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RAPID COMMUNICATION
Chronic maternal stress inhibits the capacity to up-regulate
placental 11-hydroxysteroid dehydrogenase type 2 activity
Leonie A M Welberg, K V Thrivikraman and Paul M Plotsky
Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, WMB suite 4000, 101 Woodruff Cir, Atlanta, Georgia 30322, USA
(Requests for offprints should be addressed to L A M Welberg; Email: leonie.welberg@emory.edu)
Abstract
This study investigated the effects of acute and chronic
restraint stress during the third week of pregnancy on
placental 11-hydroxysteroid dehydrogenase type 2 (11-
HSD2) activity in rats. Acute exposure to stress on
gestational day 20 immediately up-regulated placental
11-HSD2 activity by 160%, while chronic stress from
day 14 to day 19 of pregnancy did not significantly alter
basal 11-HSD2 activity. However, the latter reduced the
capacity to up-regulate placental 11-HSD2 activity in
the face of an acute stressor by 90%. Thus, immediate
up-regulation of 11-HSD2, the feto-placental barrier to
maternal corticosteroids, may protect the fetus against
stress-induced high levels of maternal corticosteroids,
but exposure to chronic stress greatly diminishes this
protection.
Journal of Endocrinology (2005) 186, R7–R12
Introduction
Animal studies of prenatal stress, environmental enrich-
ment and maternal separation have shown that events early
in life can alter the set points of the hypothalamic–
pituitary–adrenal (HPA) and corticotropin-releasing factor
(CRF) systems with permanent behavioural and endocrine
consequences (Ladd et al. 2000, Welberg & Seckl 2001).
The mechanisms underlying these programming effects
are still unknown, but exposure to elevated levels of
glucocorticoids during a time of rapid brain development
may be a major factor (Welberg & Seckl 2001). Indeed,
exposing pregnant rats to the synthetic glucocorticoid
dexamethasone results in offspring with a hyperactive
HPA axis and elevated CRF expression in the amygdala
(Welberg et al. 2001). In addition, stress-induced eleva-
tions in maternal glucocorticoid levels have been shown to
underlie at least some of the effects of prenatal stress
(Barbazanges et al. 1996). However, access of maternal
corticosterone to the fetus is regulated, in part, by the
high-affinity, high-efficiency type 2 isoform of the placen-
tal enzyme 11-hydroxysteroid dehydrogenase (11-
HSD2), that rapidly converts corticosterone (in rats) and
cortisol (in humans) into their inactive metabolites (11-
dehydrocorticosterone and cortisone respectively) (Seckl
& Meaney 2004). Animal studies have shown that
pharmacological inhibition of placental 11-HSD2 during
pregnancy results in offspring with HPA hyperactivity
and an anxious phenotype with elevated CRF expression
in the amygdala (Welberg et al. 2000). Placental 11-
HSD2 activity varies significantly between individuals, in
both rats (Benediktsson et al. 1993) and humans (Stewart
et al. 1995). Since pregnant dams produce far more cortico-
sterone than fetuses, moderate decreases in 11-HSD2
activity would result in relatively large increases in
corticosterone reaching the fetal blood stream. Thus, in
order to understand the programming effects of endogen-
ous maternal corticosteroids it is crucial to understand the
regulation of their access to the fetus.
Few studies have addressed the in vivo regulation of
placental 11-HSD2, but data from recent in vitro studies
suggest that factors associated with stress may play a role:
Catecholamines reduced 11-HSD2 gene transcription
via activation of alpha-adrenergic receptors (Sarkar et al.
2001), while the synthetic glucocorticoid dexamethasone
increased 11-HSD2 activity and gene transcription (van
Beek et al. 2004) in cultured human trophoblasts. The
present study aimed to investigate the effects of acute and
chronic stress during the third week of pregnancy on
placental 11-HSD2 activity in rats.
