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Caffeine-induced fetal growth retardation and inhibition of the fetal hypothalamic-pituitary-adrenal axis. Pregnant rats ingested different doses of caffeine (20, 60, and 180 mg/kg) once per day from gestational day (GD) 11 to GD20. On GD20, the pregnant rats were anesthetized, and all of the fetuses in each group were weighed for calculation of the intrauterine growth retardation (IUGR) rate. One whole fetal brain and one pair of fetal adrenal glands were randomly selected from each group and processed for hematoxylin and eosin (HE) staining. The fetal hypothalamus and adrenal glands were also dissected under an anatomy scope and collected. Fetal tissues from each single pregnant rat were counted as one sample. (A) Fetal body weight and IUGR rate. (B, C) Histopathology of the fetal hypothalamus in the control (B) and caffeine groups (C), magnification 1006. (D, E) Real-time quantitative RT-PCR and Western blotting detection of the mRNA and protein expression of the hypothalamus corticotropin-releasing hormone (CRH). (F, G) Histopathology changes in the fetal adrenal glands in the control (F) and caffeine groups (G), magnification 2006. (H) Real-time quantitative RT-PCR detection of the mRNA expression of the adrenal steroid acute regulatory protein (StAR) and cholesterol side-chain cleavage enzyme (P450scc). (I) ELISA detection of the endogenous level of fetal adrenal corticosterone (CORT). The CORT content was expressed relative to the adrenal protein measured using the BCA protein detection kit. For Western blotting detection, the bar graphs represent the quantitative densitometric results of CRH protein expression, the intensity of the band of each sample was normalized on the basis of GAPDH protein content. For real-time quantitative RT-PCR detection, each sample was normalized on the basis of GAPDH mRNA content. Mean 6 SEM, n = 8 pregnant rats. * p,0.05, ** p,0.01 vs. control. doi:10.1371/journal.pone.0044497.g001
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Epidemiological investigations have shown that fetuses with intrauterine growth retardation (IUGR) are susceptible to adult metabolic syndrome. Clinical investigations and experiments have demonstrated that caffeine is a definite inducer of IUGR, as children who ingest caffeine-containing food or drinks are highly susceptible to adult obesity and h...
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Citations
... The mechanisms through which prenatal caffeine exposure may contribute to elevated BMI during childhood are unclear. Experimental studies in rodents as well as human association studies have also revealed that prenatal caffeine exposure is associated with lower birth weight and being small-for gestational-age, which have been associated with higher risk of child obesity [29][30][31] . It is plausible that modifications to the fetal environment (e.g., intrauterine growth restriction) 32 , induced metabolic dysfunction (e.g., hypothalamic-pituitaryadrenal axis function) 33 , and more indirect pathways (e.g., neural reward sensitivity) 34 may contribute to the development of greater BMI during childhood. ...
Objective: Though caffeine use during pregnancy is common, its longitudinal associations with child behavioral and physical health outcomes remain poorly understood. Here, we estimated associations between prenatal caffeine exposure, body mass index (BMI), and behavior as children enter adolescence.
Method: Longitudinal data and caregiver-reported prenatal caffeine exposure were obtained from the ongoing Adolescent Brain and Cognitive Development (ABCD) Study, which recruited 11,875 children aged 9-11 years at baseline from 21 sites across the United States starting June 1, 2016. Prenatal caffeine exposure was analyzed as a 4-level categorical variable, and further group contrasts were used to characterize "any exposure" and "daily exposure" groups. Outcomes included psychopathology characteristics in children, sleep problems, and BMI. Potentially confounding covariates included familial (e.g., income, familial psychopathology), pregnancy (e.g., prenatal substance exposure), and child (e.g., caffeine use) variables.
Results: Among 10,873 children (5,686 boys [52.3%]; mean [SD] age, 9.9 [0.6] years) with nonmissing prenatal caffeine exposure data, 6,560 (60%) were exposed to caffeine prenatally. Relative to no exposure, daily caffeine exposure was associated with higher child BMI (B=0.08; FDR-corrected p=0.02), but was not associated with child behavior. Those exposed to two or more cups of caffeine daily (n=1,028) had greater sleep problems than those with lower/no exposure (B>0.92; FDR-corrected p<0.04).
Conclusion: Daily prenatal caffeine exposure is associated with heightened childhood BMI, and when used multiple times a day greater sleep problems even after accounting for potential confounds. Whether this relationship is a consequence of prenatal caffeine exposure or its correlated factors remains unknown.
