sexual status (boar (n = 6/in utero treatment) or barrow (n = 6/in utero treatment)). Plasma cortisol, non-esterified fatty acids (NEFA), insulin and glucose were evaluated 1 day prior to transport (pre-transport) and immediately after transport (post-transport). Behavioral data were collected on day 1–7 for 60 min at four different time points each day. In utero heat stressed piglets exhibited reduced cortisol concentrations compared to IUTN piglets immediately post-transport (p = 0.04). Glucose concentrations were not affected by in utero treatment. Insulin concentrations were reduced in IUTN piglets post-transport compared to pre-transport (p = 0.002), but no differences were detected for IUHS pigs. Non-esterified fatty acids tended to be reduced overall for IUHS vs. IUTN pigs (p = 0.08). Overall, IUHS piglets performed more drinking behaviors (p = 0.02) and tended to perform more aggressive behaviors (p = 0.07) than IUTN piglets in the 7 days post-transport. In summary, there was some evidence for altered physiological and behavioral responses among IUHS piglets compared to IUTN piglets following weaning and transport.
... Species-specific studies are needed because the generalization of rodent data to ungulates is limited by major inter-species differences like gestation length, in utero developmental time-line (Merlot et al., 2008) and placenta permeability to hormones (Klemcke, 1995;Fisher, 1998). Porcine HPA axis and sympatho-adrenomedullary (SAM) system were shown to be sensitive to PNS (Haussmann et al., 2000;Kanitz et al., 2003Kanitz et al., , 2006, but very few data are available concerning the immune function, and most of them are coming from studies using pharmacological models of maternal HPA axis activation. De Groot et al. (2007) suggested that the non-specific inflammatory response to a LPS challenge increased in piglets whose mothers were treated with cortisol during pregnancy. ...
... Indeed cortisol levels were similar in S and C piglets in a steady situation at different ages (birth, D4, D26 and D60) and two days after stressful events applied either on D26 or D60. This is in agreement with the literature, where no or only transient effects of PNS were reported on basal activity of the HPA axis in pigs (Haussmann et al., 2000;Otten et al., 2001;Kanitz et al., 2003Kanitz et al., , 2006Kranendonk et al., 2006a,b). The effects of PNS in stimulated conditions are not clear since cortisol secretion was reported to be unaltered (Otten et al., 2001;Kanitz et al., 2003;Kranendonk et al., 2006b;Lay et al., 2008), decreased (Kranendonk et al., 2006a) or increased (Haussmann et al., 2000;Jarvis et al., 2006) in PNS pigs. ...
... This is in agreement with the literature, where no or only transient effects of PNS were reported on basal activity of the HPA axis in pigs (Haussmann et al., 2000;Otten et al., 2001;Kanitz et al., 2003Kanitz et al., , 2006Kranendonk et al., 2006a,b). The effects of PNS in stimulated conditions are not clear since cortisol secretion was reported to be unaltered (Otten et al., 2001;Kanitz et al., 2003;Kranendonk et al., 2006b;Lay et al., 2008), decreased (Kranendonk et al., 2006a) or increased (Haussmann et al., 2000;Jarvis et al., 2006) in PNS pigs. In our study, the lack of effect of PNS on basal cortisol levels indicates that the immune alterations observed from 4 to 60 days of age in piglets were not due to altered circulating levels of this immunosuppressive hormone. ...
Events acting prenatally on developing foetuses are important determinants for disorders later in life. Prenatal stress (PNS) is one of these events. The purpose of this study was to determine the consequences of a repeated social stress applied during late gestation of the pregnant gilt on the immune system and hypothalamo-pituitary-adrenal (HPA) axis activity of the piglets from birth to two months of age. Pregnant gilts were submitted to repeated social stress which was induced by housing unfamiliar gilts in pairs modified twice a week during 4 weeks between days 77 and 105 of gestation (S group, n=18). Control gilts were housed in stable pairs during the same period (C group, n=18). Blood cortisol, haptoglobin and IgG levels, immune cell counts, mitogen-induced whole-blood proliferation and TNF-alpha production were evaluated in piglets at 4 days of age (D4), before and after weaning (D26 and 28) and before and after relocation to a new building (D60 and 62). We found that PNS did not affect growth rate of the progeny. It decreased the relative weight of adrenal glands on D4 (P<0.05) but plasma cortisol levels were similar in both groups at all ages. IgG levels in colostrum and in the serum of piglets were not affected. PNS decreased the total numbers of white blood cells, lymphocytes and granulocytes from D26 to D60 (P<0.05), the CD4(+)/CD8(+) T cell ratio on D4 (P<0.05), and LPS induced-TNF-alpha production on D60 (P<0.05). PNS increased the ConA-induced lymphocyte proliferation on D4 and D60 and the PWM-induced proliferation on D60 (P<0.05). Our results demonstrate that a repeated social stress applied to pregnant sows during late gestation can induce long-lasting effects on several parameters of the immune function of the offspring. These effects are not due to modifications of the HPA axis activity and may impair the abilities of the piglets to efficiently react against infections during the suckling period and around weaning.
... For example, high maternal glucocorticoids at parturition can alter the offspring stress response (i.e. the change in plasma cortisol concentration from pre-stressor to post-stressor levels; Sheriff et al. 2010b;Homberger et al. 2015) by weakening internal negative feedback mechanisms that normally limit the offspring stress response (e.g. Kanitz et al. 2003;Kapoor et al. 2006). Thus, offspring of highly stressed mothers may be more physiologically responsive to external stressors (Kanitz et al. 2003;Kapoor et al. 2006;Love et al. 2013), although increased post-natal care can attenuate the stress response (Bókony et al. 2009;McGhee and Bell 2014). ...
... Kanitz et al. 2003;Kapoor et al. 2006). Thus, offspring of highly stressed mothers may be more physiologically responsive to external stressors (Kanitz et al. 2003;Kapoor et al. 2006;Love et al. 2013), although increased post-natal care can attenuate the stress response (Bókony et al. 2009;McGhee and Bell 2014). These developmental differences may serve to adapt offspring to stressful environmental conditions such as high population density (Dantzer et al. 2013), high predation risk (Boonstra et al. 1998;Sheriff et al. 2010a;Vitousek et al. 2014), or unpredictable resource availability (Homberger et al. 2015). ...
Activation of the hypothalamic-pituitary-adrenal (HPA) axis liberates glucocorticoids, which provides an acute indication of an individual's response to stressors. The heritability of the stress response in wild mammals, however, remains poorly documented. We quantified the cortisol stress response of female Richardson's ground squirrels (RGSs) to handling and physical restraint, testing for: (1) the effects of individual age, time of day, and sample latency; (2) repeatability within individuals; (3) narrow-sense heritability; and (4) differences among individuals owing to potential genetic and/or environmental effects. We detected a positive linear relationship between baseline plasma cortisol (BL-cortisol) concentration and stress-induced plasma cortisol (SI-cortisol) concentration that defined each individual's cortisol stress response. BL-cortisol, SI-cortisol, and stress response did not differ according to the time the sample was taken, or by subject age. Cortisol stress response was highly repeatable within individuals, had a mother-offspring heritability of h2 = 0.40 ± 0.24 (mean ± SE), full-sibling heritability of
h
FS
2
=
0.37
±
0.71
, and half-sibling heritability of
h
HS
2
=
0.75
±
1.41
. Stress responses of sibling groups, immediate-family groups, and squirrels within a given area did not differ, whereas those of individuals from more distantly related matrilines did. Our results highlight the natural variability in HPA axis reactivity among individuals by quantifying both BL- and SI-cortisol levels, demonstrate partial heritability of the stress response that is not attributable to environmental variation, and suggest that at least part of an individual's stress response can be accounted for by differences in matrilineal history.
... Several different types of prenatal stressors have been described in the prenatal stress literature possibly leading to the differences in results and making study comparisons difficult (de Weerth and Buitelaar, 2005). Physiological and psychological stressors including restraint (Tuchscherer et al., 2002;Kanitz et al., 2003;Vallee et al., 1997), social interactions (Gotz and Stefanski, 2007;Jarvis et al., 2006), handling (Lay Jr., et al, 2008), foot shocks (Estanislau and Morato, 2006), diet restrictions (Langley-Evans et al., 1996), and noise bursts (Clarke et al., 1996;Schneier et al., 1999;Fride et al., 1986), as well as administration of ACTH (Haussman et al., 2000;Otten et al., 2008) or cortisol (Kranendonk et al., 2006) to directly activate the adrenal response, have been used in prenatal stress studies to describe the effects of PNS on offspring development and psychology. Regardless of the stressor, the nature of it should depend on the validity necessary for the experiment (de Weerth and Buitelaar, 2005). ...
... However, Lay et al. (1997) observed PNS calves weighed more than control calves at birth. The results of the present study are consistent with Kanitz et al. (2003) who observed no differences in weight gain throughout weaning. However, differences in body weight were found at 6 months of age between PNS and control pigs in the present study; PNS pigs weighed less than CON pigs. ...
... Glucocorticosteroid receptor binding in pig brain was performed as previously described by Kanitz et al. (1998Kanitz et al. ( , 2003. Briefly, tissues of the hypothalamus and right hippocampus were homogenized in a buffer solution (10 mM Tris-HCL, 12.5 mM EDTA, 10 mM sodium molybdate, 0.25 mM sucrose, 1 mM dithiothreitol) and centrifuged at 4°C at 120,000 × g for 60 min to obtain cytosol (i.e., the supernatant fraction). ...
... Our study is the first investigating the effects of different maternal dietary protein:carbohydrate ratios on GR binding in the brains of pig offspring. Previous studies of our group on pigs revealed that maternal stress or glucocorticoid exposure during gestation decrease GR binding in the hypothalamus of neonates, which may attenuate HPA axis feedback ( Kanitz et al., 2003Kanitz et al., , 2006). The relative adrenal weight, the area of the adrenal cortex, and the cortical cell density did also not exhibit diet-dependent differences but were influenced by age. ...
Inadequate maternal nutrition during gestation may cause an adverse environment for the fetus leading to alterations of the hypothalamic-pituitary-adrenal (HPA) and sympatho-adrenomedullary (SAM) systems later in life. In the present study, we investigated the effects of diets with low and high protein:carbohydrate ratios on cortisol levels of pregnant gilts as well as the long-term effects on the function of the HPA and SAM axes in their offspring. Throughout gestation, 33 German Landrace gilts were fed high (HP, 30 %), low (LP, 6.5 %) or adequate (AP, 12.1 %) protein diets, which were made isocaloric by adjusting the carbohydrate content. The salivary cortisol levels of the sows were measured in the course of the gestation period. The offspring were cross-fostered, and the plasma cortisol and catecholamine levels of the offspring were determined on postnatal days (PND) 1 and 27 and under specific challenging conditions: after weaning (PND 29) and after ACTH and insulin challenges (PND 68 and 70, respectively). Glucocorticoid receptor (GR) binding and neurotransmitter concentrations were measured in stress-related brain regions, and histological analyses of the adrenal were performed. Maternal salivary cortisol levels increased throughout gestation (P < 0.001) and the LP gilts had higher salivary cortisol compared to the AP and HP gilts (P < 0.05). No differences between diets were found for cortisol, corticosteroid-binding globulin, and catecholamine concentrations in plasma and for GR binding in hippocampus and hypothalamus in piglets at PND 1 and 27. However, the cortisol response to weaning was increased in LP piglets (P < 0.05), and in HP offspring the basal plasma noradrenaline levels were increased (P < 0.05). The cortisol response to the ACTH and the insulin challenge did not differ between diets. On PND 81, an increased adrenal medulla area was observed in LP offspring compared to the AP offspring (P < 0.05). Our results show that maternal diets with aberrant protein:carbohydrate ratios during gestation have moderate long-term effects on the function of the HPA and SAM system in the offspring, which indicates that pigs show a considerable plasticity to cope with maternal malnutrition.
... In large animals, such as sheep or pigs, similar neurobiological factors have been found to be involved in emotional responses, especially in stressful situations. Invasive neurobiological approaches based on functional neuroanatomy (sheep: da Costa et al. 2004, Rivalland et al. 2007, Vellucci & Parrott 1994, intracerebroventricular pharmacology (pigs: Johnson et al. 1994, Salak-Johnson et al. 2004), and neurochemical brain content (e.g. in pigs, Kanitz et al. 2003, Loijens et al. 2002, Piekarzewska et al. 1999, Piekarzewska et al. 2000, Zanella et al. 1996) have demonstrated the involvement of neuropeptides such as CRF and enkephalins in different brain areas including the hypothalamus, brainstem and cortices. While neuroanatomical methods have been used to describe the immunoreactive content of brain areas (in sheep: Tillet 1995; in pigs: Kineman et al. 1989, Leshin et al. 1996, Niblock et al. 2005, Rowniak et al. 2008; in large mammals: Tillet & Kitahama, 1998), and neuronaltracing methods have been used to describe the interconnections between some of these brain areas (sheep: Qi et al. 2008, Rivalland et al. 2006, Tillet et al. 1993pigs: Chaillou et al. 2009), no dynamic functional information is available about the functional interactions among these different factors. ...
... More interestingly, we propose the use of large animal models to study the long-term effects of strong acute emotion in prenatal or perinatal life on brain development and behaviour. For example in the pig, prenatal stresses have been shown to affect ontogeny of the corticotrope axis ( Kanitz et al. 2003) and behaviour ( Jarvis et al. 2006). ...
... Prenatal stress, the stress imposed on a pregnant dam, influences her subsequent offspring by altering characteristics of the hypothalamic-pituitary-adrenal (HPA) axis (Haussmann et al., 2000;Kanitz et al., 2003;Otten et al., 2010). Increases in maternal cortisol, through either exogenous ACTH (Haussmann et al., 2000) or social stress (Jarvis et al., 2006), caused offspring to have an increased cortisol response to mixing stress. ...
... To further blur the issue, some research (Couret et al., 2009;Otten et al., 2010) has found no effect of prenatal stress on the cortisol response of the pig. Although prenatal stress research on HPA function has found diverse results, what is clear is that most studies find some alteration of the HPA axis in glucocorticoid response (mentioned above), binding globulins (Otten et al., 2010), measures of adrenal physiology (Haussmann et al., 2000), or HPA axis receptors (Haussmann et al., 2000;Kanitz et al., 2003). ...
Sows subjected to prenatal stress have been found to produce offspring that have altered responses to stress. Our objective was to determine if exposing a sow to stress would alter the response of the offspring to lipopolysaccharide (LPS) at 2 mo of age or their response to mixing stress at 4 mo of age. Sow treatments consisted of intravenous injections of ACTH (1 IU/kg of BW), exposure to rough handling for a 10-min duration (rough), or no treatment (control) once per week from d 42 to 77 of gestation. At 2 mo of age, pigs from each treatment, 1 per litter (n = 21, 17, and 15 for the ACTH, rough, and control treatments, respectively), were challenged with 2 μg of LPS/kg of BW or saline, or served as a noninjected control. Their behavioral response to a human approach test and salivary cortisol were measured. At 4 mo of age, 1 pig from each treatment (n = 14, 14, and 15 for the ACTH, rough, and control treatments, respectively) was taken from its home pen and placed in a pen of unfamiliar pigs. At this time, a punch biopsy wound (6 × 6 mm) was created to measure the ability of the pig to heal the wound. At this same time, each pig received a 1-mL intramuscular injection of 20% ovine red blood cells (oRBC), and then a second injection of oRBC at 21 d postmixing. Blood samples were collected 3 times per week for 2 wk and then once a week for 4 more weeks. Blood samples were analyzed for cortisol, porcine corticosteroid-binding globulin, antibody response to oRBC, and nitric oxide production by macrophages. Behavior was recorded during the first 5 d after mixing. All pigs in the LPS challenge responded with characteristic sickness behavior; however, pigs in the rough treatment showed less sickness behavior than those in the other 2 treatments (P < 0.05). Maternal stress treatment did not affect (P < 0.43) salivary cortisol. Pigs from all treatments responded similarly to mixing stress with regard to cortisol, porcine corticosteroid-binding globulin, antibody titers, nitric oxide production, and hematology measures, and all pigs experienced the same amount of aggression in response to mixing. Without altering peripheral measures of stress responsivity, prenatal stress enhanced the ability of pigs to cope with a simulated immune challenge, which could prove to be an adaptation to challenging environments.
... For this reason, species-specific studies are needed. In pigs, the neuroendocrine effects of PNS have been investigated18192021 but very few data are available concerning the immune function. Stress applied to female pigs during late pregnancy was shown to decrease blood leukocyte numbers, transiently decrease the blood CD4/CD8 ratio in neonates and alter blood lymphocyte proliferation after mitogen stimulation [22,23] in the progeny. ...
... The lack of effect of late PNS on basal secretion of cortisol is in agreement with the literature. Indeed, environmental maternal stressors were reported to have no effect on basal cortisol levels in pigs [36], except transiently just after birth [19]. After pharmacological increase of maternal corticoids, some authors found decreased basal levels of salivary cortisol in males [20] but not in females offspring [21], and others reported no effect on plasma cortisol [18,37]. ...