Materials and Methods
Animals
Experiments were performed in accordance with NIH
Guidelines for the care and use of laboratory animals and
R7
Journal of Endocrinology (2005) 186, R7–R12
0022–0795/05/0186–R7 2005 Society for Endocrinology Printed in Great Britain
DOI: 10.1677/joe.1.06374
Online version via http://www.endocrinology-journals.org
all protocols were approved by the Emory University
Institutional Animal Care and Use Committee. Timed-
pregnant Long–Evans rats (Charles River Laboratories,
Inc, Wilmington, MA, USA) arrived in our facilities on
the morning of day 13 of pregnancy (day 1 being the day
after mating occurred). All animals used in Experiment 1
(see below) arrived in the same transport, as did all animals
used in Experiment 2. Rats were housed in standard (W
LH: 203215 cm) cages with corn-cob bedding.
Food and water were available ad libitum, and animals were
maintained on a 12:12 light:dark cycle (lights on 0700 h).
Experimental protocol
Experiment 1 was performed to establish whether acute
or chronic stress affected placental 11-HSD2 activity.
Pregnant rats were randomly assigned to one of three
treatment groups: (1) rats in the chronic-stress group (CS,
n=7) were restrained in flat-bottom rodent restrainers
(approximately 825 cm) for 45 min on day 14 of preg-
nancy, and then twice daily for 30 or 45 min, once in the
morning and once in the afternoon, until day 19 of
pregnancy. On day 20 of pregnancy CS rats were deeply
anesthetized with isoflurane, immediately after which
caesarean section was performed; (2) rats in the acute-stress
group (AS, n=6) were left undisturbed until day 20 of
pregnancy. On that day, AS rats were restrained for
45 min and immediately afterwards anesthetized with
isoflurane and subjected to caesarean surgery; (3) a control
group of unstressed rats (NS, n=7) was left undisturbed
until the morning of day 20 of pregnancy, when NS rats
were also anesthetized and subjected to caesarean section.
Experiment 2, carried out separately from Experiment 1,
was performed to establish whether chronic stress expo-
sure altered placental 11-HSD2 activity in response to an
acute stressor. Here, pregnant rats were weighed and then
assigned to one of two groups: (1) rats in the chronic +
acute stress group (CAS, n=6) were restrained from day
14 of pregnancy onwards as the CS rats in Experiment 1
described above, but underwent a final, acute, 45 min
restraint session on day 20 of pregnancy immediately prior
to anaesthesia, weighing and caesarean section; (2) a
control group of unstressed rats (NS, n=6) was left
undisturbed until the morning of day 20 of pregnancy
when they also underwent anaesthesia, weighing and
caesarean section.
Sample collection In both experiments, dams were
sacrificed on day 20 of pregnancy between 0900 and
1100 h. Once rats were anesthetized, the abdominal cavity
was opened, the uterus exposed and two (Experiment 1)
or four (Experiment 2) feto-placental units were quickly
dissected. Each feto-placental unit was weighed (Experi-
ment 2 only), after which fetus and placenta were separ-
ated. The placenta was then rapidly frozen on powdered
dry ice and stored at 70 C until further processing.
Tissue Processing To determine the effect of maternal
stress on placental 11-HSD2 activity, in both Experiment
1 and 2 two placentas per pregnancy were homogenized
together, after which enzyme activity was measured as
described below, yielding one value per pregnancy. To
determine the correlation between 11-HSD2 activity
and feto-placental weight, the additional two placentas per
pregnancy obtained in Experiment 2 were weighed and
then processed individually for enzyme activity measure-
ments. Placentas were homogenized using a Powergen
Model 125 homogenizer (Fisher Scientific, Atlanta, GA,
USA) in 1 ml buffer (1 PBS containing 0·25 M sucrose)
per placenta. Protein concentrations of the samples
were determined using a BCA protein assay kit (Pierce,
Rockford, IL, USA).