... Reports have suggested that intrauterine growth restriction and low birth weight may be accompanied by excessive weight gain after birth, 72 although our study found a difference only after 14 days of life. Moreover, studies have reported that caffeine consumption alters brain functions, including signaling that maintains homeostasis to regulate appetite and other metabolic processes, 73,74 corroborating with our results observed in the female offspring. Similar results were obtained by Li et al., 75 who showed that maternal caffeine consumption during pregnancy is associated with an increased risk of childhood obesity 40 and developmental deficits 43 with negative effects in adulthood behavior. ...
Caffeine is a widely consumed substance, and there is a discussion about its effects when ingested by women during
pregnancy and lactation. We aimed to identify the genotoxic
effects of caffeine in female mice that consumed it during
pregnancy and lactation periods and its consequences in their
offspring. Thirty-six couples of Swiss mice received water or
caffeine (0.3 and 1.0 mg/mL) treatment during pregnancy and
lactation. The male and female offspring were divided into 12
groups according to the treatment administered to the female
mice. Genotoxicity was assessed using the comet assay and
the micronucleus test. Both doses of caffeine showed genotoxic
effects in pregnant and lactating mice groups compared to
groups not administered caffeine. In relation to offspring, it
can be observed that females and males of the offspring had
low weight in early life. In both female and male offspring,
genotoxicity was detected in the blood, liver, and kidney tissues. Thus, from the present study, we can suggest that the
caffeine consumed by female mice during the periods of pregnancy and lactation led to genotoxic effects in their
offspring
... A decrease in 11β-HSD-2 may be related to the increased expression of 11β-hydroxysteroid dehydrogenase 1 (11β-HSD-1) and glucocorticoid receptor (GR) in the fetal hippocampus, eventually leading to the reduced corticotrophin-releasing hormone (CRH). Considering that the hippocampus is an important regulatory center of HPA axis, as well as the most sensitive and vulnerable neural target site for circulatory GC, PCE inhibited the development of fetal HPA axis and further retarded fetal development [15]. In the same year, in NCI-H295A cells, a CpG site demethylation at nt −682 of the steroidogenic acute regulatory protein (StAR) promoter was found after CAF treatment, which was maintained over 10 passages after terminating CAF treatment and induced long-term stimulation of StAR expression. ...
In this review, we discuss the recent knowledge regarding the epigenetic effects of coffee extract and the three essential active ingredients in coffee (caffeine, chlorogenic acid, and caffeic acid). As a popular beverage, coffee has many active ingredients which have a variety of biological functions such as insulin sensitization, improvement of sugar metabolism, antidiabetic properties, and liver protection. However, recent researches have shown that coffee is not only beneficial for human, but also bad, which may be due to its complex components. Studies suggest that coffee extract and its components can potentially impact gene expression via alteration of DNA methylation, histone modifications, and ncRNA expression; thus, exert long lasting impacts on the epigenome. More importantly, coffee consumption during pregnancy has been linked to multiple negative effects on offspring due to epigenetic modifications; on the other hand, it has also been linked to improvements in many diseases, including cancer. Therefore, understanding more about the epigenetic effects associated with coffee components is crucial to finding ways for improving human health.
... coupled to the fact that its metabolism is immature during embryonic and postnatal development, can lead to a high concentration of this compound in the body of these fetuses/neonates and compromise the correct development of different systems. In fact, there are a number of studies that relate the administration of high doses of caffeine during embryonic development in animal models with teratogenic effects (Tye et al. 1993;Sahir et al. 2000;Momoi et al. 2008;Li et al. 2012;Ma et al. 2012Ma et al. , 2014Tan et al. 2012;Xu et al. 2012). In humans, epidemiological surveys have shown an increased risk of low birth weight (Momoi et al. 2008;Sengpiel et al. 2013), fetal growth restriction (Klebanoff et al. 2002;Bracken et al. 2003;Bakker et al. 2010) and miscarriage as caffeine intake increases. ...