The aim of this work was to investigate the immune effects of prenatal stress (PNS) in pigs, when maternal stressor is applied during early or late gestation. In two separate experiments, gilts were submitted to a social-stress routine between either days 24 and 48 (stress (S) group, n=8 vs. control (C) group, n=6) or days 79 and 103 of gestation (S group, n=10 vs. C group, n=7). During the first month of life of the piglets, their cortisol levels were assessed in basal state and after stressful events (castration, new environment, and weaning). Piglets were immunized against ovalbumin (OVA) at 7 (D7) and 19 (D19) days of age. Lymphocyte proliferation in response to OVA and mitogens was investigated in blood in both sexes from D5 to D29 as well as in the spleen, thymus and crural lymph nodes from females euthanized on D5 and D26. On D27, the cytokine response of male piglets to an injection of lipopolysaccharide was investigated. Special care was taken to minimize the stress at blood sampling and euthanasia. We found that early gestational stress only affected the relative weight of adrenals on D5 (S<C, P<0.05). On the contrary, late gestational stress increased the proliferation index of blood cells regardless of the age, in both sexes in response to PHA (P=0.06), and in females only in response to ConA (P<0.01) and PWM (P<0.05). Overall, the effects of PNS in pigs seem to depend on the stage of gestation, gender and the immune compartment.
... Under normal conditions, glucocorticoids also stimulate negative feedback by binding to GR in the hypothalamus and anterior pituitary to downregulate production of both CRH and ACTH, respectively, which ultimately downregulates peripheral responses to stress 15 . Previous research in pig prenatal stress models have observed altered postnatal HPA axis function in offspring, which has been linked to altered postnatal physiological and behavioral stress responses [16][17][18] . As previously mentioned, IUHS causes alterations in postnatal physiological and behavioral stress responses of pigs 3-8 , yet to our knowledge there has not been research conducted to describe HPA axis function in these models. ...
In utero heat stress alters postnatal physiological and behavioral stress responses in pigs. However, the mechanisms underlying these alterations have not been determined. The study objective was to characterize the postnatal hypothalamic–pituitary–adrenal axis response of in utero heat-stressed pigs. Pigs were subjected to a dexamethasone suppression test followed by a corticotrophin releasing hormone challenge at 10 and 15 weeks of age. Following the challenge, hypothalamic, pituitary, and adrenal tissues were collected from all pigs for mRNA abundance analyses. At 10 weeks of age, in utero heat-stressed pigs had a reduced ( P < 0.05) cortisol response to the corticotrophin releasing hormone challenge versus controls. Additionally, the cortisol response tended to be greater overall ( P < 0.10) in 15 versus 10-week-old pigs in response to the dexamethasone suppression test. The cortisol response tended to be reduced overall ( P < 0.10) in 15 versus 10-week-old pigs in response to the corticotrophin releasing hormone challenge. Hypothalamic corticotropin releasing hormone mRNA abundance tended to be greater ( P < 0.10) in in utero heat-stressed versus control pigs at 15-weeks of age. In summary, in utero heat stress altered some aspects of the hypothalamic–pituitary–adrenal axis related to corticotropin releasing hormone signaling, and age influenced this response.
... Only 15-30 min. after the exposition to a stressor or after handling, serum cortisol levels peak, and basal levels are reobtained after approximately 60-90 min 21,36 . A sampling of blood in free-ranging animals often includes hunting (to sample from dead animals, often possible in larger quantities) or capturing and handling or, which can be considered as additional stressors and could lead to elevated cortisol values. ...
Hunting can easily be linked to stress in wildlife. Drive hunts performed two to three times in one area during the respective hunting period, are thought to decrease the pressure hunting places on wildlife. Nevertheless, the expression of cortisol—one of the main mammalian stress hormones—is considered to have negative impacts on animals’ well-being if expressed excessively, which may occur during some (especially repeated) hunting events. We explored the effect of drive hunts on cortisol levels in wild boar in Lower Saxony, Germany, compared these cortisol levels to reference values given by a similar study, and investigated the effect of age, sex, and pregnancy. Blood collected from wild boar shot on drive hunts was analysed using a radioimmunoassay. As expected, we observed elevated cortisol levels in all samples, however, we still found significant differences between age groups and sexes, as well as an influence of pregnancy on cortisol levels. The effect of drive hunts on cortisol levels appears to be weaker than predicted, while the effects of other variables, such as sex, are distinct. Only half of the evaluated samples showed explicitly increased cortisol levels and no significant differences were found between sampling months and locations. Group living animals and pregnant females showed significantly higher cortisol levels. The impact of hunting is measurable but is masked by natural effects such as pregnancy. Thus, we need more information on stress levels in game species.
... Also, literature data are mostly on male rats. The reported upregulation of GRs in the hippocampus of male and female rats with a history of PNS in the present study is in accordance with other studies conducted with different strains, structures, time and duration of prenatal stress exposure (Kanitz et al. 2003;Wei et al. 2004). ...
The prenatal stress (PNS) model in rodents can induce different abnormal responses that replicate the pathophysiology of depression. We applied this model to evaluate the efficacy of piromelatine (Pir), a novel melatonin analog developed for the treatment of insomnia, in male and female offspring. Adult PNS rats from both sexes showed comparable disturbance associated with high levels of anxiety and depressive responses. Both males and females with PNS demonstrated impaired feedback inhibition of the hypothalamic–pituitary–adrenal (HPA) axis compared to the intact offspring and increased glucocorticoid receptors in the hippocampus. However, opposite to female offspring, the male PNS rats showed an increased expression of mineralocorticoid receptors in the hippocampus. Piromelatine (20 mg/kg, i.p., for 21 days injected from postnatal day 60) attenuated the high anxiety level tested in the open field, elevated plus-maze and light–dark test, and depressive-like behavior in the sucrose preference and the forced swimming tests in a sex-specific manner. The drug reversed to control level stress-induced increase of plasma corticosterone 120 min later in both sexes. Piromelatine also corrected to control level the PNS-induced alterations of corticosteroid receptors only in male offspring. Our findings suggest that the piromelatine treatment exerts beneficial effects on impaired behavioral responses and dysregulated HPA axis in both sexes, while it corrects the PNS-induced changes in the hippocampal corticosteroid receptors only in male offspring.
... Hausmann et al. (2000 reported that stress of sows during farrowing impaired wound healing in piglets, while Otten et al. (2001) observed that prenatal stress increased mortality and disease incidence rates. In contrast, Kanitz et al. (2003) investigated the effect of movement restriction of pregnant sows and found that it had no consequences in the physiology of piglets after birth. In our study we observed that in general, a higher lymphocyte proliferation index was observed in the FM group. ...
Prolonged exposure to stress may cause adverse effects on animal physiology. It is especially important during the gestation period as female physiology can affect the unborn offspring in the form of prenatal stress. Intensive pig farming industry developed gestation crates that enable to keep sows during gestation period in small stalls which do not allow animals to move freely for a maximum of 4 weeks after successful insemination (Council Directive 2008/120/EC). Although these crates have production advantages, many health and welfare issues have been raised recently. In this study we tested to what extent the lack of movement of sows kept in the gestation crates had an impact on some blood and saliva constituents of new-born piglets. In total, the samples were collected from 80 piglets when they were 3, 7 and 21 days of age and tested for cortisol levels in blood and saliva, acute phase proteins (amyloid A, C-reactive protein, haptoglobin) and lymphocytes proliferation index (in response to ConA, PHA and PWM). 40 piglets were from sows kept in free movement housing (FM group) from day 1 to day 100 of pregnancy and forty piglets were from sows in the movement restriction group (MR), in which the sows were kept in crates just allowing them to stand up and lie down from day 1 to day 100 of the pregnancy (research was conducted before the implementation Directive 2008/120/EC i.e. January 1,2013). The results of the study showed that the piglets delivered by sows kept under movement restriction conditions exhibited higher cortisol and acute phase protein levels as well as a lower lymphocytes proliferation index. This suggests that lack of movement in sows during the gestation period influences piglets' physiology and indicates that the piglets are suffering from prenatal stress caused by insufficient housing conditions of their mothers potentially leading to poor health and welfare of their offspring.
... Previous in utero stress studies with swine have reported modified offspring HPA-axis activity such as greater circulating cortisol concentrations in response to postnatal stressors (Haussmann et al., 2000) and an altered feedback loop (Kanitz et al., 2003). Because a marked increase in glucocorticoids, norepinephrine, and epinephrine has been observed in livestock species (including pigs) during times of postnatal heat stress (Collier et al., 1982;Beede and Collier, 1986;Machado-Neto et al., 1987;, the offspring's HPA-axis and stress response may be altered due to maternal heat stress exposure. ...
Postnatal heat stress negatively impacts pig productivity and well-being as animals attempt to manage the resultant strain response. This is especially true when postnatal heat stress is combined with production stressors (e.g., mixing, weaning, transport, handling, and isolation) that have the potential to increase disease occurrence, morbidity and mortality. While pigs can utilize adaptive physiological mechanisms to compensate, these are often unfavorable to efficient livestock production. Specifically, postnatal heat stress decreases weight gain, reduces growth and production efficiency, alters carcass composition, and increases morbidity and mortality. Consequently, decreased animal
performance constrains profitability and affects economic sustainability. In addition to the negative effects of postnatal heat stress, prenatal heat stress has long-term consequences that may compromise future piglet well-being and performance. Pigs gestated under heat stress conditions have an increased postnatal stress response and an increase in maintenance energy requirements. Furthermore, prenatal heat stress decreases swine birth weight, and increases teratogenicity, core body temperature set-point, and alters postnatal body composition (more adipose tissue and less skeletal muscle). Taken together, the effects of heat stress during pre- and postnatal pig development negatively influences productivity and well-being, a scenario that threatens the sustainability of global swine production.
... Previous in utero stress studies with swine have reported modified offspring HPA-axis activity such as greater circulating cortisol concentrations in response to postnatal stressors (Haussmann et al., 2000) and an altered feedback loop (Kanitz et al., 2003). Because a marked increase in glucocorticoids, norepinephrine, and epinephrine has been observed in livestock species (including pigs) during times of postnatal heat stress (Collier et al., 1982;Beede and Collier, 1986;Machado-Neto et al., 1987;, the offspring's HPA-axis and stress response may be altered due to maternal heat stress exposure. ...
Postnatal heat stress negatively impacts pig productivity and well-being as animals attempt to manage the resultant strain response. This is especially true when postnatal heat stress is combined with production stressors (e.g., mixing, weaning, transport, handling, and isolation) that have the potential to increase disease occurrence, morbidity and mortality. While pigs can utilize adaptive physiological mechanisms to compensate, these are often unfavorable to efficient livestock production. Specifically, postnatal heat stress decreases weight gain, reduces growth and production efficiency, alters carcass composition, and increases morbidity and mortality. Consequently, decreased animal performance constrains profitability and affects economic sustainability. In addition to the negative effects of postnatal heat stress, prenatal heat stress has long-term consequences that may compromise future piglet well-being and performance. Pigs gestated under heat stress conditions have an increased postnatal stress response and an increase in maintenance energy requirements. Furthermore, prenatal heat stress decreases swine birth weight, and increases teratogenicity, core body temperature set-point, and alters postnatal body composition (more adipose tissue and less skeletal muscle). Taken together, the effects of heat stress during pre- and postnatal pig development negatively influences productivity and well-being, a scenario that threatens the sustainability of global swine production.
... Elevated levels of cortisol reach the foetus and modify the activity of foetal HPA axis [15][16][17]. This modification of the foetal HPA axis exerts a detrimental effect on further growth and development through a series of complex endocrine mechanisms [18][19][20]. In animals, prenatal stress also exerts an inhibitory effect on the placental enzyme 11 βhydroxysteroid-dehydrogenase type 2 which converts maternal cortisol to inactive cortisone resulting in a rise in amniotic fluid cortisol level which affects foetal HPA functioning [21]. ...
Background
The mental health status of a pregnant woman and its consequent impact on foetal well being is not given much importance compared to the risk imposed by obstetric complications and medical conditions. Maternal psychological distress is a major public health problem and needs timely detection and intervention to prevent any adverse pregnancy outcome. There is ample evidence from literature that justifies the association of prenatal maternal mental stress and elevated cortisol with delayed infant motor and cognitive development; evidence from India being rather limited. The study aim is to prospectively assess the association of maternal psychological distress and cortisol level with motor and cognitive development of the infant.
Methods
A sample of 2612 eligible pregnant women who have been registered for antenatal care at selected public sector hospitals in Bengaluru will be recruited after obtaining written informed consent. They will be assessed for the presence of maternal psychological distress in the form of depression and anxiety using appropriate scales and saliva samples will be collected for cortisol estimation during early, mid and late pregnancy. Follow up visits after delivery will be done on day 10, 3 months, 8 months and 12 months. The Bayley Scales of Infant and Toddler Development [BSID] (Third edition) will be used to measure both motor and mental milestones in terms of Psychomotor Development Index (PDI) and Mental Development Index (MDI). Logistic regression model will be used to determine the association between the exposure variables and outcomes which will be reported as Odd’s Ratio (OR) and 95% confidence intervals (CI).
Discussion
Our study findings could add to the growing evidence that maternal psychological distress during pregnancy adversely influences growth and development in the offspring and subsequent development of the child. While maternal anxiety and depression can be measured by using self reporting instruments, estimation of maternal endogenous cortisol levels could serve as a biomarker of prenatal psychological stress. Findings from this study could be used to focus upon the burden of mental health problems during pregnancy and to consider steps to scale up prenatal mental health services in health care settings.
... GR binding analysis was performed on the pooled samples as previously described [15,16]. Briefly, tissues were homogenized in ice-cold 10 mM Tris-HCl buffer, pH 7.5, containing 12.5 mM EDTA, 10 mM sodium molybdate, 0.25 mM sucrose, and 5 mM dithiothreitol using an electric homogenizer (Ultra-Turrax, IKA, Staufen, Germany). ...
The glucocorticoid receptor (GR) is a central player in the neuroendocrine stress response; it mediates feedback regulation of the hypothalamus-pituitary-adrenal (HPA) axis and physiological actions of glucocorticoids in the periphery. Despite intensive investigations of GR in the context of receptor-ligand interaction, only recently the first naturally occurring gain-of-function substitution, Ala610Val, of the ligand binding domain was identified in mammals. We showed that this mutation underlies a major quantitative trait locus for HPA axis activity in pigs, reducing cortisol production by about 40–50 percent. To unravel the molecular mechanisms behind this gain of function, receptor-ligand interactions were evaluated in silico, in vitro and in vivo. In accordance with previously observed phenotypic effects, the mutant Val610 GR showed significantly increased activation in response to glucocorticoid and non-glucocorticoid steroids, and, as revealed by GR-binding studies in vitro and in pituitary glands, enhanced ligand binding. Concordantly, the protein structure prediction depicted reduced binding distances between the receptor and ligand, and altered interactions in the ligand binding pocket. Consequently, the Ala610Val substitution opens up new structural information for the design of potent GR ligands and to examine effects of the enhanced GR responsiveness to glucocorticoids on the entire organism.
... Social stress experienced during pregnancy has been shown to increase expression of corticotropin-releasing hormone (CRF) mRNA in the amygdala and paraventricular nucleus of the hypothalamus, as well as altering the ratio of CRF 1 and CRF 2 receptors in the amygdala (Jarvis et al. 2006;Rutherford et al. 2014). Artificial (restraint) stress has also been shown to increase numbers of glucocorticoid receptors in the hippocampus and reduce them in the hypothalamus (Kanitz et al. 2003). ...
The concept that post-natal health and development can be influenced by events that occur in utero originated from epidemiological studies in humans supported by numerous mechanistic (including epigenetic) studies in a variety of model species. Referred to as the âdevelopmental origins of health and diseaseâ or âDoHaDâ hypothesis, the primary focus of large-animal studies until quite recently had been biomedical. Attention has since turned towards traits of commercial importance in farm animals. Here we review the evidence that prenatal risk factors including suboptimal parental nutrition, gestational stress, exposure to environmental chemicals and advanced breeding technologies can determine traits such as postnatal growth, feed efficiency, milk yield, carcass composition, animal welfare, and reproductive potential. We consider the role of epigenetic and cytoplasmic mechanisms of inheritance, and discuss implications for livestock production and future research endeavours. We conclude that although the concept is proven for a number of traits, issues relating to effect size, and hence commercial importance, remain. Studies have also invariably been conducted under controlled experimental conditions, frequently assessing single risk factors, thereby limiting their translational value for livestock production. We propose concerted international research efforts that consider multiple, concurrent stressors to better represent effects of contemporary animal production systems.
... In general, prenatal stress (PNS) of swine alters neurohormone secretion, reduces immunity, impairs wound healing and increases plasma cortisol levels during stress events (Haussmann et al., 2000;Tuchscherer et al., 2002;Kanitz et al., 2003;Otten et al., 2004). Furthermore, injecting pregnant sows with adrenocorticotropic hormone (ACTH; weekly from d 42-77 of gestation) raises plasma cortisol levels and shortens the anogenital distance (distance from anus to genital orifice; AGD) of the male progeny at birth (Lay et al., 2008). ...