11-HSD2 assay Enzyme activity was estimated using
a radiometric conversion assay according to protocols
described previously (Benediktsson et al. 1993), with small
variations. Briefly, 1 mg/ml protein of placental homoge-
nate was incubated with 500 nM NAD and 12 nM of
[1,2,6,7]
3
H-corticosterone (specific activity, 75·6 Ci/
mmol) in a final volume of 500 µl 1X PBS containing
0·25 M sucrose at 37 C for 30 min. The reaction was
terminated by the addition of 2 ml ethyl acetate (Fisher
Scientific). Steroids were extracted using ethyl acetate and
separated by means of thin-layer chromatography using
chloroform-ethanol (92:8) as solvent (Ethanol: Fisher
Scientific). Spots corresponding to corticosterone and
11-dehydrocorticosterone were visualized under ultra
violet light, cut out, transferred to vials containing liquid
scintillant, and their radioactivity was measured in a
beta-counter (1209 Rackbeta; LKB/Wallac/Perkin
Elmer, Boston, MA, USA). All samples were assayed in
duplicate. Blank controls were included in all assays, as
well as samples assayed as described above but with
addition of 40 µM carbenoxolone, an inhibitor of 11-
HSD. Activity of 11-HSD2 in each sample was estimated
by calculating the fractions of
3
H-dehydrocorticosterone
and
3
H-corticosterone (NEN/Perkin Elmer). Unless
otherwise specified, all reagents obtained from Sigma.
Data analysis Conversion levels are expressed as a
percentage of (unstressed) control values. Data from
Experiment 1 were analyzed using one-way ANOVA.
When the overall response was significant, post-hoc com-
parisons were performed using the Tukey HSD test. Data
from Experiment 2 were analyzed using unpaired t-tests.
Significance was set at P< 0·05.
Results
Experiment 1
Analysis of variance on conversion levels revealed a
significant effect of maternal stress on placental 11-HSD2
L A M WELBERG and others · Maternal stress and placental 11-HSD2 activityR8
www.endocrinology-journals.orgJournal of Endocrinology (2005) 186, R7–R12
activity (F=19·57, P< 0·0001). Post-hoc analysis showed
that acute stress increased 11-HSD2 activity by 160%
compared with activity in unstressed pregnant rats
(P< 0·0005), and by 84% compared with activity in
chronically-stressed pregnant rats (P< 0·001). Chronic
stress did not significantly affect placental 11-HSD2
activity (P=0·26) 16 h after the last exposure to stress
(Figure 1).
Experiment 2
As shown in Table 1, NS and CAS dams had similar body
weights on day 13 and day 20 of pregnancy, and their
percentage weight gain was not significantly different.
CAS reduced weights of whole feto-placental units on
gestational day 20, but not placental weights (Table 1).
A t-test showed that combined chronic and acute stress
increased placental 11-HSD2 activity by 16% compared
with activity in placentas from unstressed pregnancies
(t=2·33, P< 0·05) (Figure 2).
Correlations between placental 11-HSD2 activity and
weights of the feto-placental units as measured on gesta-
tional day 20 are shown in Table 2. Enzyme activity
correlated negatively with feto-placental weight (Figure 3)
and with frozen placental weight, although only the
Figure 1 Effect of acute or chronic exposure to stress during
pregnancy on placental 11-HSD2 activity. Stress took place
between days 14 and 20 of pregnancy; feto-placental units were
harvested on day 20 of gestation. NS=no stress (n=7); AS=acute
stress (n=6); CS=chronic stress (n=7); **P< 0·001; ***P< 0·0005
Table 1 Body weight gain and feto-placental weights in unstressed
dams (NS, n=6) and in dams exposed to chronic + acute stress
(CAS, n=6). Stress took place between days 14 and 20 of
pregnancy, feto-placental units of NS (n=23) and CAS (n=24)
pregnancies were harvested on day 20 of pregnancy. Frozen
placental weights were also measured in NS (n=12) and CAS
(n=12) pregnancies
NS CAS P-value
Body weight GD13 (g) 2608 2757 0·17
Body weight GD20 (g) 29810 3198 0·16
Weight gain (% start weight) 17·30·9 16·01·4 0·45
Feto-placental weight (g) 2·730·04 2·620·03 0·03*
Placental weight (mg) 42816 43119 0·90
NB: One feto-placental unit in the NS group was not weighted. *denotes a
significant difference. GD; Gestational day.
Figure 2 Effect of exposure to combined chronic and acute
exposure to stress during pregnancy on placental 11-HSD2
activity. Stress took place between days 14 and 20 of pregnancy;
feto-placental units were harvested on day 20 of gestation.