Ischemia is characterized by a transient, insufficient, or permanent interruption of blood flow to a tissue, which leads to an inadequate glucose and oxygen supply. The nervous tissue is highly active, and it closely depends on glucose and oxygen to satisfy its metabolic demand. Therefore, ischemic conditions promote cell death and lead to a secondary wave of cell damage that progressively spreads to the neighborhood areas, called penumbra. Brain ischemia is one of the main causes of deaths and summed with retinal ischemia comprises one of the principal reasons of disability. Although several studies have been performed to investigate the mechanisms of damage to find protective/preventive interventions, an effective treatment does not exist yet. Adenosine is a well-described neuromodulator in the central nervous system (CNS), and acts through four subtypes of G-protein-coupled receptors. Adenosine receptors, especially A1 and A2A receptors, are the main targets of caffeine in daily consumption doses. Accordingly, caffeine has been greatly studied in the context of CNS pathologies. In fact, adenosine system, as well as caffeine, is involved in neuroprotection effects in different pathological situations. Therefore, the present review focuses on the role of adenosine/caffeine in CNS, brain and retina, ischemic events.
... The 11β-HSD2 can reduce glucocorticoids from entering fetal circulation by inactivating glucocorticoids [15]. In our previous studies, through a series of animal experiments, we have established stable IUGR offspring rat models caused by prenatal xenobiotics exposure such as caffeine, nicotine, and ethanol and confirmed that prenatal xenobiotics exposure induced-IUGR was associated with a low expression level of placental 11β-HSD2 [10,16,17]. P-gp is one of the most abundantly expressed proteins of the ATP binding cassette efflux transporter family in the placentas. ...
... Epidemiological investigations have proved that prenatal caffeine exposure (PCE) can cause toxic effects of reproduction and fetal development, such as the increased risk of congenital malformations, premature delivery, spontaneous abortion, IUGR, and susceptibility to chronic diseases [21,22]. Our animal experiments also demonstrated that PCE could not only increase maternal glucocorticoid levels but also cause fetal overexposure to glucocorticoid by inhibiting placental 11β-HSD2, leading to the occurrence of IUGR and susceptibility to multiple chronic diseases in adult offspring [16,[23][24][25][26]. However, whether caffeine causes IUGR by affecting placental Pgp has not been reported yet. ...
... Previous studies in our laboratory have found that daily dose of caffeine exposure [20 mg/kg·d in rats, equivalent to 194 mg of caffeine per day for a 60 kg woman according to the dose conversion between humans and rats (1:6.17 )] can cause an increased rate of IUGR occurrence, dysplasia of multiple organs (including the hippocampus, adrenal gland, liver, bone), and susceptibility to multiple chronic diseases, such as nonalcoholic fatty liver, metabolic syndrome, and osteoarthritis, which are related to PCE-induced maternal glucocorticoid overexposure [16,[23][24][25][26]. In this study, by using the PCE-induced IUGR rat model, we analyzed the role of placental P-gp in mediating the IUGR occurrence and clarified its underlying mechanism. ...
Background
Prenatal adverse environments can cause fetal intrauterine growth retardation (IUGR) and higher susceptibility to multiple diseases after birth, related to multi-organ development programming changes mediated by intrauterine overexposure to maternal glucocorticoids. As a glucocorticoid barrier, P-glycoprotein (P-gp) is highly expressed in placental syncytiotrophoblasts; however, the effect of P-gp on the occurrence of IUGR remains unclear.
Methods
Human placenta and fetal cord blood samples of IUGR fetuses were collected, and the related indexes were detected. Pregnant Wistar rats were administered with 30 mg/kg·d (low dose) and 120 mg/kg·d (high dose) caffeine from gestational day (GD) 9 to 20 to construct the rat IUGR model. Pregnant mice were administered with caffeine (120 mg/kg·d) separately or combined with sodium ferulate (50 mg/kg·d) from gestational day GD 9 to 18 to confirm the intervention target on fetal weight loss caused by prenatal caffeine exposure (PCE). The fetal serum/placental corticosterone level, placental P-gp expression, and related indicator changes were analyzed. In vitro, primary human trophoblasts and BeWo cells were used to confirm the effect of caffeine on P-gp and its mechanism.
Results
The placental P-gp expression was significantly reduced, but the umbilical cord blood cortisol level was increased in clinical samples of the IUGR neonates, which were positively and negatively correlated with the neonatal birth weight, respectively. Meanwhile, in the PCE-induced IUGR rat model, the placental P-gp expression of IUGR rats was decreased while the corticosterone levels of the placentas/fetal blood were increased, which were positively and negatively correlated with the decreased placental/fetal weights, respectively. Combined with the PCE-induced IUGR rat model, in vitro caffeine-treated placental trophoblasts, we confirmed that caffeine decreased the histone acetylation and expression of P-gp via RYR/JNK/YB-1/P300 pathway, which inhibited placental and fetal development. We further demonstrated that P-gp inducer sodium ferulate could reverse the inhibitory effect of caffeine on the fetal body/placental weight. Finally, clinical specimens and other animal models of IUGR also confirmed that the JNK/YB-1 pathway is a co-regulatory mechanism of P-gp expression inhibition, among which the expression of YB-1 is the most stable. Therefore, we proposed that YB-1 could be used as the potential early warning target for the opening of the placental glucocorticoid barrier, the occurrence of IUGR, and the susceptibility of a variety of diseases.