Boars from sows with elevated plasma cortisol during pregnancy have shorter anogenital distance (AGD), a trait associated with subfertility. Since gestating sows often experience summer heat stress (HS), a mouse model was used to evaluate the effect of prenatal HS on AGD and fertility; efficacy of the heat stress-mitigating supplement artemisia absinthium (AB) was also evaluated. Dams were treated from d 8–18 of gestation, residing in ambient temperatures from 0700 – 1900 h. From 1900 – 0700 h females were exposed to 34.13±0.27 °C (HS) with access to water (HSW; n=9), HS with access to a 1% w/v decoction of AB (HSA; n=9), 20.81±0.20 °C (thermal neutral; TN) with water (TNW; n=10) or TN with AB (TNA; n=10). Daily liquid consumption was measured from d 6–18, and tail temperature was recorded at 0700 and 1900 h from d 8–18. Progeny weight and AGD were recorded at birth and weaning. At maturity, males were mated to non-littermate females from each treatment; these females were euthanized after 16 d of TN gestation. Reproductive traits were compared among all male/female treatment combinations; testes were weighed. Average liquid intake differed among treatments with HS and AB animals drinking more (P<0.0004). A treatment by time interaction for tail temperature (P<0.001) was observed; HS increased tail temperature of HSA and HSW animals similarly compared to TNA and TNW. Treatment affected (P<0.01) male birth AGD (HSW shortest; P<0.07). At maturity, HSW males also had the smallest testes (P<0.02). However, we observed no differences in fertility (P>0.10). These data indicate that in utero HS decreases both male birth AGD and adult testis size, effects which maternal AB consumption mitigates.
... Saturation Binding Assays for Glucocorticoid Receptors. Glucocorticoid receptor binding in calf liver was performed as previously described by Kanitz et al. (2003), with few modifications. Briefly, 1 g of crushed liver tissue powder was homogenized in ice-cold 10 mM Tris-HCl buffer (pH 7.5), containing 12.5 mM EDTA, 10 mM sodium molybdate, 0.25 mM sucrose, and 5 mM dithiothreitol, using a Teflon-glass homogenizer. ...
Neonatal energy metabolism in calves has to adapt to extrauterine life and depends on colostrum feeding. The adrenergic and glucocorticoid systems are involved in postnatal maturation of pathways related to energy metabolism and calves show elevated plasma concentrations of cortisol and catecholamines during perinatal life. We tested the hypothesis that hepatic glucocorticoid receptors (GR) and α1- and β2-adrenergic receptors (AR) in neonatal calves are involved in adaptation of postnatal energy metabolism and that respective binding capacities depend on colostrum feeding. Calves were fed colostrum (CF; n = 7) or a milk-based formula (FF; n = 7) with similar nutrient content up to d 4 of life. Blood samples were taken daily before feeding and 2 h after feeding on d 4 of life to measure metabolites and hormones related to energy metabolism in blood plasma. Liver tissue was obtained 2 h after feeding on d 4 to measure hepatic fat content and binding capacity of AR and GR. Maximal binding capacity and binding affinity were calculated by saturation binding assays using [3H]-prazosin and [3H]-CGP-12177 for determination of α1- and β2-AR and [3H]-dexamethasone for determination of GR in liver. Additional liver samples were taken to measure mRNA abundance of AR and GR, and of key enzymes related to hepatic glucose and lipid metabolism. Plasma concentrations of albumin, triacylglycerides, insulin-like growth factor I, leptin, and thyroid hormones changed until d 4 and all these variables except leptin and thyroid hormones responded to feed intake on d 4. Diet effects were determined for albumin, insulin-like growth factor I, leptin, and thyroid hormones. Binding capacity for GR was greater and for α1-AR tended to be greater in CF than in FF calves. Binding affinities were in the same range for each receptor type. Gene expression of α1-AR (ADRA1) tended to be lower in CF than FF calves. Binding capacity of GR was related to parameters of glucose and lipid metabolism, whereas β2-AR binding capacity was negatively associated with glucose metabolism. In conclusion, our results indicate a dependence of GR and α1-AR on milk feeding immediately after birth and point to an involvement of hepatic GR and AR in postnatal adaptation of glucose and lipid metabolism in calves.
... The effects of stress in growing pigs have aroused great interest due to its deleterious effects on meat quality. Psychosocial stress has been studied in young pigs showing that it affects the endocrine and the immune system [141] and is able to alter the expression of stress-related genes in the brain as well as the pattern of neuroendocrine stress hormones and neurotransmitters [142][143][144]. Several studies address the search for serum biomarkers of stress in pigs due to conditions such as road transport and food administration [89,145]. ...
Traditional biomedical models are easy to manage in experimental facilities and allow fast and affordable basic genetic studies related to human disorders, but in some cases they do not always represent the complexity of their physiology. Translational medicine demands selected models depending on the particularities of the human disease to be investigated, reproducing as closely as possible the evolution, clinical symptoms and molecular pathways, cells or tissues involved in the dysfunction. Thus, pig models offer an alternative because of their anatomical and physiological similarities to humans and the availability of genomic, transcriptomic and, progressively more, proteomic tools for analysis of this species. Furthermore, there is a wide range of natural, selected and transgenic porcine breeds. The present review provides a summary of the applications of the pig as a model for metabolic, cardiovascular, infectious diseases, xenotransplantation and neurological disorders and an overview of the possibilities that the diverse proteomic techniques offer to study these pathologies in depth.This article is protected by copyright. All rights reserved
... The test sensitivity was 8.1 nmol/l, and intra-and inter-assay coefficients of variation (CV) were 8.2% and 9.8%, respectively. GR binding in pig spleens was performed as previously described in detail by Kanitz et al. [22]. Briefly, spleen tissue was homogenized in a buffer solution (10 mM Tris-HCl, 12.5 mM EDTA, 10 mM sodium molybdate, 0.25 mM sucrose, 1 mM dithiothreitol) and centrifuged at 120,000 × g for 60 min at 4°C to obtain cytosol (i.e., the supernatant fraction). ...
There is growing evidence that positive social interactions can attenuate the effects of stressful life experiences. However, little is known about the benefits of social partners on stress responses in farm animals. Therefore, in this study we examined the effects of social support on the endocrine and immune stress responses to a single 4 h social deprivation in domestic piglets at 7, 21 or 35 days of age. The piglets were socially deprived of their mother and littermates. They were left alone (DA) or in the presence of a familiar (DF) or unfamiliar (DU) age-matched piglet. Non-socially deprived piglets served as a control. DA piglets displayed elevated plasma cortisol levels, higher lipopolysaccharide (LPS)-stimulated proliferation of splenocytes and increased TNF-α and IL-6 production in splenocyte cultures than the control piglets. There were no significant buffering effects of social partners on stress-induced plasma cortisol levels and splenocyte proliferation in response to LPS. However, the presence of an age-matched conspecific diminished the IL-6 production by splenocytes in younger, socially deprived piglets, and it reduced the TNF-α release in the older piglets. Compared to the controls, LPS-stimulated splenocytes from DA piglets were more resistant to the inhibitory effects of cortisol, which was demonstrated by a higher proliferative response and increased production of pro-inflammatory cytokines. The dose-dependent cortisol resistance was attenuated by the presence of a familiar or an unfamiliar conspecific at each of the three age categories. Indeed, in the present study, the familiarity level of the social partners did not seem to play a role in the alleviation of social stress-induced inflammatory activity and splenocyte cortisol resistance. In addition, the buffering effect of social support provided by an age-matched conspecific was more pronounced in older piglets. Conclusively, these findings suggest that social support is an important factor for enhancing piglets' abilities to cope with stressful challenges, and it may be a key approach needed to improve the health and welfare of farm animals.
... Like the results from this study, previous studies have not observed an association between social stress and increased mortality (Jarvis et al., 2006;Kranendonk et al., 2008;Couret et al., 2009a,b). In contrast, late gestation restraint stress often results in greater morbidity and mortality (Otten et al., 2000;Otten et al., 2001;Tuchscherer et al., 2002;Kanitz et al., 2003). Paralleling these results maternal social stress has few negative effects on offspring immune function (Couret et al., 2009a,b). ...
In many mammalian species, prenatal stress masculinizes female and feminizes male offspring impairing their reproductive capacity. Regrouping gestating sows is a common, stressful production practice, but its impact on the sow's developing pigs is not fully known. This study examined the effects of regrouping gestating sows and the administration of exogenous glucocorticoids on the growth and external reproductive morphology of pigs. At 37.2 ± 0.26 d of gestation, 6 cohorts of 18 sows (N = 108) were placed in 1 of 3 treatments: socially stable (Stable), hydrocortisone acetate (HCA), or mixed (Mixed). The HCA sows were administered 70 mg HCA, a synthetic glucocorticoid, twice daily during the 21 d experimental period. Each Mixed sow was penned with 2 companion sows (Companion) and regrouped on d 7 and 14 with 2 different Companion sows in a new pen. Stable and HCA sows were penned in treatment groups of 3 sows. Sow social rank was assessed weekly during feeding. After the 21 d experimental period, all sows were housed in gestation stalls for the duration of pregnancy. During the 21 d, Companion sows gained more weight than HCA and Mixed sows (P < 0.05) with Stable sows intermediate. High ranked sows gained more weight than middle and low ranked sows (P < 0.05). Mixed sows had greater head lesion scores than Stable and HCA sows (P < 0.05) with Companion sows intermediate. Head lesions increased with lower social rank (P < 0.001). Sow treatment did not affect farrowing rate, litter size, or sex ratio (P > 0.10). Social rank also had no effect on farrowing rate (P > 0.10), but affected total litter size (P = 0.03). High ranked sows bore and weaned more live females than low ranked sows (P < 0.05), in part due to differential preweaning mortality among female pigs (P = 0.01). Only male pigs were affected by sow treatment. Preweaning mortality was higher among male pigs from HCA than from Mixed sows (P = 0.04) with other treatments intermediate. Despite no weight differences in the preweaning period, at 160 d of age males from HCA sows weighed more than males from Stable sows (P = 0.01) with other treatments intermediate. Males born to Companion sows had longer relative anogenital distances, a marker of fetal testosterone exposure, than males from Mixed sows (P = 0.03) with other treatments intermediate. The prenatal environment affected the pigs in a sex-specific manner altering the growth and reproductive morphology of the males more than that of the females.
... The authors also found a tendency for lower birth weights in prenatally stressed piglets, which is in accordance with results from another study, where significantly reduced birth weights of the offspring were found after oral hydrocortisone-acetate administrations during pregnancy (Kranendonk et al., 2006). In a previous study of our group we could show that a daily 5-min restraint stress of sows during the last trimester of gestation caused a decrease of basal plasma cortisol levels and glucocorticoid receptors in the hypothalamus, but an increase of glucocorticoid receptors in the hippocampus of the piglets after birth (Otten et al., 2001; Kanitz et al., 2003). This form of maternal stress had no significant effects on birth weights, but reduced the immunoglobulin G (IgG) concentrations in serum of newborn piglets and had a suppressive effect on lymphocyte proliferation after mitogen stimulation in vitro. ...
This study investigated whether repeated administrations of adrenocorticotropic hormone (ACTH) during mid or late gestation, a treatment which induces endogenous cortisol release, affect growth performance, early vitality, open-field behaviour and immune responses of neonatal pigs. Administrations of ACTH (100 IU per animal, Synacthen-« Depot) were given intramuscularly to gilts every second day either during mid (Day 49 until 75, Experiment 1) or late gestation (Day 85 until 107, Experiment 2). Control gilts received repeated injections of saline. The repeated ACTH stimulation of gilts during late gestation significantly reduced their daily weight gain during this period, but not when applied during mid gestation. Gestation length, number of born piglets and vitality measures of the newborn piglets, such as the rectal temperatures after birth and times elapsed between birth and first udder contact or milk uptake were not affected by the prenatal treatments. Administration of ACTH during late but not during mid gestation significantly increased the birth weights of piglets, and this difference in postnatal body weight was detectable until an age of 21-ádays. In addition, only the stimulation with ACTH during late gestation had an immunosuppressive effect on the lymphocyte proliferation of piglets 1-áday after birth in response to the T-cell mitogen ConA and, in tendency, on the proliferation in response to the B-cell mitogen LPS. Twenty-four day old piglets from gilts treated during late gestation showed significantly more escape behaviour in an open-field than piglets from control litters. In conclusion, elevated maternal glucocorticoid levels during critical periods of prenatal development in pigs may affect prenatal growth, cell-mediated immunity and emotional reactivity in the neonatal piglets. The occurrence of these effects depends on the timing of increased maternal cortisol levels during gestation
... 29 In another porcine model based on maternal restraint stress, Kanitz et al. were able to show that the prenatally stressed piglets had raised CBG levels on the third postnatal day. 30 However, subsequent studies by the same group found that piglets exposed to maternal hypercortisolaemia had lower CBG levels on postnatal day 1, but higher levels in male offspring on day 28 as compared with the untreated controls. 31 Yet, another porcine model based on rough handling or ACTH administration between days 42 and 77 of gestation produced no change in CBG concentrations in the offspring. ...
Objective
Prenatal programming of the hypothalamic-pituitary-adrenal (HPA) axis may link reduced foetal growth with higher adult chronic disease risk. South Asians have a high prevalence of low birth weight and a thin-fat phenotype, which is associated with subsequent type 2 diabetes and the metabolic syndrome. Altered HPA activity could be one of the pathological processes underlying this link. Methods
Plasma morning cortisol and corticosteroid-binding globulin (CBG) concentrations were determined in 528 children aged 95years from a prospective birth cohort in India. They had detailed anthropometry at birth, and current measurements of anthropometry, plasma glucose, insulin and lipid concentrations and blood pressure. Insulin resistance (Homeostasis Model Assessment) and insulin secretion (the 30-min insulin increment) were also assessed. ResultsNone of the birth measurements were associated with cortisol concentrations, but both birth weight (P=003) and length (P=0004) were inversely associated with CBG concentrations. Cortisol concentrations were inversely associated with current body mass index (P=002), and positively associated with glucose (fasting: P<0001; 30-min: P=0002) concentrations, and systolic blood pressure (P=0005), but not insulin resistance or the insulin increment. Conclusion
Higher morning cortisol is associated with higher cardiometabolic risk markers in Indian children. Although cortisol concentrations did not appear to be related to birth size, small size at birth was associated with higher CBG levels, and may be one of the processes by which foetal undernutrition affects adult health. The findings suggest a need for dynamic testing of HPA axis activity (such as measuring stress responses).
... Across species, including laboratory animals, nonhuman primates, and humans, reduced birth weight is a major outcome of disturbances during gestation [3] that may be associated with altered activity of the neuroendocrine system [4] and modified immune function in offspring [5]. Also in domestic pigs, prenatally stressed offspring displayed altered hypothalamic-pituitary-adrenal (HPA) axis regulation [6,7], suppressed humoral and cellular immune responses [8,9], increased cortisol levels after social mixing [10,11] and stronger fever and cytokine responses to an inflammatory stimulus [12,13]. Inadequate maternal dietary protein and/or carbohydrate levels during pregnancy in pigs have been shown to retard intrauterine growth resulting in low body weight at birth, and to affect body composition and properties of skeletal muscle and adipose tissue of the offspring [14][15][16]. ...
Background
Inadequate nutrition in utero may retard foetal growth and alter physiological development of offspring. This study investigated the effects of low and high protein diets fed to primiparous German Landrace sows throughout pregnancy on the immune function of their offspring at different ages. Sows were fed diets with adequate (AP, 12.1%; n = 13), low (LP, 6.5%; n = 15), or high (HP, 30%; n = 14) protein content, made isoenergetic by varying carbohydrate levels. Cortisol, total protein and immunoglobulin (IgG, IgM, IgA) concentrations were measured in the blood of sows over the course of pregnancy. Cortisol, total protein, immunoglobulins, lymphocyte proliferation, immune cell counts, and cytokines were assessed in the blood of offspring at baseline and under challenging conditions (weaning; lipopolysaccharide (LPS) administration).
Results
In sows, the LP diet increased cortisol (P < 0.05) and decreased protein levels (P < 0.01) at the end of pregnancy. Immunoglobulin concentrations were decreased in LP (IgA) and HP piglets (IgG, IgM and IgA) on the first day of life (P < 0.05), whereas the number of lymphocytes and mitogen-induced lymphocyte proliferation of the piglets were unaffected by the maternal diet. Mortality during the suckling period was higher in LP piglets compared with AP and HP offspring (P < 0.01). Furthermore, LP piglets showed an elevated cortisol response to weaning, and in HP piglets, the CD4+ cell percentage and the CD4+/CD8+ ratio increased after weaning (P < 0.05). The lipopolysaccharide-induced rise of IL-6 was higher in LP (P = 0.09) and HP (P < 0.01) compared with AP piglets, and LP piglets displayed higher IL-10 levels than AP piglets (P < 0.05).
Conclusions
Our results indicate that both low and high protein:carbohydrate ratios in the diet of pregnant sows can induce short-term as well as long-lasting effects on immune competence in piglets that may have serious consequences for host defence against bacterial pathogens.
... It has been shown that prenatal glucocorticoid exposure resulted in significant alterations in glucocorticoid receptor mRNA levels in the HPA axis, thus linking glucocorticoid exposure with alterations in negative feedback control of the axis (Levitt et al. 1996). Altered expression of central GR and mineralo corticoid receptors (MR) systems leading to decreased negative feedback at the paraventricular nucleus (PVN) and enhanced facilitation of the HPA response has also been reported after prenatal stress in rats and piglets (Henry et al. 1994, Maccari et al. 1995, Barbazanges et al. 1996, Kanitz et al. 2003. In the present study, given the higher cortisol concentrations detected after feeding restoration in association with data that placental 11bHSD2 activity is reduced at the day 50 of gestation after periconceptional undernutrition (Jaquiery et al. 2006), it is tempting to speculate that the enhanced HPA axis function seen at 2 months post partum was due to increased exposure to excess cortisol in utero. ...