NS=no stress (n=6); CAS=chronic+acute stress (n=6); *P< 0·05
Table 2 Correlations (R-values) between placental 11-HSD2
activity and weights of feto-placental units. Stress took place
between days 14 and 20 of pregnancy; feto-placental units were
harvested on day 20 of gestation
Feto-placental weight Placental weight
All units (n=24) 0·47* 0·31
Unstressed (NS, n=12) 0·31 0·31
Stressed (CAS, n=12) 0·61* 0·57
*correlation significant at P< 0·05.
Figure 3 Correlation between feto-placental weight and placental
11-HSD2 activity. Feto-placental units were harvested on
gestational day 20 from unstressed (white circles, n=12) and CAS
pregnancies (black circles, n=12). R=-0·46, P=0·02.
Maternal stress and placental 11-HSD2 activity · L A M WELBERG and others R9
www.endocrinology-journals.org Journal of Endocrinology (2005) 186, R7–R12
former reached statistical significance. These correlations
disappeared when only values from unstressed pregnancies
were taken into account, but became stronger when
considering only values from stressed pregnancies (Table 2).
Discussion
This is, to our knowledge, the first study that assessed
placental 11-HSD2 activity in response to maternal
stress. Placental 11-HSD2 is thought to act as a barrier
against maternal glucocorticoids and thus to protect the
fetus from potential harmful effects that the elevated levels
of these steroids can exert during development (Seckl &
Meaney 2004). The finding that placental 11-HSD2
activity increased in response to an acute stressor is
important since it shows that plasma corticosteroids pro-
duced by the dam in response to a single stressor are not
necessarily harmful to the fetus, provided that enzyme
activity is high enough to ‘inactivate’ them. Importantly,
however, the present study also showed that the capacity
to adapt placental 11-HSD2 activity in response to an
acute stressor was greatly reduced by previous exposure to
chronic stress.
In the present study CAS reduced feto-placental weight
on day 20 of gestation. Intrauterine growth retardation is a
common finding in prenatal stress studies (Patin et al.
2002, Lesage et al. 2004), as well as after administration of
synthetic glucocorticoids during pregnancy (Welberg et al.
2001). This indicates that stress-induced glucocorticoids
indeed reached the fetus in this study. Moreover, feto-
placental weight correlated negatively with 11-HSD2
activity, especially in the CAS group, suggesting that the
units with the largest growth retardation were exposed
to the highest levels of maternal corticosterone and up-
regulated their placental 11-HSD2 activity in an attempt
to prevent more corticosterone entering the fetal blood.
CAS-induced reduction in feto-placental weight
(around 100 mg) cannot be accounted for by the parallel
reduction in placental weight, as NS and CAS placentas
differed only by about 3 mg. Thus, although fetal weights
were not measured, it is likely that CAS reduced both
placental and fetal weights while slightly increasing
placental 11-HSD2 activity.
The combination of increased placental 11-HSD2
activity and decreased in utero growth appears to partly
contradict an earlier report in which placental 11-HSD2
activity correlated positively with birth weight and nega-
tively with placental weight (Benediktsson et al. 1993), but
several explanations are possible. In the present study, the
correlation between feto-placental weight and enzyme
activity is not necessarily a causal one, as the increased
placental 11-HSD2 activity in CAS pregnancies probably
resulted from both the acute stress exposure immediately
before harvesting and previous exposures, while the
placental (and likely, fetal) growth retardation in CAS was
due to the chronicity of the stressor. In contrast, in
Benediktsson et al. (1993), fetuses and placentas were
taken from unstressed pregnancies, thus linking ‘basal’
placental 11-HSD2 activity with birth weight. This
correlation probably does describe a causal relationship, as
artificially inhibiting placental 11-HSD2 activity without
stressing the pregnant dams also reduced intrauterine
growth (Welberg et al. 2000), as did chronic exposure
during pregnancy to synthetic glucocorticoids, which are
not metabolized by 11-HSD2 (Welberg et al. 2001).
Another important difference between the present
study and that by Benediktsson et al. (1993) is that the
latter measured body weight at term, whereas here, feto-
placental weights were recorded on day 20 of gestation,
three days before expected delivery. Crucially, both
expression and activity of placental 11-HSD2 drop dra-
matically between gestational days 20 and 22 (Burton et al.