Conclusions
This study, for the first time, clarified the critical role and epigenetic regulation mechanism of P-gp in mediating the opening mechanism of the placental glucocorticoid barrier, providing a novel idea for exploring the early warning, prevention, and treatment strategies of IUGR.
... Glucocorticoids are key hormones that modulate the growth and maturation of the fetus, and also participate in the occurrence of iuGr (34,35). it has been reported that multiple adverse factors during pregnancy, including maternal prenatal food restriction, smoking and alcohol consumption, may induce iuGr, and increased serum glucocorticoids levels are observed in those fetuses with adverse factors during pregnancy (36)(37)(38)(39)(40). our previous studies also revealed that the increased serum glucocorticoid level originated from the maternal blood, which could suppress the development of the HPa axis, thereby causing iuGr in the fetuses (39,41). in the present study, increased serum corT concentration was observed in the iuGr fetuses induced by PFr, along with decreased aVP, Gad65 and vGluT2 mrna expression levels, and an increased vGluT2/Gad65 ratio. Such changes were similar to the data from the adult male offspring, which indicated that the stimulated potential excitability of the hypothalamus may originate from the fetus. ...
Prenatal food restriction (PFR) induces dysfunction of the hypothalamic‑pituitary‑adrenal (HPA) axis in the adult offspring. The aim of the present study was to identify the underlying mechanism of this process. Pregnant rats were placed on a restricted diet between gestational day 11 and 21. The offspring were fed with a high‑fat diet and were subjected to unpredictable chronic stress (UCS) from postnatal week 17 to 20. A higher serum corticosterone (CORT) level was observed in the PFR fetuses. Although lower arginine vasopressin (AVP), hippocampal vesicular glutamate transporter 2 (vGLUT2) and glutamic acid decarboxylase 65 (GAD65) mRNA expression levels were detected in the hippocampi of PFR fetuses, the ratio of the mRNA expression levels of vGLUT2 and GAD65 was higher compared with that of the controls, which was accompanied by histopathological and ultrastructural abnormalities of both the hypothalamus and hippocampus. However, there were no marked changes in the hippocampal expression levels of glucocorticoids receptor (GR) and mineralocorticoids receptor (MR) or the ratio of MR/GR ratio. After the fetuses had matured, lower serum CORT and adrenocorticotropic hormone (ACTH) levels were observed in PFR rats without UCS when compared with the control. A higher rise rate of serum ACTH was also observed after UCS when compared with that in rats without UCS. Furthermore, the hypothalamic mRNA expression level of corticotrophin‑releasing hormone (CRH) was lower in PFR rats without UCS, while expression levels of CRH, AVP, GAD65 and vGLUT2 were enhanced after UCS when compared with the control, accompanied by an increased vGLUT2/GAD65 expression ratio. MR mRNA expression was lower, and GR mRNA expression was higher in the hippocampus of the PFR rats without UCS when compared with the control. However, the mRNA expression levels of both MR and GR in the PFR rats were higher compared with those of the control after UCS, which was accompanied histopathological changes in the dentate gyrus, cornu ammonis (CA1) and CA3 areas. In summary, it was suggested that PFR induced fetal alterations of the HPA axis manifesting as hypothalamic hyperexcitability and poor hippocampal feedback, which persisted to adulthood and affected the behavior of the rat offspring.
... However, we did not have available information on maternal BMI, weight or maternal weight gain during pregnancy, which could also be key variables, associated with our outcome measures. The vulnerability for a higher BMI with prenatal caffeine exposure may reflect epigenetic modifications in the hypothalamic-pituitary-adrenocortical axis that affect metabolism, perhaps via its antagonism of A 1 adenosine receptors, as suggested by preclinical studies (Buscariollo et al., 2014;Xu et al., 2012). Alternatively, it could also reflect the effects of prenatal caffeine in fat tissue via its antagonism of A 2A and A 2B receptors, which modulate fat metabolism and have been shown to counteract obesity (Gnad et al., 2014(Gnad et al., , 2020. ...