Epidemiological and experimental data support the hypothesis of 'fetal programming', which proposes that alterations in fetal nutrition and endocrine status lead to permanent adaptations in fetal homeostatic mechanisms, producing long-term changes in physiology and determine susceptibility to later disease. Altered hypothalamic-pituitary-adrenal (HPA) axis function has been proposed to play an important role in programming of disease risk. The aim of the present study was to examine the effects of maternal nutrient restriction imposed during different periods of gestation on the HPA axis function in sheep, at different ages postnatal. Pregnant ewes were fed a 50% nutrient-restricted diet from days 0-30 (group R1, n = 7), or from days 31-100 of gestation (group R2, n = 7) or a control 100% diet throughout pregnancy, (Control, n = 8). Blood samples were collected at 10-day intervals from day 40 of gestation to term. Lambs were born naturally and fed to appetite throughout the study period. At 2, 5.5, and 10 months of age lambs were given an i.v. injection of corticotrophin-releasing hormone (CRH) and blood samples were collected at -15, 0, 15, 30, 60, 120, and 180 min postinjection. Maternal cortisol levels were significantly higher (P < 0.05) in group R1 compared with the other two groups, whereas maternal insulin levels were lower (P < 0.05) in group R2 compared with control. Birth weight of lambs was not affected by the maternal nutritional manipulation. The area under the curve for ACTH and cortisol response to CRH challenge was greater (P < 0.05) in lambs of group R1 at two months of age, whereas no difference was detected at the ages of 5.5 and 10 months. However, significantly higher (P < 0.01) basal cortisol levels were observed in lambs of R1 group at 5.5 months of age. There was no interaction between treatment and sex for both pituitary and adrenal responses to the challenge. A significant sex effect was evident with females responding with higher ACTH and cortisol levels at the age of 5.5 months (P < 0.01, P < 0.001 respectively) and with higher cortisol levels (P < 0.01) at 10 months of age than males. It is concluded that the HPA axis is programmable by altered nutrition in utero. The sensitivity of the axis to exogenous stimulation is enhanced during early postnatal life and attenuated with age, suggesting a role for the postnatal influences in resetting of the HPA axis and emphasizing the importance of identifying the impact of maternal undernutrition at several time points after birth.
... Juvenile and adult rats born to PS mothers exhibit reduced hippocampal GR and MR expression which is associated with a marked increase in stress-level plasma corticosterone and a longer duration in corticosterone response (Henry et al. 1994;Maccari et al. 1995;Barbazanges et al. 1996;Koehl et al. 1997). Piglets whose mothers were subjected to PS (daily restraint, last 5 weeks of gestation) exhibit reduced hypothalamic GR binding sites but increased hippocampal GR sites with no effect on the hippocampal MR possibly indicating decreased negative feedback at the PVN and enhanced facilitation of the HPA response (Kanitz et al. 2003). Some studies also indicate the possibility that programming of GR and MR, like the HPA axis, is sex-specific with the effect of prenatal glucocorticoids being greater in female offspring. ...
Prenatal stress (PS) and maternal exposure to exogenous glucocorticoids can lead to permanent modification of hypothalamo-pituitary-adrenal (HPA) function and stress-related behaviour. Both of these manipulations lead to increased fetal exposure to glucocorticoids. Glucocorticoids are essential for many aspects of normal brain development, but exposure of the fetal brain to an excess of glucocorticoids can have life-long effects on neuroendocrine function. Both endogenous glucocorticoid and synthetic glucocorticoid exposure have a number of rapid effects in the fetal brain, including modification of neurotransmitter systems and transcriptional machinery. Such fetal exposure permanently alters HPA function in prepubertal, postpubertal and ageing offspring, in a sex-dependent manner. Prenatal stress and exogenous glucocorticoid manipulation also lead to the modification of behaviour, brain and organ morphology, as well as altered regulation of other endocrine systems. It is also becoming increasingly apparent that the timing of exposure to PS or synthetic glucocorticoids has tremendous effects on the nature of the phenotypic outcome. Permanent changes in endocrine function will ultimately impact on health in both human and animal populations.
... However studies in both humans and animals have demonstrated that this type of treatment can have long term effect on other aspects of the offspring. Treating mothers with synthetic glucocorticoids during gestation has been shown to reduce the offspring's birth weight (reviewed by Sloboda et al., 2005) cause permanent hypertension (reviewed by Nuyt, 2008), hyperglycaemia and hyperinsulinemia (reviewed by O' Regan et al., 2001), increased HPA-axis activity ( Kapoor et al., 2008;Tegethoff et al., 2009), and anxiety-like behaviour in adult offspring ( Kanitz et al., 2003;Chung et al., 2005;Drake et al., 2005Drake et al., , 2007Sloboda et al., 2005;Jarvis et al., 2006), with the effects being most prominent when the synthetic glucocorticoid treatment is applied in the last third of gestation ( Welberg et al., 2001). Unlike corticosterone and cortisol, synthetic glucocorticoids, like dexamethasone and betamethasone, can readily cross the placental barrier and reach the foetus without being inactivated by the enzyme 11-Hydroxysteroid Dehydrogenase (11-HSD; Seckl, 1997). ...
... Comparatively, Roussel et al. (2005) found no effect of transport stress in the last third of pregnancy on basal cortisol concentration of goat kids, but they did find an increased enzyme activity in one of the medullo-adrenals. Nevertheless, in accordance with our results, Kanitz et al. (2003) and Otten et al. (2001) found that piglets born to sows stressed by restraint during the last third of pregnancy, had a lower basal cortisol concentration than controls. Furthermore, Duvaux-Ponter et al. (2003) also documented a lower basal cortisol concentration in prenatally stressed goat kids at 2 days of age. ...
The aim of the present study was to study the effects of social instability (regrouping) during the second trimester (7 weeks) of pregnancy on aggression, cortisol concentrations and growth in goats and its consequences for survival, growth and some aspects of behavioural development in the kids. Six weeks after mating, 32 goats were distributed into eight groups. In four of the groups, randomly chosen pairs of goats were rotated between groups every Monday morning (around 08:30h) for 7 weeks (unstable groups), starting 6 weeks into gestation (second trimester). The remaining four groups were kept stable throughout the entire pregnancy (stable groups). The adult goats were video recorded for 6h twice a week for the first, second, fourth and seventh regrouping and for the 2 last weeks before expected birth. Blood samples of the adult goats were collected in a period from 1 week before the start of the first regrouping and until 1 week before expected birth. Blood samples from a maximum of two kids from each litter were collected at 3 weeks of age. Two kids from each litter were subjected to two types of behavioural tests: a 'social test' at the age of 1 and 7 weeks and a 'novel object test' at the age of 5 weeks. Except for the higher aggression level in the unstable groups, social instability did not have any other significant effects on factors such as growth, cortisol level or kid production in the goats. There were only minor effects on the behavioural development in the goat kids. However, kids from the unstable groups showed more escape attempts in the first trial of a 'social test', spent more time in contact with a novel object and unfamiliar kids, and showed less fear (escape attempts) after they were given one exposure to the social test situation. Furthermore, kids from unstable groups had a lower basal cortisol level than kids from stable groups.
... Glucocorticosteroid receptor binding in pig brain was performed as previously described in detail by Kanitz et al. [37,38]. Briefly, tissues of the hypothalamus and right hippocampus were homogenized in a buffer solution (10 mM Tris-HCL, 12.5 mM EDTA, 10 mM sodium molybdate, 0.25 mM sucrose, 1 mM dithiothreitol) and centrifuged at 4 • C at 120,000 × g for 60 min to obtain cytosol (ie, the supernatant fraction). ...
Maternal stress in pregnant sows may induce long-lasting alterations in the behavior, physiology, and immunity of their offspring. The aim of the present study was to investigate the consequences of repeated social stress during late gestation on determinants of the hypothalamic-pituitary-adrenal axis and on hippocampal neurotransmitter profiles in pig offspring. All pregnant gilts were housed in pairs. Each Stress gilt was mixed with an unfamiliar gilt twice a week between days 77 and 105 of gestation (n=18). Control gilts were housed in stable pairs over the same period (n=18). Plasma cortisol and corticosteroid binding globulin (CBG) were measured in 1 male and 1 female per litter in a basal situation on postnatal days (PND) 4, 26, and 60 and in a stressful situation at PND 28 (2 d after weaning) and 62 (2 d after relocation to a new building). Prenatal stress had no effect on plasma cortisol, but it decreased CBG at PND 26. Brain and adrenals were collected from 1 female per litter after weaning or relocation at PND 28 and PND 62. Adrenals were additionally collected at PND 4. Glucocorticoid receptor binding in the hippocampus and hypothalamus was not affected by prenatal treatment. However, prenatal stress increased the expression of 11beta-hydroxysteroid dehydrogenase type 1 mRNA in the hippocampus after weaning (P<0.05) and after relocation (P=0.08). In addition, prenatally stressed piglets showed an increased 5-hydroxyindole-3-acetic acid to 5-hydroxytryptamine ratio in the hippocampus after weaning and increased hippocampal c-fos mRNA expression and noradrenaline concentration after relocation (P<0.05). Prenatal stress also increased the relative adrenal weight at PND 4 and the cell density in the cortex and the medulla at PND 28, whereas no difference was found for activities of catecholamine-synthesising enzymes in the medulla. Overall, our data indicate that repeated social stress during pregnancy has long-lasting consequences on hypothalamic-pituitary-adrenal axis and hippocampal neurotransmitter activity in the offspring of pigs.
... High concentrations of cortisol present in follicles have also been shown to have a negative effect on fertilisation in vitro (Jimena et al., 1992), but fertilisation rate in the present studies did not differ between the two groups. During pregnancy, high concentrations of maternal cortisol might affect the embryo directly since the maternal concentrations are reflected in the embryo (Klemcke, McGuire & Christenson, 1999), the survival of the offspring (Kanitz et al., 2003) and also in the stress-axis of the offspring later in life (Haussmann et al., 2000). However, in the present study only the early embryos were examined, and no differences could be found between the embryos from the C group and those from the ACTH group. ...
Regrouping of weaned sows gives rise to stressful situations during the critical time when the sows must resume oestrous activity after lactation. The aim of these studies was to simulate the social stress seen after regrouping through repeated injections of synthetic ACTH during oestrus in the sow. The period of treatment lasted for about 48 h from the onset of standing oestrus. The following reproductive events were studied and compared between the ACTH-treated sows (ACTH group) and the control sows (C group): duration of standing oestrus, time of ovulation, hormonal patterns, the number of spermatozoa and their morphology as well as the intraluminal environment of the uterine tubal junction (UTJ) and of isthmus shortly after ovulation, oocyte/embryo transport in the oviduct, and embryo development at 48 or 60 h after ovulation.
The sows in the ACTH group stopped displaying signs of standing oestrus sooner after ovulation than the C group, but no effect was found on the time of ovulation. Cortisol and progesterone concentrations were elevated significantly in jugular blood samples taken after the ACTH injections. There were minor differences in oestradiol and LH concentrations between the groups. Overall, inhibin α concentrations were significantly higher during the treatment period in the ACTH group than in the C group.
There was a tendency towards a larger number of spermatozoa in the UTJ and oviduct among the sows in the ACTH group. A majority of sows in the ACTH group had moderately to exaggerated amounts of mucus in the intraluminal environment of the sperm reservoir.
The ACTH injections had no effect on embryo development. However, fewer oocytes/embryos were retrieved from the ACTH group than from the C group and there was a tendency towards faster embryo transportation to the uterus.
In conclusion, simulated stress caused significant loss of oocytes and embryos, shortened the duration of standing oestrus and changed the hormonal pattern of progesterone, and possibly of inhibin α, oestradiol and LH. There were also tendencies towards an altered intraluminal environment in the oviduct and UTJ and augmented transportation of spermatozoa and embryos through the female genital tract in the ACTH-treated sows.
... Use of the excess of DEX is very often studied for establishing the role of GCs in perinatal programming of physiological processes and behaviour of animals and humans as well (Holemans et al., 1998;Orzechowski et al., 2000;Newnham and Moss, 2001;Kanitz et al., 2003;Seaman-Bridges et al., 2003;Ś liwa et al., 2004, 2005c. Among animal species, pigs show many similarities with humans, especially in the trabecular architecture (Smink et al., 2003;Rocha and Plastow, 2006). ...
In mammals, the release from growth-inhibiting conditions results in catch-up growth. To investigate animal evidence for whether prenatal dexamethasone (DEX) treatment leads to the development of growth restriction especially reduced mineralization of skeleton, and release from it leads to the phenomenon of catch-up, piglets were prenatally exposed to DEX (3.0 mg/sow per day(-2)) during the last 24 days of prenatal life and tested further in two different ways: discontinued at birth and continued administration of DEX (0.5 mg/kg day(-2)) to piglets through 30 days of neonatal life. Using dual energy X-ray absorptiometry methods, bone mineral density (BMD) and bone mineral content (BMC) were measured. The three-point bending test was applied to determine the mechanical properties of the bones. Furthermore, geometric properties of the bones were assessed. Serum concentration of osteocalcin (OC) was determined. Histomorphological analysis of the ribs was also performed. The consequences of neonate DEX treatment and in utero DEX exposure were reflected in a dramatic decrease of BMD, BMC and blood serum OC concentration and geometric parameters of piglets' bones. Prenatal action of DEX during the last 24 days of pregnancy resulted in continued neonatal modification of bone tissues, thus diminishing bone quality, and negatively influenced structural development and mechanical properties, finally increasing the risk of fractures of ribs and limb bones. Prenatal DEX treatment limited to the last 24 days of foetal life did not reduce the term birth weight and the growth of suckling piglets followed up to 30 days of neonatal life, and catch-up in bone mineralization did not occur.
The prenatal environment influences offspring health and development, and this is readily apparent when considering the well-described effects of maternal nutrition and stress on the postnatal metabolism, neural function, and stress response of progeny. Moreover, in laboratory species, sheep, and humans, the effects of in utero heat stress on offspring development have been described in detail for >50 years. Despite our extensive knowledge of the postnatal phenotypes elicited by in utero stressors, the carryover effects of in utero heat stress in pigs have only recently begun to be elucidated. The effects of climate change on increasing global temperatures, combined with greater metabolic heat production in modern swine, has increased heat stress susceptibility in pigs. Greater heat stress susceptibility can negatively affect swine welfare and performance and may impact future generations of pigs through in utero heat stress. Pigs exposed to in utero heat stress develop a variety of postnatal phenotypes that prevent profitable production, and compromise health, and welfare in commercial production systems. Specifically, in utero heat stress alters the postnatal stress response, core body temperature, response to an immune challenge, and is teratogenic. In addition, in utero heat stress changes postnatal body composition through reduced lean and increased adipose tissue accretion rates, respectively. Furthermore, in utero heat stress reduces piglet birth weight, body weight gain, and reproductive efficiency. Although the economic impact of in utero heat stress in pigs has yet to be determined, it likely rivals the postnatal consequences of heat stress and is a threat to the global sustainability of swine production.
CAPITOLUL 8. FERTILITATEA sau o ultimă realitate, cu termeni aflaţi sub impactul tehnologiilor.
În lumea „metro” a secolului XXI, nu există limite; practic, fertilitatea poate fi aproape nelimitată...aspectul care decurge de aici este însă acela că întotdeauna ceea ce se câştigă la un caracter poate aduce cu sine pierderea valorii altor caractere; în atare condiţii, tehnologul este pus în situaţia de a gândi ...ce se pierde atunci când ceva se câştigă? În reproducerea intensivă, nu interesează în mod deosebit maximizarea prolificităţii, limitarea la minim a pierderilor prin mortalitate sau intensificarea numărului de parturiţii în unitatea de timp: lucrul care interesează cu adevărat este maximizarea rezultatului interacţiunii dintre aceste trei aspecte, interacţiune exprimată în numărul de purcei înţărcaţi de către fiecare scroafă în fiecare an de activitate reproductivă. Obiectivul capitolului este acela de a prezenta prolificitatea, numărul de fătări dintr-un an şi pierderile de purcei sugari ca termeni ai fertilităţii şi posibilităţile tehnologice de îmbunătăţire, influenţă şi control a valorii acestor termeni. Numărul de purcei înţărcaţi/scroafă şi an sau fertilitatea sunt, în studiul de faţă, o ultimă realitate, sau mărimea de ieşire, care exprimă performanţele reproductive ale unei ferme sau sistem reproductiv.
This chapter reviews the literature on the development of event memory and the brain system that underlies it. It describes what is known about the explicit memory system and its development, as well as areas in which more could be understood about the development of the system. It reviews the literature on effects of stress on the development of the explicit memory system, and proposes ways in which timing and plasticity could play a role in long-term effects of stress on the brain basis of memory.