1996, Waddell et al. 1998) in the labyrinth zone of the
placenta, the site of maternal–fetal transfer, and this will
likely change existing correlations between weight and
enzyme activity on those days. Taken together, it is likely
that in the present study CAS-induced maternal cortico-
sterone reached the fetal blood stream in spite of increased
enzyme activity.
An alternative explanation for our finding that chronic
stress reduced the capacity to respond the acute stress with
an up-regulation of placental 11-HSD2 activity may be
that repetition of the restraint procedure caused it no
longer to be perceived as stressful. This interpretation
would be supported by the fact that CAS dams did not
show reduced weight gain during pregnancy, in contrast
to previous findings (Darnaudery et al. 2004). Since
maternal plasma corticosterone was not measured, it is
impossible to verify the stressfulness of repeated exposure
to restraint in this study. However, other studies have
shown that repeated restraint during pregnancy reliably
elevated maternal plasma corticosterone levels (Ward &
Weisz 1984, Barbazanges et al. 1996, Weinstock 2005)
and repeated restraint has been used many times as a
prenatal stressor with long-term effects on the offspring
(Barbazanges et al. 1996, Lesage et al. 2004). In addition,
as mentioned before, feto-placental weights from CAS
pregnancies were smaller than those from unstressed
pregnancies, confirming the common finding of fetal
growth retardation in prenatal stress paradigms (Patin et al.
2002, Lesage et al. 2004). It is important to note that dams
used in the present study arrived in our facilities on day 12
of pregnancy, and an effect of the stress of the transporta-
tion on basal placental 11-HSD2 activity or its response
to chronic or acute stress cannot be ruled out.
Although no other studies have investigated regulation
of placental 11-HSD2 by stress per se, it has been shown
that its gene expression in human trophoblast cells is
rapidly inhibited by catecholamines via activation of alpha-
adrenergic receptors (Sarkar et al. 2001). Moreover,
glucocorticoids can both up- and downregulate placental
L A M WELBERG and others · Maternal stress and placental 11-HSD2 activityR10
www.endocrinology-journals.orgJournal of Endocrinology (2005) 186, R7–R12
11-HSD2 mRNA expression, depending on species,
timing and mode of administration (Kerzner et al. 2002,
Ma et al. 2003, van Beek et al. 2004). Another study
reported a reduction in ovine placental 11-HSD2 activity
in response to chronically elevated glucocorticoid levels
(Clarke et al. 2002). Importantly, none of the above studies
investigated immediate regulation of placental 11-HSD2
activity in response to glucocorticoids, although this pre-
sumably would be the most efficient way to inactivate
stress-induced corticosteroids from maternal blood.
A recent investigation showed that activity of the renal
11-HSD2 enzyme, which is identical to that in the
placenta, is up-regulated within at least two hours (the
earliest time point studied) by corticosterone injections,
but also by stress in adrenalectomized rats (Zallocchi et al.
2004). This indicates that 11-HSD2 activity can be
regulated by adrenal steroids as well as by extra-adrenal
factors, although the exact mechanism remains to be
determined. Thus, the capacity of placental 11-HSD2
activity to rapidly increase in response to stress in combi-
nation with an attenuated maternal HPA reactivity during
pregnancy (Neumann et al. 1998) may function to control
access of corticosteroids to the fetal blood stream, ensuring
the proper level of glucocorticoids necessary for normal
growth and maturation.
In conclusion, this study showed that immediate up-
regulation of 11-HSD2, the feto-placental barrier to
maternal corticosteroids, may protect the fetus against
stress-induced elevations of maternal corticosteroids,
but exposure to chronic stress greatly diminishes this
protection.
Funding
This work was supported by a Young Investigator Award
from the National Alliance for Research on Schizophrenia
and Depression (LAMW). The authors declare that they
have no conflict of interest that would preclude their
impartiality of this work.
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Received 15 June 2005
Accepted 27 July 2005
Made available online as an
Accepted Preprint 27 July 2005
L A M WELBERG and others · Maternal stress and placental 11-HSD2 activityR12
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