Background
Despite the widespread use of caffeine including consumption during pregnancy, the effect of prenatal caffeine exposure on child brain development and behavior is unclear.
Methods
To address this, we used data from the Adolescent Brain and Cognitive Development Study (n = 11,875 children aged 9–11 years from 22 sites across the United States). We explored the associations between prenatal caffeine exposure and various developmental outcomes including birth outcomes, physical health, behavior problems, cognition, substance use and brain structure in children, and evaluated dose effects.
Results
Among 9,978 children (4,745 females) who had valid data for prenatal caffeine exposure and whose mothers did not use drugs of abuse after knowing of pregnancy, 4,170 (41.79%) had no prenatal caffeine exposure, 2,292 (22.97%) had daily, 1,933 (19.37%) had weekly, and 1,583 (15.86%) had less than weekly exposures. Prenatal caffeine exposure including the widely recommended ‘safe’ dose was associated with greater externalizing problems, whereas greater BMI and soda consumption were only observed in children with high dose exposures (3+ per day). Notably, the effect size for association of externalizing problems with prenatal caffeine exposure was comparable with that reported for prenatal alcohol (The American Journal of Psychiatry, 177, 2020 and 1060) and prenatal cannabis (JAMA Psychiatry, 78, 2020 and 64) exposures from previous ABCD publications. Additionally, prenatal caffeine exposure was associated with brain structural changes that included greater posterior and lower frontal cortical thickness and altered parietooccipital sulcal depth.
Conclusions
The recommended ‘safe’ dose of caffeine during pregnancy should be carefully studied to assess whether the behavioral and brain correlates observed here are clinically relevant and determine whether it needs adjustment. Because of the high prevalence of caffeine use in the general population, studies on prenatal exposure to drugs of abuse should include prenatal caffeine use as a covariate.
... Caffeine is a neural stimulant and can penetrate the placental barrier and enter fetal circulation [52]. Caffeine can affect fetal neurological development which regulates appetite and metabolic processes [53,54]. In addition, prenatal caffeine exposure induces a lower level of fetal blood leptin, resulting in greater appetite and energy storage [55]. ...
Prenatal metabolomics profiles, providing measures of in utero nutritional and environmental exposures, may improve the prediction of childhood outcomes. We aimed to identify prenatal plasma metabolites associated with early childhood body mass index (BMI) trajectories and overweight/obesity risk in offspring.
This study included 450 African American mother-child pairs from the Conditions Affecting Neurocognitive Development and Learning in Early Childhood Study. An untargeted metabolomics analysis was performed on the mothers’ plasma samples collected during the second trimester. The children’s BMI-z-score trajectories from birth to age 4 [rising-high- (9.8%), moderate- (68.2%), and low-BMI (22.0%)] and overweight/obesity status at age 4 were the main outcomes. The least absolute shrinkage and selection operator (LASSO) was used to select the prenatal metabolites associated with childhood outcomes.
The mothers were 24.5 years old on average at recruitment, 76.4% having education less than 12 years and 80.0% with Medicaid or Medicare. In LASSO, seven and five prenatal metabolites were associated with the BMI-z-score trajectories and overweight/obese at age 4, respectively. These metabolites are mainly from/relevant to the pathways of steroid biosynthesis, amino acid metabolism, vitamin B complex, and xenobiotics metabolism (e.g., caffeine and nicotine). The odds ratios (95% CI) associated with a one SD increase in the prenatal metabolite risk scores (MRSs) constructed from the LASSO-selected metabolites were 2.97 (1.95–4.54) and 2.03 (1.54–2.67) for children being in the rising-high-BMI trajectory group and overweight/obesity at age 4, respectively. The MRSs significantly improved the risk prediction for childhood outcomes beyond traditional prenatal risk factors. The increase (95% CI) in the area under the receiver operating characteristic curves were 0.10 (0.03–0.18) and 0.07 (0.02–0.12) for the rising-high-BMI trajectory (P = 0.005) and overweight/obesity at age 4 (P = 0.007), respectively.
Prenatal metabolomics profiles advanced prediction of early childhood growth trajectories and obesity risk in offspring.
... To verify the expression differences among different genders, the fold change of the control group of female placenta was normalized to "1". A previous study has confirmed that the expression of Hsd11b2 mRNA and protein was significantly reduced after PCE in rat placenta [25]. Another study declared that the expression of HSD11B2 was decreased by caffeine in a dose-dependent way in primary human trophoblast cells [26]. ...