Stress that occurs during pregnancy can have consequences on the behaviour of offspring such as increased emotional reactivity, impaired learning ability and feminisation of male sexual behaviour. A modification of the hypothalamo-pituitary axis is often observed, for example, an increase in basal glucocorticoid concentrations and a higher secretion rate after a stressful event. Immune responses can also be modified, and birth-weight reduced. However, there is a high level of variability in the effects of prenatal stress. This may be due to the type of stressor, its intensity and period of application during pregnancy. The effect may also differ according to the gender of the offspring, with females appearing to be more affected than males. Stress experienced by a dam during pregnancy could have consequences on neuroendocrine development in the foetus. Maternal hormones secreted during stress, which can cross the placental barrier, could be one of the mechanisms explaining these effects. Modification of maternal behaviour due to chronic stress may also be involved in the effect on the behaviour of the offspring. Most studies have been performed on rodents and primates but the few experiments involving farm animals tend to show that the consequences can be important.
Stress that occurs during pregnancy can have consequences on the behaviour of offspring such as increased emotional reactivity, impaired learning ability and feminisation of male sexual behaviour. A modification of the hypothalamo-pituitary axis is often observed, for example, an increase in basal glucocorticoid concentrations and a higher secretion rate after a stressful event. Immune responses can also be modified, and birth-weight reduced. However, there is a high level of variability in the effects of prenatal stress. This may be due to the type of stressor, its intensity and period of application during pregnancy. The effect may also differ according to the gender of the offspring, with females appearing to be more affected than males. Stress experienced by a dam during pregnancy could have consequences on neuroendocrine development in the foetus. Maternal hormones secreted during stress, which can cross the placental barrier, could be one of the mechanisms explaining these effects. Modification of maternal behaviour due to chronic stress may also be involved in the effect on the behaviour of the offspring. Most studies have been performed on rodents and primates but the few experiments involving farm animals tend to show that the consequences can be important.
In farm animals, restricted housing conditions or inadequate management practices during gestation may be potential stressors for the mother, with possible consequences on the growth, vitality, health and welfare of the dam and its offspring, and thus can have economic as well as ethical implications. The current review summarizes data from studies in pigs on the impact of maternal stress during gestation on the litter characteristics and phenotypic traits of offspring. The outcomes from the different experimental models using either maternal stress paradigms or artificially increased maternal cortisol are presented, and possible reasons for the consistent or divergent results are discussed. Maternal stress models are of particular importance, because social stress, restraint, rough handling and heat or cold stress are of practical relevance during housing of pregnant sows, whereas in other models the specific role of maternal cortisol as a mediator for pre-natal stress is studied. The data reveal that pre-natal stress in pigs can impair growth and modify the immune function, stress reactivity and behaviour of offspring. There is evidence that the materno-foetal cortisol regulation is a major determinant of the alterations in offspring. Neuroendocrine and behavioural data in the offspring indicate that pre-natally stressed pigs can express a modified phenotype characterized by increased reactivity of the hypothalamic–pituitary–adrenal axis, altered emotionality, more fearfulness in a novel environment and disturbed social and maternal behaviour. Further research is needed and should focus on the long-term consequences on immune function, reproductive traits and maternal behaviour in female offspring used as breeding animals.
Catecholamines and glucocorticoids are involved in fetal maturation of organ systems to prepare the fetus for extrauterine life. Calves, especially when born preterm, depend on function of the adrenergic system and the glucocorticoid axis to adapt energy metabolism for the neonatal period. We tested the hypothesis that hepatic glucocorticoid and α1- and β2-adrenergic receptors in neonatal calves are involved in adaptation of energy metabolism around birth and that respective binding capacities depend on stage of maturation during the neonatal period. Calves (n = 7 per group) were delivered by section preterm (PT, 9 d before term) or were born at term (full-term, FT; spontaneous vaginal delivery), or spontaneously born and fed colostrum for 4 d (FTC). Blood samples were taken immediately after birth and before and 2 h after feeding at 24 h after birth (PT, FT) or on d 4 of life (FTC) to determine metabolic and endocrine changes. After slaughter at 26 h after birth (PT, FT) or on d 4 of life (FTC), liver tissue was obtained to measure hepatic binding capacity of glucocorticoid and α1- and β2-adrenergic receptors. Maximal binding capacity and binding affinity were calculated by saturation binding assays using [(3)H]-prazosin and [(3)H]-CGP-12177 for determination of α1- and β2-adrenergic receptors, respectively, and [(3)H]-dexamethasone for determination of glucocorticoid receptor in liver. Additional liver samples were taken to measure mRNA abundance of glucocorticoid and α1- and β2-adrenergic receptors, of key enzymes and factors related to hepatic lipid metabolism, and of insulin-like growth factor 1 (IGF1). Plasma concentrations of β-hydroxybutyrate and leptin changed with time, and leptin concentrations were affected by stage of maturation. The binding capacities for hepatic glucocorticoid and β2-adrenergic receptors as well as gene expression of IGF1 were greater in FTC than in FT and PT, and binding affinity for β2-adrenergic receptor was lowest in PT. The binding capacity of hepatic α1-adrenergic receptor was greatest in FTC and greater in FT than in PT. The binding capacities of glucocorticoid and α1-adrenergic receptors were mainly related to variables of glucose and lipid metabolism. In conclusion, our results indicate dependence of hepatic glucocorticoid and adrenergic receptors on stage of maturation in neonatal calves and emphasize the association of α1-adrenergic receptor and glucocorticoid receptor with neonatal glucose and lipid metabolism.
Copyright © 2014 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.
Fifty-two sows were subjected to a human approach test (HAT) at 2 weeks, and again at 3–4 days, before expected farrowing. Latency to contact and time spent exploring the experimenter, and overall confidence score (1=low to 6=high) were recorded. Fifty percentage of the sows received positive handling for 1min twice daily, 5 days a week from first HAT to farrowing, whilst the others were controls without additional handling. Behaviour was video-recorded from 2 days before until 4 days after farrowing.In the first HAT, 37% of sows immediately made contact with the experimenter (score 6), whereas 20% withdrew (scores 1 and 2). To give the sows a positive association to the handler, feed rewards were given. The sows accepted a feed nut from the hand significantly sooner than petting (P=0.05). After 2 weeks of handling, the confidence score had increased significantly (P
The present study was performed to examine the effects of a repeated noise exposure (4 weeks) on basal and noise-induced plasma adrenocorticotrophin (ACTH), cortisol and corticosteroid binding globulin (CBG) levels, brain glucocorticoid receptors (GR) and corticotropin-releasing hormone (CRH) concentrations as well as on the morphology of adrenal glands in German Landrace pigs. Chronically cannulated pigs were exposed to either a daily stimulation with broad-band noise (2 h, 90 dB) (N1), or to the same stimulus three times a week (N2), or to an equal handling procedure without noise stimulation. Noise exposure caused an increase of basal CBG concentrations in N1 animals in the first week. During noise session, an increase of plasma ACTH and cortisol levels in N1 animals was measured in week 1 followed by a subsequent decrease until week 4. The ACTH and cortisol response of the N2 animals increased after week 1 and was significantly elevated in week 4. Furthermore, noise stress caused an increased hippocampal GR binding of N2 pigs, but had no effects on GR binding in the amygdala and on hypothalamic CRH levels. There were also significant structural modifications in the adrenal gland of N1 pigs resulting in differentiated effects on the adrenal cortex and medulla. The present results show that repeated noise exposure of pigs causes considerable alterations at different levels of the HPA system in association with the frequency of noise stimulation. This may have substantial impact on the general vulnerability of the animal with respect to productivity, health and welfare.
Using suction light traps biting midges of the genus Culicoides
Latreille (Diptera: Ceratopogonidae) were collected between 2004 and 2006 on nine
cattle and/or sheep farms distributed throughout the length of the island of Sardinia
(Italy). A total of 42,664 adult midges (36,655 females, 6,009 males) were collected
during 287 trapping nights; 41 species of Culicoides were identified, of which 16 are
new records for Sardinia. Eight of these, i.e., Culicoides derisor Callot and Kremer,
Culicoides duddingstoni Kettle and Lawson, Culicoides kingi Austen, Culicoides para-
disionensis Boorman, Culicoides santonicus Callot, Kremer, Rault and Bach, Culicoides
subfagineus Dele ´colle and Ortega, Culicoides submaritimus Dzhafarov, and Culicoides
truncorum Edwards, are also new to the biting midge fauna of Italy. The six most-abundant
species captured wereCulicoides newsteadiAusten (21.7%),Culicoides univitattusVimmer
(12.6%), Culicoides circumscriptus Kieffer (12.5%), Culicoides paolae Boorman (12.0%),
Culicoides obsoletus (Meigen), Culicoides scoticus Downes and Kettle (10.6%) and Culi-
coides imicola Kieffer (10.1%); the last-mentioned species is the principal vector for
bluetongue virus (BTV) affecting sheep in theMediterranean basin. Bar charts depicting the
seasonality at three collecting sites of six proven or potential vectors for BTV, and belonging
mostly to the obsoletus and pulicaris species complexes, are presented and discussed. Fi-
nally, an updated checklist is provided for the 45 species of Culicoides now known to occur
on Sardinia and includes corrections on misidentifications made in an earlier checklist.
In the framework of a bluetongue surveillance program including clinical, serological, and entomological activities, Culicoides biting midges were light trapped weekly in two regions of central Italy, Lazio and Tuscany. In the period January 2002 through December 2005, 3,944 collections were carried out in 189 trap sites distributed in all the provinces of the two regions. Abundance data of C. obsoletus group were analyzed in relation to trap site altitude, distance from the sea, land use, and number of farmed animals. Species seasonality and overall temporal trend were also described. C. obsoletus was distributed over the whole study area, almost in all trapping sites and with high abundances. The species group was dominant among all captured Culicoides, with higher abundances recorded inland and in areas where land cover was partially or completely natural-wooded. Adults on the wing were caught all year round, with peaks in May-June and middle October. The observed trend through years recorded a peak during autumn 2002, in concomitance with a local epidemic of bluetongue.
Culicoides imicola is the main vector for bluetongue (BT) and African horse sickness (AHS) viruses in the Mediterranean basin and in southern Europe. In this study, we analysed partial mitochondrial cytochrome c oxidase subunit I (COI) gene to characterize and confirm population expansion of Culicoides imicola across Spain. The data were analysed at two hierarchical levels to test the relationship between C. imicola haplotypes in Spain (n = 215 from 58 different locations) and worldwide (n = 277). We found nineteen different haplotypes within the Spanish population, including 11 new haplotypes. No matrilineal subdivision was found within the Spanish population, while western and eastern Mediterranean C. imicola populations were very structured. These findings were further supported by median networks and mismatch haplotype distributions. Median networks demonstrated that the haplotypes we observed in the western Mediterranean region were closely related with one another, creating a clear star-like phylogeny separated only by a single mutation from eastern haplotypes. The two, genetically distinct, sources of C. imicola in the Mediterranean basin, thus, were confirmed. This type of star-like population structure centred around the most frequent haplotype is best explained by rapid expansion. Furthermore, the proposed northern expansion was also supported by the statistically negative Tajima's D and Fu's Fs values, as well as predicted mismatch distributions of sudden and spatially expanding populations. Our results thus indicated that C. imicola population expansion was a rapid and recent phenomenon.
Fetal exposure to elevated levels of bioactive glucocorticoids early in gestation, as in suspected cases of congenital adrenal hyperplasia, may result in adverse neurological events. Fetal hypothalamic-pituitary-adrenal development and function may be involved. We investigated immediate and long-term effects of maternal dexamethasone (DEX) administration early in pregnancy on fetal growth and pituitary-adrenal activity in sheep. Pregnant ewes carrying singleton fetuses (total n = 119) were randomized to control (2 ml saline/ewe) or DEX-treated groups (im injections of 0.14 mg/kg ewe weight . 12 h) at 40-41 d gestation (dG). At 50, 100, 125, and 140 dG, fetal plasma and tissues were collected. DEX-exposed fetuses were lighter than controls at 100 dG (P < 0.05) but not at any other times. Fetal plasma ACTH levels and pituitary POMC and PC-1 mRNA levels were similar between groups. Fetal plasma cortisol levels were significantly reduced after DEX exposure in both male and female fetuses at 50 dG (P < 0.05), were similar at 100 and 125 dG, but were significantly higher than controls at 140 dG. At 140 dG, there was increased adrenal P450C(17) and 3beta-HSD mRNA in female fetuses and reduced expression of ACTH-R mRNA in males. Fetal hepatic CBG mRNA levels mimicked plasma cortisol patterns. DEX exposure reduced CBG only in males at 50 dG (P < 0.05). Placental mRNA levels of 11beta-HSD2 were increased after DEX in males (P < 0.05). Therefore, in sheep, early DEX may alter the developmental trajectory of the fetal hypothalamic-pituitary-adrenal axis, directly increasing fetal adrenal activation but not anterior pituitary function. In females, this effect may be attributed, in part, to increased fetal adrenal steroidogenic activity.
Some housing conditions and practices in livestock husbandry may be stressful for the animals and may impair their welfare.This is of particular relevance for pregnant dams, because it is known from rodents and primates that prenatal stress (i. e. stress experienced by the mother with impact on the fetal ontogeny) may have long-lasting effects on growth, health and behaviour of the offspring. This review gives a survey of current research on prenatal stress and its consequences in farm animals. In comparison to the well-studied rodent model there are differences in placental structure and prenatal ontogeny. However, the research reveals that also in farm animals prenatal stress can lead to an impairment of growth, immune function, behaviour and stress reactivity in the offspring. Maternal glucocorticoids are discussed as potential mediators and it has been demonstrated that the effects on the offspring depend on the nature of the stressor as well as on its time and duration during gestation. Because prenatal stress in farm animals may be a source of economic and welfare problems by reason of reduced vitality and well-being of the offspring, suggestions for future work in this field of research are made.
There is growing evidence that stressors occurring during pregnancy can impair biological and behavioral adaptation to stress in the adult offspring. Mechanisms by which stress in the pregnant rat can influence development of the offspring are still unknown. In the present study, we investigated the involvement of maternal corticosterone secretion during pregnancy on the hypothalamo-pituitary-adrenal axis activity of adult offspring. We investigated stress-induced corticosterone secretion and hippocampal type I and type II corticosteroid receptors in male adult rats submitted to prenatal stress born to either mothers with intact corticosterone secretion or mothers in which stress-induced corticosterone secretion was blocked by adrenalectomy with substitutive corticosterone therapy. Repeated restraint during the last week of pregnancy was used as prenatal stressor. Furthermore, the specific role of an injection of corticosterone before the restraint stress on adrenalectomized mothers with substitutive corticosterone treatment was also studied. We report here that blockade of the mother's stress-induced glucocorticoid secretion suppresses the prolonged stress-induced corticosteroid response and the decrease in type I hippocampal corticosteroid receptors usually observed in prenatally stressed adults. Conversely, corticosterone administered during stress, to mothers in which corticosterone secretion is blocked, reinstates the effects of prenatal stress. These results suggest for the first time that stress-induced increases in maternal glucocorticoids may be a mechanism by which prenatal stress impairs the development of the adult offspring's glucocorticoid response.
Recent studies have indicated complex relationships between the neuroendocrine system, immune system, and behaviour. These systems are functionally linked in order to restore homeostasis during stress. There is now evidence for a relationship between stress and disease susceptibility. Stressors containing both physical and psychological components have successfully been used to investigate the link between stress, fear/anxiety and immune modulation. Reproductive performance depends on the production of sexual hormones and may therefore be suppressed when stressors interfere with sexual hormones. Glucocorticosteroids and opioid peptides are known to interfere with reproductive function. There is some evidence that acute stressors impair reproductive performance during critical periods of the reproductive cycle, early pregnancy and lactation. The impact of social stress on production performance is significant. Stressors such as mixing of unfamiliar animals and crowding may cause substantial growth depression. Stress does not always influence the performance and health negatively. For example, there are circumstances where stress seems to increase resistance to specific diseases. It is therefore questionable to evaluate and explain stress by observing single behavioural phenomena or physiological alterations. As a consequence, multiple criteria, such as ethological, physiological, health, production, and reproduction criteria should be used to evaluate possible stress situations under various production and management systems.
Variations in maternal care affect the development of individual differences in neuroendocrine responses to stress in rats.
As adults, the offspring of mothers that exhibited more licking and grooming of pups during the first 10 days of life showed
reduced plasma adrenocorticotropic hormone and corticosterone responses to acute stress, increased hippocampal glucocorticoid
receptor messenger RNA expression, enhanced glucocorticoid feedback sensitivity, and decreased levels of hypothalamic corticotropin-releasing
hormone messenger RNA. Each measure was significantly correlated with the frequency of maternal licking and grooming (all
r's > −0.6). These findings suggest that maternal behavior serves to “program” hypothalamic-pituitary-adrenal responses to
stress in the offspring.
It is generally regarded that only free corticosteroid is available for entry into tissues in vivo, although some studies have suggested that albumin-bound corticosteroid is available for liver uptake. However, recent studies suggest that owing to favorable kinetic relationships among tissue capillary transit times and hormone dissociation rates from plasma proteins, free plus albumin-bound hormone may be available to peripheral tissues. Moreover, globulin-bound hormone may enter the liver under normal conditions and be available to peripheral tissues under pathological circumstances. The present studies measure the free and noncorticosteroid-binding globulin (non-CBG)-bound corticosteroid fractions in vitro and compare these measurements to the fraction of corticosteroid in human sera that is available for entry into rat brain and rat liver in vivo. Corticosterone was used as the model corticosteroid, since this compound binds to CBG with the same affinity as does cortisol, and the brain extraction of corticosterone is more readily measured in vivo than is the brain extraction of cortisol. Serum was obtained from 51 human subjects and included samples from newborns, pregnant mothers, normal subjects, and patients with either cirrhosis or renal failure. Serum levels of CBG varied more than 6-fold, and both the free and the non-CBG-bound fractions were generally inversely related to the CBG concentration. The fraction of corticosterone available for entry into the brain was much greater than the free fraction, but was not significantly different from the non-CBG-bound moiety. Moreover, the rate of corticosterone dissociation from CBG (t 1/2 = 27 +/- 1 sec at 22 C) was not increased in any of the serum samples studied. The fraction of corticosterone available for uptake by the liver was up to 3-fold greater than that of the non-CBG fraction and had no relationship with the serum concentration of CBG. These studies indicate that albumin-bound, but not globulin-bound, corticosteroid is available for entry into a peripheral tissue such as the brain. However, globulin-bound corticosteroid is readily transported into the liver. It is suggested that the routine measurements of the non-CBG-bound corticosteroid provide a more accurate index of the corticosteroid available to peripheral tissues in vivo than does the measurement of free corticosteroid.
The development of the organism is subjected to critical and complex influences during the perinatal period. Prenatal and postnatal stresses can have different long-term behavioral effects, and appropriate postnatal manipulations can counteract the behavioral effects of prenatal stress. In the present study, we investigated the involvement of changes in the activity of the hypothalamo-pituitary-adrenal (HPA) axis in the long-term effects of prenatal and postnatal events and of interactions between them. We investigated stress-induced corticosterone secretion and hippocampal corticosteroid receptors in male adult rats submitted to prenatal and/or postnatal manipulations. Repeated restraint during the last week of pregnancy was used as prenatal stressor, and adoption at birth was used to change the postnatal environment. We found that (1) prenatal stress prolongs stress-induced corticosterone secretion in adult rats, which was attributed to the observed decrease in central corticosteroid receptors; (2) adoption, irrespective of the stress experience of the foster mother, reverses the effects of prenatal stress; and (3) adoption per se increases maternal behavior and decreases the stress-induced corticosterone secretion peak in the adult offspring. In conclusion, certain prenatal and postnatal manipulations appear to have opposite long-term effects on the activity of the HPA axis, and adoption, probably by modifying maternal behavior, can protect against the effects of prenatal stress. Thus, changes in the activity of the HPA axis may be one of the biological substrates of the long-term effects of certain perinatal events.
There is growing evidence that stressors occurring during pregnancy can impair biological and behavioral adaptation to stress in the adult offspring. Mechanisms by which stress in the pregnant rat can influence development of the offspring are still unknown. In the present study, we investigated the involvement of maternal corticosterone secretion during pregnancy on the hypothalamo-pituitary-adrenal axis activity of adult offspring. We investigated stress-induced corticosterone secretion and hippocampal type I and type II corticosteroid receptors in male adult rats submitted to prenatal stress born to either mothers with intact corticosterone secretion or mothers in which stress-induced corticosterone secretion was blocked by adrenalectomy with substitutive corticosterone therapy. Repeated restraint during the last week of pregnancy was used as prenatal stressor. Furthermore, the specific role of an injection of corticosterone before the restraint stress on adrenalectomized mothers with substitutive corticosterone treatment was also studied. We report here that blockade of the mother's stress-induced glucocorticoid secretion suppresses the prolonged stress-induced corticosteroid response and the decrease in type I hippocampal corticosteroid receptors usually observed in prenatally stressed adults. Conversely, corticosterone administered during stress, to mothers in which corticosterone secretion is blocked, reinstates the effects of prenatal stress. These results suggest for the first time that stress-induced increases in maternal glucocorticoids may be a mechanism by which prenatal stress impairs the development of the adult offspring's glucocorticoid response.
The adrenal glucocorticoids and catecholamines comprise a frontline of defense for mammalian species under conditions which threaten homeostasis (conditions commonly referred to as stress). Glucocorticoids represent the end product of the hypothalamic-pituitary-adrenal (HPA) axis and along with the catecholamines serve to mobilize the production and distribution of energy substrates during stress. The increased secretion of pituitary-adrenal hormones in response to stress is stimulated by the release of corticotropin-releasing hormone (CRH) and/or arginine vasopressin (AVP) from neurons in the nucleus paraventricularis. In this way, a neural signal associated with the stressor is transduced into a set of endocrine and sympathetic responses. The development of the HPA response to stressful stimuli is altered by early environmental events. Animals exposed to short periods of infantile stimulation or handling show decreased HPA responsivity to stress, whereas maternal separation, physical trauma and endotoxin administration enhance HPA responsivity to stress. In all cases, these effects persist throughout the life of the animal and are accompanied by increased hypothalamic levels of the mRNAs for CRH and often AVP. The inhibitory regulation of the synthesis for these ACTH releasing factors is achieved, in part, through a negative feedback loop whereby circulating glucocorticoids act at various neural sites to decrease CRH and AVP gene expression. Such inhibitory effects are initiated via an interaction between the adrenal steroid and an intracellular receptor (either the mineralocorticoid or glucocorticoid receptor). We have found that these early environmental manipulations regulate glucocorticoid receptor gene expression in the hippocampus and frontal cortex, regions that have been strongly implicated as sites for negative-feedback regulation of CRH and AVP synthesis. When the differences in glucocorticoid receptor density are transiently reversed, so too are those in HPA responses to stress. Taken together, our findings indicate that the early postnatal environment alters the differentiation of hippocampal neurons. This effect involves an altered rate of glucocorticoid receptor gene expression, resulting in changes in the sensitivity of the system to the inhibitory effects of glucocorticoids on the synthesis of CRH and AVP in hypothalamic neurons. Changes in CRH and AVP levels, in turn, determine the responsivity of the axis to subsequent stressors; increased releasing factor production is associated with increased HPA responses to stress. Thus, the early environment can contribute substantially to the development of stable individual differences in HPA responsivity to stressful stimuli. These data provide examples of early environmental programming of neural systems. One major objective of our research is to understand how such programming occurs within the brain.
Variations in maternal care affect the development of individual differences in neuroendocrine responses to stress in rats. As adults, the offspring of mothers that exhibited more licking and grooming of pups during the first 10 days of life showed reduced plasma adrenocorticotropic hormone and corticosterone responses to acute stress, increased hippocampal glucocorticoid receptor messenger RNA expression, enhanced glucocorticoid feedback sensitivity, and decreased levels of hypothalamic corticotropin-releasing hormone messenger RNA. Each measure was significantly correlated with the frequency of maternal licking and grooming (all r's > -0.6). These findings suggest that maternal behavior serves to "program" hypothalamic-pituitary-adrenal responses to stress in the offspring.
Physiological and biochemical variations in neurotransmitter (NT) systems might be correlated with brain functional acid structural sex differences. To determine the physiological significance of this correlation, we measured the hypothalamic levels of serotonin (5HT) and its metabolite 5-hydroxyindolacetic acid (5HIAA), dopamine (DA) and norepinephrine (NE) by radioenzymatic methods in male and female rats during early (1-5 days) and late (7-25 days) postnatal periods. Results showed: (a) Differences in NT levels during both postnatal periods, (b) Changes in an opposite direction between NE and DA levels and (c) A clear sex difference in 5HT levels, particularly on day 10. These data suggest that monoaminergic metabolism may be an important factor contributing to hormonal and environmental-induced changes (morphological and behavioural), that occur during brain sexual differentiation.
Negative feedback regulation of basal activity in the hypothalamo-pituitary-adrenal (HPA) axis requires less corticosterone (B) at the trough (morning) than at the peak (evening) of the diurnal rhythm. It has been hypothesized that in the morning in rats, occupation of the high affinity, type I corticosteroid receptors is sufficient to inhibit adrenalectomy (ADX)-induced increases in plasma ACTH secretion, whereas in the evening, regulation occurs through the occupation of the lower affinity type II corticosteroid receptors. To examine this hypothesis, the sensitivity of ACTH to inhibition by two different doses of B or of dexamethasone (DEX) were compared in ADX rats killed in the morning or the evening (B has a higher affinity for type I receptors in vitro and in vivo; in vivo, DEX has a higher affinity for type II receptors). The requirement for greater concentrations of corticosteroids to inhibit ACTH secretion in the evening was verified. The effect of these treatments on the number of neurons immunoreactive for vasopressin (AVP) and on the expression of AVP messenger RNA (mRNA) in the parvocellular portion of the paraventricular nuclei was also examined. In the morning, plasma concentrations of B equivalent to the IC50 for the reduction of plasma ACTH in the morning reduced the amount of AVP mRNA, but not immunoreactive AVP cell number as compared with ADX rats. DEX reduced plasma ACTH in the morning but did not prevent high levels of expression of AVP mRNA or protein. AVP mRNA was more sensitive to B in the morning than in the evening. Antagonist to the type I receptor (spironolactone) given chronically to ADX rats treated with B increased plasma ACTH secretion at both times of day, even though the plasma B concentrations suggested occupancy of a large proportion of the type II receptors. To test the hypothesis that an interaction between the type I and II receptor is necessary for the control of HPA activity at the peak of the diurnal rhythm, ADX rats were given B or DEX, alone or in combination. DEX reduced evening plasma ACTH only in the presence of very low concentrations of B, suggesting that for full potency, type II receptor occupation requires type I receptor occupation. In summary, these results demonstrate that occupation of type I corticosteroid receptors is capable of controlling basal activity in the HPA axis in the morning and that in the evening, type I receptor occupation potentiates the inhibition of plasma ACTH by occupation of type II receptors.
These studies further evaluated the relative role of mineralocorticoid (type I) and glucocorticoid (type II) receptors in mediating corticosteroid feedback regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Acute treatment of rats with the selective mineralocorticoid receptor antagonist, RU28318 (50 mg/kg sc), produced elevated basal corticosterone levels in the morning, but had no effect on basal corticosterone levels in the evening or on restraint stress corticosterone levels at either time of day. Acute treatment with the selective glucocorticoid receptor antagonist, RU40555 (30 mg/kg sc) had no effect on basal or restraint stress corticosterone levels at either time of day. However, combined treatment with RU28318 and RU40555 produced an elevation of evening basal corticosterone levels (and morning basal on one occasion) and produced an increase in corticosterone levels during and after stress at both times of day. In a separate experiment conducted in the morning, the combined RU28318 and RU40555 treatment also produced elevated ACTH responses during restraint stress. Based on available corticosteroid receptor measures, the RU28318 treatment was estimated to selectively occupy approximately 85% of mineralocorticoid receptors in rat brain, whereas the RU40555 treatment was estimated to selectively occupy approximately 50% of glucocorticoid receptors in rat brain. We conclude that mineralocorticoid receptor activation is necessary and sufficient to maintain low basal corticosterone levels during the circadian trough, whereas glucocorticoid receptor activation is necessary to constrain corticosterone secretion during the circadian peak or during acute stress. However, even during the circadian peak or acute stress, mineralocorticoid receptor activation plays an important role in facilitating the glucocorticoid receptor dependent regulation of HPA axis activity by corticosterone.
The study was conducted to investigate the adrenocortical capacity after injection of ACTH and the sensitivity of the pituitary and the adrenal to immobilization in neonatal pigs at different ages. Furthermore, the endocrine reactivity of the offspring was compared with the stress reactivity of their mothers. Four piglets were selected from each of six different litters and subjected to an immobilization test and an adrenal function test using synthetic ACTH(1-24) at the ages of 7, 21 and 35 days; the six sows were also subjected to restraint and an ACTH stimulation test. Plasma beta-endorphin, norepinephrine and epinephrine concentrations were measured in blood samples taken 2 min after restraint and cortisol concentrations were measured 60 min after ACTH administration. A highly sensitive adrenal response was demonstrated in both sows and piglets and adrenal reactivity showed also a considerable consistency over time within sows. In neonatal pigs, the cortisol response to ACTH was greatest on day 7 and decreased up to day 35. Plasma epinephrine and norepinephrine levels after the 2-min immobilization were also higher at day 7 compared with the other ages (P < 0.01). Piglets from sows, classified as high reacting according to their cortisol or epinephrine response, also showed significantly higher cortisol levels after ACTH challenge at all ages and significantly higher epinephrine levels after restraint at day 7 than piglets from low reacting sows. The results show an age-related change of pituitary-adrenocortical and sympatho-adrenomedullary responses in neonatal pigs and an absence of a stress hyporesponsive period at all ages studied. The results also indicate different levels of excitability in the offspring depending on the maternal stress reactivity
Studies in rodents and primates strongly indicate that prenatal stress affects the survival, behaviour and physiology of the offspring. Stressful stimuli during gestation may have a direct or hormone mediated effect on the development of stress systems in the foetal organism, resulting in an altered coping during stressful situations. The present study was conducted to elucidate prenatal stress effects in domestic pigs on the responses of the hypothalamic-pituitary-adrenocortical (HPA) axis and the sympatho-adrenomedullary (SAM) system as well as on morbidity, mortality and growth of the offspring. Pregnant sows were subjected to a restraint stress for five minutes daily during the last five weeks of gestation. Endocrine reactions of the piglets were tested at 3, 7, 21 and 35 days of age using an immobilization test and an ACTH challenge test. Prenatally stressed piglets showed lower basal plasma cortisol and increased corticosteroid binding globulin (CBG) concentrations at 3 days of age, indicating decreased free cortisol concentrations after birth. Cortisol levels after ACTH stimulation and catecholamine levels after immobilization were not affected by the stress treatment of the sows. Piglets from stressed sows tended to have lower noradrenaline : adrenaline ratios at three days of age compared with the control piglets. In addition, stressed sows tended to have lower litter weights after birth. The morbidity and mortality during the suckling period was higher in the prenatally stressed litters, as shown by a higher frequency of diseased and perished piglets per litter. We suppose that prenatal stress during late gestation in pigs alters the development of the HPA system and impairs the vitality of the offspring
Four trials were carried out, where in each trial during a selection test two groups of growing pigs (12 weeks old) with nine animals each were randomly formed. After a week, the top (TR) and bottom (BR) ranking pig from each group was isolated and kept under single housing conditions. At the age of 15 to 16 weeks, the test animals were confronted once with the familiar and once with the unfamiliar group. During the 10-h social confrontation test, agonistic behaviour (agonistic interactions, individual dominance values) and physiological stress reactions (epinephrine, norepinephrine, cortisol, heart rate) were investigated simultaneously. The social confrontation of a pig with a familiar or an unfamiliar group caused very frequent agonistic interactions during the first 30 min. This behaviour was accompanied by a rapid increase of the heart rate and the plasma catecholamine concentrations and a delayed increase of cortisol. TR pigs elicited more agonistic interactions during the first 30 min and displayed higher plasma catecholamine concentrations. Additionally, TR animals showed significantly higher dominance values during the 10-h testing situation compared to the BR pigs. The confrontation of an animal with the unfamiliar group resulted in a more pronounced adrenocortical reaction compared to the confrontation with the familiar group. In particular, the TR animals showed a distinct increase of plasma cortisol during the first hour and a later bradycardia when they were confronted with the unfamiliar group. The preliminary results presented in this paper indicate that pigs show different, but inconsistent behavioural and physiological reactions when they are confronted with a social group. The agonistic behaviour and the physiological stress reactions during a social confrontation test are still influenced by the former rank of the animal, even when the animal was isolated under single housing conditions in the meantime for 2 to 3 weeks.