The selection of suitable reference genes (RGs), especially the identification of the proper combination of RGs is the key to obtain reliable results of gene expression for quantitative real-time polymerase chain reaction (qRT-PCR). To date, there is no relevant study dealing with the stability of RGs in rat placenta. In this study, the geNorm, NormFinder, and BestKeeper software were used to analyze the expression stability of the candidate RGs in placenta under physiological and prenatal caffeine exposure (PCE) conditions. The expression of Tbp, Gapdh and Ywhaz in female and Polr2a, Gapdh and Ywhaz in male placenta were highly stable under physiological conditions, and there was no obvious gender difference. We further found that two RGs were sufficient for reliable normalization in female and male placenta and the combination of Ywhaz and Gapdh was the most suitable compound RGs under physiological conditions. Under PCE conditions, Ywhaz, Gapdh and Polr2a were the most stable genes in both female and male placenta. Among them, Ywhaz and Gapdh were chosen as the best paring. Finally, selected RGs were employed for normalization of the expression of a clear target gene and the results of standardization supported our choice. In conclusion, our study confirmed that Ywhaz/Gapdh combination was the most suitable RGs in rat placenta under physiological and PCE pathological conditions and provided a theoretical and experimental basis for physiological and pathological research of the rat placenta.
... Furthermore, it has been indicated that epigenetic alterations might act as more stable and reliable molecular markers of early-life events than the expression of the target genes [30]. Our previous studies have confirmed the "excessive maternal glucocorticoid" phenomenon in IUGR offspring with prenatal xenobiotic exposure, which might trigger the susceptibility to osteoarthritis of these IUGR offspring [13,31,32]. Accordingly, we speculated that fetal-originated osteoarthritis might be attributed to the alterations in epigenetic programming induced by maternal glucocorticoid overexposure. ...
Background
Epidemiological investigation and our previous reports indicated that osteoarthritis had a fetal origin and was closely associated with intrauterine growth retardation (IUGR). Human Wharton’s jelly-derived mesenchymal stem cells (WJ-MSCs) could be programmable to “remember” early-life stimuli. Here, we aimed to explore an early-warning biomarker of fetal-originated adult osteoarthritis in the WJ-MSCs.
Methods
Firstly, two kinds of WJ-MSCs were applied to evaluate their chondrogenic potential in vitro through inducing chondrogenic differentiation as the first step of our strategy, one from newborns with IUGR and the other from normal newborns but treated with excessive cortisol during differentiation to simulate the excessive maternal glucocorticoid in the IUGR newborns. As for the second step of the strategy, the differentiated WJ-MSCs were treated with interleukin 1β (IL-1β) to mimic the susceptibility to osteoarthritis. Then, the expression and histone acetylation levels of transforming growth factor β (TGFβ) signaling pathway and the expression of histone deacetylases (HDACs) were quantified, with or without cortisol receptor inhibitor RU486, or HDAC4 inhibitor LMK235. Secondly, the histone acetylation and expression levels of TGFβRI were further detected in rat cartilage and human umbilical cord from IUGR individuals.
Results
Glycosaminoglycan content and the expression levels of chondrogenic genes were decreased in the WJ-MSCs from IUGR, and the expression levels of chondrogenic genes were further reduced after IL-1β treatment, while the expression levels of catabolic factors were increased. Then, serum cortisol level from IUGR individuals was found increased, and similar changes were observed in normal WJ-MSCs treated with excessive cortisol. Moreover, the decreased histone 3 lysine 9 acetylation (H3K9ac) level of TGFβRI and its expression were observed in IUGR-derived WJ-MSCs and normal WJ-MSCs treated with excessive cortisol, which could be abolished by RU486 and LMK235. At last, the decreased H3K9ac level of TGFβRI and its expression were further confirmed in the cartilage of IUGR rat offspring and human umbilical cords from IUGR newborn.
Conclusions
WJ-MSCs from IUGR individuals displayed a poor capacity of chondrogenic differentiation and an increased susceptibility to osteoarthritis-like phenotype, which was attributed to the decreased H3K9ac level of TGFβRI and its expression induced by high cortisol through GR/HDAC4. The H3K9ac of TGFβRI in human umbilical cord could be a potential early-warning biomarker for predicting neonatal cartilage dysplasia and osteoarthritis susceptibility.