Summary Two lines of pigs selected for rate of gain and backfat thickness in opposite directions were used to study the possible role of some steroid hormones for meat vs fat accretion. Both growth rate and sidefat thickness differed between lines (P~.001). The concentration of cytosolic protein was lower (P
Prenatal stress impairs activity of the hypothalamo–pituitary–adrenal (HPA) axis in response to stress in adult offspring. So far, very few data are available on the effects of prenatal stress on circadian functioning of the HPA axis. Here, we studied the effects of prenatal stress on the circadian rhythm of corticosterone secretion in male and female adult rats. To evaluate the effects of prenatal stress on various regulatory components of corticosterone secretion, we also assessed the diurnal fluctuation of adrenocorticotropin, total and free corticosterone levels, and hippocampal corticosteroid receptors. Finally, in the search of possible maternal factors, we studied the effects of repeated restraint stress on the pattern of corticosterone secretion in pregnant female rats. Results demonstrate that prenatal stress induced higher levels of total and free corticosterone secretion at the end of the light period in both males and females, and hypercorticism over the entire diurnal cycle in females. No diurnal fluctuation of adrenocorticotropin was observed in any group studied. The effects of prenatal stress on corticosterone secretion could be mediated, at least in part, by a reduction in corticosteroid receptors at specific times of day. Results also show that prepartal stress alters the pattern of corticosterone secretion in pregnant females. Those data indicate that prenatally stressed rats exhibit an altered temporal functioning of the HPA axis, which, taken together with their abnormal response to stress, reinforces the idea of a general homeostatic dysfunction in those animals. © 1999 John Wiley & Sons, Inc. J Neurobiol 40: 302–315, 1999
The effects of glucocorticoids on various brain functions including the negative feedback control of HPA axis are mediated by two types of receptor (type I or mineralocorticoid and type II or glucocorticoid) in the central nervous system. Furthermore, noradrenergic systems have been showed to stimulate the activity of hypothalamo-pituitary-adrenal (HPA) axis. The neural and receptor controls of HPA axis activity are generally thought to be independent. Although receptor numbers, especially type-II receptors, are thought to be regulated by circulating levels of corticosterone, they may also be under direct neural control. Thus, it may be suggested that these two types of control are functionally related and that noradrenergic systems may affect HPA axis activity either directly or indirectly via change in receptor characteristics. A major problem in the interpretation of studies examining neurotransmitter regulation of corticosteroid receptors is that the effects of drugs or brain lesions on receptors levels may be secondary to their effects on adrenocortical function. In order to demonstrate a neuronal control on corticosteroid receptors, we tested the effect of 6-hydroxydopamine lesion of noradrenergic systems in the pedunculus cerebellaris superior in adrenalectomized animals whose corticosterone levels were maintained within normal limits by corticosterone replacement implants. Both types of receptor were assayed in hypothalamus and amygdala. We show that: (1) corticosteroid receptors are influenced by noradrenergic systems; (2) this effect depends on the brain region and the receptor type. After the noradrenergic lesion type-I receptors were reduced in hypothalamus and amygdala, whereas type-II receptor were only increased in hypothalamus while receptor affinities were unaltered.(ABSTRACT TRUNCATED AT 250 WORDS)
WEINSTOCK, M. Does prenatal stress impair coping and regulation of hypothalamic-pituitary-adrenal axis? NEUROSCI BIOBEHAV REV 21(1),1–10 1997.—Prenatally stressed (PS) human infants and experimental animals show attentional deficits, hyperanxiety and disturbed social behavior. Impaired coping in stressful situations in adult PS monkeys and rodents is associated with dysregulation of the HPA axis, characterized by decreased feedback inhibition of corticotropin-releasing hormone (CRH) and prolonged elevation of plasma glucocorticoids in response to stress. PS rats have higher levels of CRH in the amygdala, fewer hippocampal glucocorticoid receptors and less endogenous opioid and GABA/BDZ (benzodiazepine) inhibitory activity. The mechanisms by which maternal stress hormones induce these long-lasting changes in the developing fetal neuroaxis remain to be elucidated. It is suggested that impaired coping in stressful situations and dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, result from the action of maternal hormones released during stress on the developing fetus. The similarities in coping behavior and dysregulation of the HPA axis in PS animals to those in humans with depression, suggest that gestational stress, at a critical time during fetal development, may increase the propensity to develop this condition. Copyright © 1996 Elsevier Science Ltd.
Basal corticosterone (B) levels increase with age in the rat, a result of decreased negative-feedback inhibition of hypothalamic-pituitary-adrenal (HPA) activity. Postnatal handling increases CNS negative-feedback sensitivity and appears to attenuate some of the changes occurring in the HPA axis in later life. In the experiments described here, we have examined basal HPA function in young (6-8 months) and old (22 months), handled (H) and nonhandled (NH) rats in relation to changes in corticosteroid receptor binding. Among young animals, there were no group differences in basal adrenocorticotropin (ACTH) or B levels at any point in the diurnal cycle. In contrast, plasma ACTH and B levels during the PM phase were significantly higher in old NH animals in comparison to old H animals and to both groups of young animals. The H and NH groups did not differ in in vivo adrenal responsiveness to exogenous ACTH. As expected, ACTH sensitivity was greater in all groups during the PM phase and in general, old animals showed a greater response to ACTH regardless of the treatment group. There were no differences across the groups in AM plasma corticosterone-binding globulin (CBG) levels. However, during the PM phase of the cycle, CBG levels were significantly lower and the percentage of B in the free form was significantly higher in the old NH animals. As expected, levels of free B during the PM phase of the cycle were significantly higher in the old NH animals. Thus, there is a significant increase in the PM corticoid signal in the old NH animals that occurs as a function of elevated B and decreased CBG levels; these age-related changes in basal HPA activity were not seen in the old H animals. Type I (mineralocorticoid-like) receptor binding in the hippocampus did not differ as a function of handling and was significantly reduced with age in both H and NH animals. Type II (glucocorticoid) receptor binding decreased as a function of age in both H and NH animals, but was consistently higher in the H animals. There were no differences in type II receptor binding in the hypothalamus or pituitary as a function of age or handling. These data suggest that the increase in basal HPA activity occurring in aged rats is largely restricted to the dark phase of the cycle and is attenuated by postnatal handling, a treatment that increases hippocampal type II corticosteroid receptor binding.
Previous studies demonstrated that throughout the preweaning period prenatally stressed rats have an overactive hypothalamic-pituitary-adrenal (HPA) system. This increased HPA activity was accompanied by an increase in defensive behavior. This study examined whether these alterations in HPA activity and defensive behavior continued into adulthood. Brain catecholamines in the cerebral cortex and locus coeruleus were also measured in prenatally stressed and control rats. Shock-induced levels of defensive freezing were significantly higher in prenatally stressed rats than in controls. However, plasma ACTH and corticosterone concentrations did not differ between groups either in the basal state or after exposure to foot shock. Concentrations of norepinephrine (NE) in the cerebral cortex and locus coeruleus region were significantly reduced in prenatally stressed rats. In addition, concentrations of NE metabolites were significantly elevated in prenatally stressed rats, suggesting an increased turnover of brain NE. Prenatally stressed rats also had, in the locus coeruleus region, significantly reduced dopamine (DA) levels but elevated concentration of DA metabolites. Results indicate that prenatal stress produces an increased behavioral responsiveness to stress that is evident in early life and continues into adulthood. The early hyperactivity of the HPA system in prenatally stressed rats, however, appears to normalize in adulthood. The increased turnover in brain catecholamines measure in the cerebral cortex and locus coeruleus region of prenatally stressed rats may be associated with the heightened expression of stress-induced behavior.
A study was made of the effects of prenatal stress on the reactivity of the hypothalamic-pituitary adrenal (HPA) axis in male and female offspring. Rat dams were subjected to noise and light stress on an unpredictable basis throughout pregnancy. At 28 days of age mRNA for POMC, proenkephalin and prodynorphin were measured in the hypothalamus of the offspring. A marked reduction was found in POMC mRNA in PS females (PSF) but not in males (PSM), but the other mRNA's did not differ from controls (C). At 60 days of age, PSF has 3 times higher resting levels of serum corticosterone (COR) and significantly lower dexamethasone (DEX)3H hippocampal binding sites than CF. Overnight adrenalectomy abolished the difference in DEX binding. After 10 min exposure to open field PS males and females voided more fecal pellets and made fewer center entries than C offspring, testifying to increased emotionality. Open field stress caused a 3-5-fold rise in circulating COR in all groups within 15 min, which returned to baseline by 90 min in all rats except PSF. These data show that prenatal stress can cause permanent alterations in the behavior of both sexes in stressful situations but appears to cause a selective effect on the HPA axis in the female rat.
Previous experiments revealed that 14-day-old prenatally stressed rats have significantly elevated concentrations of plasma adrenocorticotrophic hormone (ACTH) and corticosterone suggesting these animals have an overactive hypothalamic-pituitary-adrenal (HPA) system. In these studies, however, stress-induced hormone levels were determined only immediately after exposure to an acute stressor. Therefore, in the current study, we examined in postnatal days 7, 14 and 21 prenatally stressed rats the stress-induced time course of this pituitary-adrenal hormone elevation. Plasma ACTH and corticosterone were measured in the basal state and at 0.0, 0.5, 1.0, 2.0 and 4.0 h after a 10-min exposure period to foot shocks administered in the context of social isolation. Results indicated that at all 3 ages, plasma ACTH in prenatally stressed rats was significantly elevated. Corticosterone concentrations were also significantly higher in prenatally stressed than in control rats, especially in day 14 rats. Analysis of stress-induced hormone fluctuations over time indicated that by 14 days of age, both prenatally stressed than in control and control rats had significant increases in plasma ACTH and corticosterone after exposure to stress. Furthermore, although prenatally stressed rats had significantly higher pituitary-adrenal hormone concentrations than control animals, the post-stress temporal patterns of decline in ACTH and corticosterone levels were similar between groups. Results suggest that throughout the preweaning period, prenatal stress produces an HPA system that functions in a manner similar to that of controls but at an increased level.
Previous studies have shown that maternal stress modifies 5-hydroxytryptamine (5-HT) receptor binding in several brain regions of the adult offspring and alters the intensity of the behavioral responses to 5-HT receptor agonists. We now report that the same stress, crowding combined with daily saline injections during the final week of pregnancy, elevates maternal plasma free tryptophan level without significantly affecting total tryptophan. The increased maternal plasma tryptophan was associated with significantly increased fetal brain levels of tryptophan, 5-HT and 5-hydroxyindoleacetic acid. These increases were maintained after birth until at least postnatal day 10. Since 5-HT is recognised as having a role in the control of neuron development during the perinatal period, we suggest that the stress-induced increase in fetal brain 5-HT synthesis may play a part in the mechanisms by which prenatal stress alters adult behavior.
A study was conducted to determine whether within-breed differences in adrenocortical response to exogenous adrenocorticotropin ( acth ) might be accounted for by differences in responsiveness of the adrenocortical cells per se. Large White × Landrace male pigs (n = 20) were used; 10 had high adrenocortical response to acth administration and 10 had low response. Five high and 5 low responders were euthanatized at 15 weeks of age, and the remaining 5 high and 5 low responders were euthanatized at 21 weeks of age. Adrenal glands were removed and weighed, and adrenocortical cells were dispersed by tryptic digestion and incubated for 2 hours with synthetic acth at concentrations ranging from 0.5 to 10,000 pg/ml. Samples were taken at 30-minute intervals, and cortisol concentration was determined by use of a radioimmunoassay. Results indicate that for pigs of both age groups, high responders had heavier adrenal glands, with higher adrenocortical cell density and higher cell yield than did low responders. Synthetic acth had a stimulatory effect on dispersed porcine adrenocortical cells, as indicated by changes in cortisol concentration in vitro. Adrenocortical cells from high responders produced less cortisol, on a per-cell basis, than did those from low responders. However, when corrected for total cell yield, the potential cortisol production by each pair of adrenal glands was significantly ( P < 0.05) higher in the high responders than in the low responders. Thus, high-responding pigs have larger adrenal glands and higher adrenocortical cell density, which may result in higher output of cortisol after acth administration or exposure to stressors.
For high- and low-responding groups, 15-week-old pigs had higher adrenal gland weight to body weight ratio, higher adrenocortical cell density, and higher steroidogenic function per adrenocortical cell than did 21-week-old pigs.
Two types of corticosteroid receptors can be distinguished in rat brain. The type 1 receptor resembles the kidney mineralocorticoid receptor and has two functional expressions in brain, i.e. type 1 corticosterone (CORT) preferring sites (CR) and mineralocorticoid receptors (MR). The type 2 receptor is similar to the liver glucocorticoid receptor (GR). CORT binds to both CR and GR. The localization, binding specificity, and capacity of the receptor systems have served as criteria to evaluate steroid dependent events in brain biochemistry and behaviour. The GR is widely distributed in neurons and glial cells, with the highest density in frontal brain regions. The GR becomes occupied concomitant with rising plasma CORT levels after stress and as part of the circadian rhythm. The GR mediates the feedback action of CORT on stress-activated brain processes.
This chapter reveals prenatal stress effects on functional development of the off spring. The term “psychological stress” is used to denote situations that, although not physically harmful in terms of causing direct tissue damage, evoke behavioral and physiological responses that are characteristic of the “stress” response. Early reports that prenatal psychological stress in human subjects may influence the behavior of the offspring prompted a large number of studies in experimental animals in an attempt to provide more precise information about the nature of the changes induced by such stress and their underlying mechanisms. In the absence of any direct neural connections between the mother and foetus, it has been postulated that hormones (e.g., glucocorticoids, adrenaline) transported from the maternal blood to the placenta are the most likely mediators. The nature of the effect of prenatal stress on early physical development and later behavior appears to depend upon genetic factors, the severity of the stress, and its timing. These in turn determine whether abnormal maternal and foetal hormonal and neuronal activity occurs at a critical period of foetal development.
Effects of unpredictable (random) prenatal stress on the level of anxiety and cerebral lateralization of dopamine turnover rates were studied in rats. The observation of a decrease in the amount of time spent in the open arms of a "plus-maze" supported earlier findings of an increased fearfulness to stressful situations in the offspring in adulthood. We also observed elevated rates of dopamine turnover in the right prefrontal cortex and reduced dopamine activity in the right nucleus accumbens and left corpus striatum of the prenatally stressed animals. This resulted in directional shifts of left-right differences in dopamine activity in all 3 areas. These findings indicate that prenatal stress induces permanent alterations in dopaminergic activity and in cerebral asymmetry. We suggest that the changes in cerebral lateralization of dopamine function may underly the increase in reactivity to anxiety-provoking situations in prenatally stressed offspring.
Corticosterone (CORT) binds to two receptor systems in rat brain: the type I CORT-preferring receptor (CR) and the type II glucocorticoid receptor (GR). Discrimination between the two receptor types can be achieved with the 'pure' synthetic glucocorticoid RU 28362. In this study, we show that the binding capacity of GR in the rat hippocampus exhibits a strikingly different response from CR to adrenalectomy (ADX), chronic steroid replacement, hypophysectomy (HYPOX) and during circadian variation. Under those experimental conditions neither receptor site showed changes in binding affinity. After ADX, CR number remained relatively constant for a period of 13 days, while GR capacity increased by 133%, a level which was reached 5 days post-surgery. CR capacity showed circadian variation, since CR number was 65% higher in the evening than in the morning. GR capacities at those two time points were not significantly different. Replacement with subcutaneous CORT implants (100-mg pellets) for 7 days following ADX rats did not affect CR number, but caused a 38% decrease in GR number compared to control animals (cholesterol-treated, 7-day-ADX rats). On the other hand, dexamethasone (DEX) implants (5-, 15-, 25-mg pellets) elicited a dose-dependent increase in CR capacity (up to 99%) and a dose-dependent decrease in GR capacity (40-44%). Finally, 2 weeks after HYPOX, CR and GR numbers were increased by 60 and 38%, respectively. We conclude that the type II GR capacity responds in an autoregulatory manner to changes in circulating plasma glucocorticoid levels, while type I CR does not.
Pregnant rats were subjected to once daily stress treatments consisting of handling and a saline injection. The offspring showed region-specific changes in brain 5-hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid (5-HIAA) and norepinephrine (NE) levels in infancy but only the hypothalamus still showed significant changes at 60 days of age. In a reaction-to-stress test 23-day-old offspring in the prenatal stress group showed a greater elevation in plasma corticosterone level but smaller changes in hypothalamic NE and 5-HIAA levels than control offspring suggesting that prenatal stress may have altered the functioning of the hypothalamic-pituitary-adrenal axis. It is suggested that changes in the development of specific monoamine-containing neurons may be associated with the reported behavioral deficits in offspring of female rats stressed during pregnancy.
This chapter discusses the serum transport of steroid hormones. Steroid hormones are extensively bound to plasma proteins including albumin, corticosteroid binding globulin (CBG), and sex hormone binding globulin (SHBG). Because of its high concentration, albumin binding is important in determining the magnitude of the nonprotein bound or free fraction of a steroid in plasma. The generally accepted model of steroid hormone action suggests that free steroid (in equilibrium with circulating binding proteins) diffuses passively through target cell membranes and binds to a soluble intracellular receptor. The steroid-receptor complex apparently moves into the nucleus where it modifies the chromatin transcriptional activity which results in, among other things, altered levels of protein synthesis. CBG has been differentiated from the intracellular glucocorticoid and progesterone receptors by its inability to bind synthetic glucocorticoids and progestins.
A glucocorticoid receptor exchange assay has been developed for the accurate quantification of both free and steroid-bound receptors in rat liver cytosol. Hepatic cytosol from adrenalectomized rats was saturated in vitro with unlabeled corticosterone. Cytosol was subsequently treated with [3H]dexamethasone (with and without 1000-fold cold dexamethasone) for 2-28 h at 4 C in the presence of 10 mM molybdate plus 5 mM dithiothreitol (DTT). Complete exchange occurred between 16-28 h in the presence of molybdate plus DTT. In control and 10 mM molybdate (alone) treated samples only about 50% exchange was achieved. In the presence of 5 mM DTT (alone) approximately 60-70% exchange was observed. The exchange assay (utilizing molybdate plus DTT) was also applied to hepatic cytosol of adrenalectomized rats injected with corticosterone in vivo and to samples prebound with unlabeled dexamethasone.
Recently, both glucocorticoid receptor immunoreactivity and glucocorticoid receptor messenger RNA levels were found in multiple brain areas, especially in the neuroepithelium during the late prenatal development of the rat brain. To better understand the potential influence of stress on fetal brain development by release of maternal adrenocortical steroids, we have investigated the effects of corticosterone administration to pregnant rats on the locomotor activity of their prepubertal offspring. On day 16 of pregnancy female rats were implanted with either placebo or corticosterone pellets (release of 2.4 mg/day for seven days). After birth their offspring were nursed by foster mothers to avoid any postnatal effects of the corticosterone pellets. At three weeks of age, the offspring were tested for spontaneous motor behaviours. Both male and female offspring from corticosterone treated mothers showed significantly increased spontaneous ambulation, motility and rearing compared to placebo treated groups. No significant sex differences were found in locomotor activity between male and female offspring from placebo groups. Following d-amphetamine (1.5 mg/kg) treatment, a preferential dopamine releasing agent, we observed a significant increase in ambulation, motility and rearing activity in the male offspring treated with corticosterone. In the female offspring, only the rearing activity was significantly higher after d-amphetamine treatment in the prenatal corticosterone group compared with the placebo treated group. Basal dopamine metabolism (dihydroxyphenylacetic acid/dopamine ratio) was increased in the dorsal striatum and ventral striatum of male and female offspring from corticosterone-treated dams. In the male offspring, corticosterone treatment was associated with a disappearance of the right side dominance of dopamine metabolism in the dorsal striatum.(ABSTRACT TRUNCATED AT 250 WORDS)
After pargyline treatment the turnover rates of dopamine (DA), noradrenaline (NA), 3,4-dihydroxyphenylacetic acid (DOPAC), serotonin (5-hydroxytryptamine (5-HT) and 5-hydroxy-3-indolacetic acid (5-HIAA) has been measured in control and aged hippocampus of the rats. In addition, the tyrosine hydroxylase (TH) activity and monoamine oxidase-A and monoamine oxidase-B activities have also been studied. The TH activity did not change in aged hippocampus as compared to controls. The monoamine oxidase-B: monoamine oxidase-A ratio increased in 26-month-old rats compared with controls. The turnover of DA, DOPAC and NA did not show significant changes while 5-HT synthesis, 5-HT accumulation rate and 5-HIAA turnover increased in aged rats. Serotonin fibers showed morphological dissimilarities between the hippocampus of young and aged rats using immunocytochemistry techniques. In aged rats aberrant serotoninergic fibers mainly appear in the molecular layer of the dentate gyrus and molecular of the hippocampal CA1. It is suggested that the aberrant morphology of 5-HT fibers may reflect the local degeneration of serotoninergic hippocampal afferents during aging. Increase of 5-HT turnover in aged might be a signal of degeneration.
Stress affects cognition in a number of ways, acting rapidly via catecholamines and more slowly via glucocorticoids. Catecholamine actions involve beta adrenergic receptors and also availability of glucose, whereas glucocorticoids biphasically modulate synaptic plasticity over hours and also produce longer-term changes in dendritic structure that last for weeks. Prolonged exposure to stress leads to loss of neurons, particularly in the hippocampus. Recent evidence suggests that the glucocorticoid- and stress-related cognitive impairments involving declarative memory are probably related to the changes they effect in the hippocampus, whereas the stress-induced catecholamine effects on emotionally laden memories are postulated to involve structures such as the amgydala.
The emergence of cognitive deficits in a subgroup of aged rats is associated with increased hypothalamic-pituitary-adrenal axis activity, decreased hippocampal mineralocorticoid and/or glucocorticoid receptor gene expression and neuronal loss. Short-term treatment with antidepressant drugs in young rats increases hippocampal corticosteroid receptor gene expression. In this study, the effects of chronic antidepressant administration on hippocampal mineralocorticoid and glucocorticoid receptor gene expression and spatial memory in young and aged rats were investigated. Young (eight months) and old (22 ± 1 months) Lister-hooded rats were ranked according to watermaze performance. Matched pairs of rats were treated with amitriptyline (10 mg/kg) or saline daily for nine weeks, then reassessed in the watermaze. Amitriptyline significantly improved spatial memory in the young rats (33% increase in transfer test time) and increased hippocampal mineralocorticoid, but not glucocorticoid receptor messenger RNA expression. By contrast, in aged rats, amitriptyline had no effect on spatial memory or hippocampal corticosteroid receptor gene expression, either in cognitively unimpaired or cognitively-impaired animals. In aged rats, basal plasma corticosterone levels, which were significantly higher than in young animals, correlated negatively with spatial memory, while hippocampal glucocorticoid receptor mRNA expression correlated negatively with plasma corticosterone levels and positively with spatial memory. Amitriptyline had no significant effect on basal morning plasma corticosterone levels in either young or aged rats, but significantly decreased evening corticosterone levels in aged rats.
Central corticosteroid receptors play an important role in the regulation of the secretion of corticosterone. Although these receptors are thought to be regulated by circulating levels of corticosterone, there is evidence for direct neural control. For example, it has been shown that noradrenergic lesions can both increase and decrease corticosteroid receptors depending on the brain structure involved. In the present study, we investigated the role of different noradrenergic receptors in the rat, by examining the effect of the acute administration of agonists and antagonists of beta and alpha 1 noradrenergic receptors on hippocampal type I and type II corticosteroid receptor levels. The effects of these drugs were studied in adrenalectomized animals whose plasma levels of corticosterone were maintained in the physiological range by implantation of coritcosterone pellets. Our results show that the beta receptor agonist salbutamol (5 mg/kg) increased the number of type I and type II hippocampal corticosteroid receptors. This effect was blocked by the beta receptor antagonist propranolol (5 mg/kg), which had no effect on its own. In contrast, the alpha 1 receptor agonist phenylephrine (100 micrograms) reduced the number of type I and type II corticosteroid receptors, whereas the alpha 1 receptor antagonist prazosin (0.5 mg/kg) increased type I receptors. The effect of prazosin was attributed to an increase in the relative beta tonus resulting from blockade of alpha 1 receptors. Its effect was reversed by the simultaneous injection of the beta receptor antagonist propranolol. In conclusion, our results show that noradrenergic transmission can have both a facilitatory and an inhibitory action on central corticosteroid receptors by acting respectively on beta and alpha 1 noradrenergic receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
Previous research indicates that the offspring of dams exposed to stress during late gestation show altered hypothalamic-pituitary-adrenal (HPA) responses to stress. However, the results are inconsistent and a review of the literature suggests that the effects may differ depending upon the gender of the offspring. In the present study, we measured plasma adrenocorticotropin (ACTH) and corticosterone (B) levels prior to, and at 0, 20, 40 and 70 min following restraint stress in catheterized adult male and female offspring of dams stressed in the last week of gestation (i.e. days 15-19 of gestation). Prenatal stress significantly increased both plasma ACTH and B levels in response to restraint, but only in females; male offspring were largely unaffected. In addition, plasma corticosteroid-binding globulin (CBG) levels were significantly increased in prenatally-stressed females, but not in males. Despite these differences in plasma CBG, estimated free B levels following restraint were also significantly elevated in prenatally-stressed females. We then examined glucocorticoid receptor binding in a variety of forebrain structures. Prenatal stress had no effect on glucocorticoid receptor density in the hypothalamus or hippocampus in either males or females. Differences in glucocorticoid receptor density across groups were observed in the septum, frontal cortex, and amygdala. However, the pattern of observed differences across the groups was not consistent with the pattern of hormonal differences. In summary, the effect of prenatal stress on HPA function is substantially more marked in females than in males. Interestingly, a similar pattern of effects on HPA activity has been reported for prenatal alcohol exposure.
Offspring of mothers with adrenal hyperactivity during pregnancy have been reported to have changes in brain monoamines and altered emotional, reactive, sexual and maternal behavior. Since the hypothalamic-pituitary-adrenal (HPA) axis is known to be involved in the expression of such behaviors and is itself under monoaminergic control, we examined the development of the HPA axis and brain monoamines in pups whose mothers had adrenal hyperactivity, reflecting administration of ACTH during the last third of their pregnancy. The adrenals of the experimental animals weighed less and had aberrant morphology. The abnormal histology was more pronounced in the adrenals of the experimental females than of the males, suggesting that females were more vulnerable to the prenatal treatment. In both experimental males and females, basal plasma corticosterone levels were higher compared to the controls, while after exposure to stress, experimental animals attained lower plasma corticosterone levels than the controls. In the brain of the experimental animals, dopaminergic activity appeared to be decreased, while serotonergic activity increased. Our results indicate that the prenatal treatment affected brain development in the offspring and as a consequence programmed the developing HPA axis in such a way as to hyperfunction under basal conditions, leading to its exhaustion and its inability to react properly to stress.
In response to stressors, the central nervous system of livestock (and other mammalian species) evokes physiological responses that ultimately result in activation of the hypothalamo-pituitary-adrenocortical (HPA) axis and the sympatho-adrenal axis. The responses of these major systems are presumed to have adaptive and homeostatic value during periods of stress. The major hormone regulating the synthesis and secretion of adrenal glucocorticoids is ACTH. In sheep, cattle, and pigs, both corticotropin-releasing hormone (CRH) and vasopressin (VP) participate in the regulation of secretion of ACTH, and the two peptides seem to interact to enhance that secretion. In cattle and pigs, CRH is the more potent peptide, whereas VP is the more potent in sheep. In addition to its better-known role in regulating pituitary function, CRH also may participate as a neurotransmitter acting centrally to enhance sympathetic activation of the adrenal medulla. Many experimental models of stress have been evaluated that reliably activate the HPA axis and the sympatho-adrenal medullary axis, and some of these model systems also reduce functions of cells of the immune system. Recent data support an important role of stressor-activation of the sympathetics rather than increased glucocorticoids per se in modulating some measures of immune function in response to stress. Thus, current dogma of glucocorticoids as the primary mediator of stressor-associated alteration in immune function of domestic livestock may require reevaluation.
Negative feedback regulation of basal activity in the hypothalamo-pituitary-adrenal (HPA) axis requires less corticosterone (B) at the trough (morning) than at the peak (evening) of the diurnal rhythm. It has been hypothesized that in the morning in rats, occupation of the high affinity, type I corticosteroid receptors is sufficient to inhibit adrenalectomy (ADX)-induced increases in plasma ACTH secretion, whereas in the evening, regulation occurs through the occupation of the lower affinity type II corticosteroid receptors. To examine this hypothesis, the sensitivity of ACTH to inhibition by two different doses of B or of dexamethasone (DEX) were compared in ADX rats killed in the morning or the evening (B has a higher affinity for type I receptors in vitro and in vivo; in vivo, DEX has a higher affinity for type II receptors). The requirement for greater concentrations of corticosteroids to inhibit ACTH secretion in the evening was verified. The effect of these treatments on the number of neurons immunoreactive for vasopressin (AVP) and on the expression of AVP messenger RNA (mRNA) in the parvocellular portion of the paraventricular nuclei was also examined. In the morning, plasma concentrations of B equivalent to the IC50 for the reduction of plasma ACTH in the morning reduced the amount of AVP mRNA, but not immunoreactive AVP cell number as compared with ADX rats. DEX reduced plasma ACTH in the morning but did not prevent high levels of expression of AVP mRNA or protein. AVP mRNA was more sensitive to B in the morning than in the evening. Antagonist to the type I receptor (spironolactone) given chronically to ADX rats treated with B increased plasma ACTH secretion at both times of day, even though the plasma B concentrations suggested occupancy of a large proportion of the type II receptors. To test the hypothesis that an interaction between the type I and II receptor is necessary for the control of HPA activity at the peak of the diurnal rhythm, ADX rats were given B or DEX, alone or in combination. DEX reduced evening plasma ACTH only in the presence of very low concentrations of B, suggesting that for full potency, type II receptor occupation requires type I receptor occupation. In summary, these results demonstrate that occupation of type I corticosteroid receptors is capable of controlling basal activity in the HPA axis in the morning and that in the evening, type I receptor occupation potentiates the inhibition of plasma ACTH by occupation of type II receptors.
Previous studies have shown that fetal ethanol exposure (FEE) may have long-term effects on the function of catecholaminergic neurons in different regions of the CNS. The present study is the first to examine the effects of FEE on regional brain catecholamine responses following acute stress (a single 60-min restraint stress), repeated stress (single periods of restraint stress on 1, 5, or 10 consecutive days), and recovery from stress (recovery for up to 60 min in the home cage following a single 60-min period of restraint stress). Both male and female offspring from FEE, pair-fed (PF), and ad libitum-fed control (C) groups were tested in adulthood to determine catecholamine content in the cortex, hypothalamus, and hippocampus. A single period of restraint reduced cortical norepinephrine (NE) content in FEE and PF animals compared with that in the cortex of C animals, and reduced hypothalamic NE content in FEE female offspring below that found in animals in all other groups. In contrast, hippocampal NE content was higher in FEE than in C animals following a single period of restraint; PF animals had intermediate levels of hippocampal NE and did not differ significantly from either FEE or C animals. Following repeated periods of restraint, cortical NE content was lower in FEE than in C animals; PF animals once again had intermediate levels of NE. Importantly, basal (nonstressed) NE content did not differ among groups in any brain area examined. In addition, several significant changes in regional brain catecholaminergic responses to acute stress were observed in animals across all treatment groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Central type I and type II corticosteroid receptors play a principle role in the regulation of corticosterone secretion. Although the binding capacity of these receptors is thought to be regulated essentially hormonally, there is also evidence for a direct neural control. For example, experimental manipulation of central serotoninergic and noradrenergic activities modifies the binding capacity of type I and type II corticosteroid receptors via a corticosterone-independent mechanism. In this study, we tested the effect of lesions of dopaminergic neurons in the ventral tegmental area on corticosteroid receptor binding capacity. The study was performed in adrenalectomized rats whose corticosterone levels were maintained within normal limits by corticosterone pellets and corticosterone in their drinking water during the dark period to generate the circadian rhythm. Binding properties of corticosteroid receptors were analysed in target regions of the lesioned neurons, including the ventral and dorsal striatum. Corticosteroid receptors in the hippocampus were also studied as a control as these lesions do not significantly affect dopamine content in this structure. Three weeks after the lesion, type II corticosteroid receptor affinity was increased in the ventral striatum. There was no effect on receptors in the dorsal striatum or hippocampus. Our results, together with other reports showing that dopamine inhibits the expression of corticosteroid receptors in the anterior pituitary, suggest that dopamine transmission exerts a negative control on central corticosteroid receptors.
An experiment was conducted in pigs to determine the source of fetal cortisol at 50 (n = 5) or 100 days (n = 4) of gestation (term = 114 days). Equilibrium concentrations of tritiated cortisol were achieved, and all hormonal measures were made at 110, 130, 140, and 150 min in anesthetized pigs. Maternal plasma cortisol did not differ (p = 0.48) between 50 (70.2 +/- 7.4 ng/ml; mean +/- SEM) and 100 days (62.4 +/- 5.8 ng/ml). Conversely, fetal cortisol increased (p = 0.048) between 50 (8.5 +/- 2.5 ng/ml) and 100 days (24.2 +/- 4.2 ng/ml), and, at each gestational age, values were lower (p = 0.001) than those in maternal plasma. Plasma cortisone (15.1 +/- 2.3 ng/ml) did not change with gestational age (p = 0.42) in either compartment (maternal or fetal), nor did it differ between compartments (p = 0.08). Maternal cortisol accounted for 22.8 +/- 2.0% of fetal cortisol at 50 days of gestation, and this contribution decreased (p < 0.001) to 5.87 +/- 0.8% at 100 days. At both ages, maternal cortisol accounted for almost 50% of fetal cortisone. Metabolism of maternal cortisol by the entire uterofetoplacental unit was 8.4 +/- 1.7% at 50 days and 7.5 +/- 2.4% at 100 days (p = 0.76). The maternal metabolic clearance rate of cortisol increased 44% (p = 0.003) between 50 and 100 days (1.49 +/- 0.4 vs. 2.15 +/- 0.2 L/min). Hence at these gestational ages, the fetus--presumably the fetal adrenal--is the primary source of fetal plasma cortisol. The major contribution of maternal cortisol to fetal cortisone strongly suggests the presence of porcine placental 11 beta-hydroxysteroid dehydrogenase activity. Further, factors constituting the placental "barrier" that metabolize maternal cortisol to cortisone and other products may be major regulators of porcine fetal plasma cortisol and cortisone.
1. The present study aimed to develop a pharmacological model of catecholamine (CA) depletion in the hypothalamus during the period of its morphofunctional development, i.e. in fetal and neonatal rats of both sexes. 2. In the first series of experiments, pregnant females and, hence, fetuses were systemically treated daily from the embryonic day (E) 13 to E20 with the inhibitor of the CA synthesis alpha-methyl-m-tyrosine. The CA concentrations were subsequently measured in the fetal hypothalamus at E21 by high performance liquid chromatography with electrochemical detection (HPLC-ED). In the second series of experiments, neonatal rats were injected with neurotoxin, 6-hydroxydopamine and/or alpha-methyl-m-tyrosine daily from the 2nd postnatal day (P2) to P10. 3. The HPLC-ED assay of hypothalamic catecholamines (CA's) at E21 and P11 showed that both in fetuses and neonates, alpha-methyl-m-tyrosine caused more than 50% depletion of hypothalamic noradrenaline and adrenaline, while the dopamine (DA) level remained unchanged. The combined treatment of neonatal rats with alpha-methyl-m-tyrosine and 6-hydroxydopamine resulted additionally in a 25% decreased level of DA. 4. The influence of CA deficiency on the developing hypothalamic CA system was further evaluated by measuring [3H]DA uptake by nervous tissue in vitro. 5. The CA deficiency caused a 50% drop of [3H]DA uptake by the hypothalamic tissue in treated fetuses suggesting a stimulating effect of CA's on the early development of the CA system. In pharmacologically treated neonatal rats [3H]DA uptake remained at the control level showing no influence of the CA deficiency on the developing CA system after birth. 6. The usefulness of the proposed pharmacological model for studying of CA influence on differentiating hypothalamic target neurons is discussed.