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Laboratoire de Neuroendocrinologie du Développement, UPRES-EA 2701, Université de Lille 1, 59655 Villeneuve d’Ascq, France; INSERM, U-457 (B.Bl., B.Br.), 75019 Paris; and INSERM, U-501 (M.G.), 13916 Marseilles, France
Address all correspondence and requests for reprints to: Dr. J. Lesage, Laboratoire de Neuroendocrinologie du Développement, UPRES-EA 2701, Université de Lille 1, Bât. SN4, 59655 Villeneuve d’Ascq, France. E-mail: Jean.Lesage{at}pop.univ-lille1.fr
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Introduction |
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Such effects of maternal malnutrition in offspring could be related to disturbances in the maternal and/or fetal hormonal environment. Of particular interest, this is the case for glucocorticoids. Indeed, in humans, maternal undernutrition increases cortisol plasma levels in both mothers (9) and growth-retarded fetuses (10). Moreover, some studies have shown that exposing rats in utero to high levels of dexamethasone reduced birth weight and caused both permanent hypertension and hyperglycemia in the adult offspring (11, 12). On the other hand, a deficiency in placental 11ß-hydroxysteroid dehydrogenase type 2 (11ßHSD2), which converts physiological glucocorticoids to inactive 11-keto products (13, 14), has been reported in babies with reduced body weight at birth (15). Thus, low placental 11ßHSD2 activity and consequent exposure of fetuses to high levels of glucocorticoids from maternal origin could lead to disturbances of the intrauterine development.
However, there is a lack of direct proof of fetal overexposure to high levels of glucocorticoids when pregnant females are subjected to undernutrition. Therefore, as we previously reported that increased circulating glucocorticoids in the mother during late gestation induced inhibition of the hypothalamo-pituitary adrenal (HPA) axis in pups at birth (16, 17), our first aim was to investigate in rats the HPA axis activity in both mothers and fetuses in response to a 50% food restriction (FR50) during the last week of gestation [from embryonic day 14 (E14) to E21], as well as the placental 11ßHSD2 expression at term. The second purpose of this study was to check whether putative disturbances of both fetal growth and the HPA axis in pups from mothers exposed to FR50 are due to maternal hypersecretion of corticosterone (B) by using mothers in which the plasma B level was maintained at basal levels by adrenalectomy and B supply.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Animal use accreditation by the French Ministry of Agriculture (no. 04860) has been granted to our laboratory for experimentation with rats.
Adrenalectomy and substitutive treatment
On day 13 of gestation, pregnant females were weighed and
assigned to one of the three following experimental groups (n =
8–12 animals/group) of equal average body weight: intact,
adrenalectomized (ADX), and sham-adrenalectomized (sham) females. On
day 14 of gestation, some females were either ADX or sham operated
between 0900–1200 h under ether anesthesia via the dorsal approach.
ADX females were then implanted sc with a 100-mg B pellet (mixture of
50% B and 50% cholesterol), which has been reported to provide stable
and basal levels of B (18). ADX mothers were given saline
(0.9% NaCl) as drinking water. Intact females were left undisturbed in
their home cage.
Feeding regimens
On day 14 of gestation, pregnant females (intact, ADX, and sham)
were subjected to specific feeding regimens until day 21 of pregnancy
(E21). Some of them were fed ad libitum (control), and the
others (FR50) were fed daily with 12 g commercial rat chow, which
represents about 50% of the daily intake of pregnant intact dams, from
E14–E21. The pregnant females exposed to undernutrition were fed every
day at 1800 h to allow food intake at the usual time (night). Tap
water was always available ad libitum. Pregnant females were
subsequently weighed on E15, E17, and E19.
Blood sampling
On days E13, E15, E17, and E19, just before weighing the
pregnant females, a blood sample (
250 µl) was taken from the tail
vein between 1000–1200 h to determine plasma B levels. All blood
samples were collected in prechilled tubes containing EDTA (20 µl of
a 5% solution), gently shaken, and centrifuged at 4000 rpm for 10 min
at 4 C. Aliquots of the supernatants were stored at -30 C until
assayed.
Decapitation, plasma, and tissue collections
Pregnant females at term (E21) were rapidly weighed and killed
by decapitation between 1000–1200 h. Each litter usually contained
between 8–12 fetuses, which were collected by cesarean section and
immediately killed by decapitation or kept at 25 C in a humidified
atmosphere for 120 min before being killed. Pups were rapidly weighed
just before death, and sex was determined by examination of the
genitals. For each litter, only a limited number of pups was used for
each studied parameter to avoid possible physiological variations
between litters.
Trunk blood samples of mothers and littermate fetuses were collected after decapitation and put in polyethylene tubes prerinsed with EDTA. The blood samples were centrifuged at 4000 rpm for 10 min at 4 C. Plasma samples were kept at -30 C until ACTH and corticosterone assays and corticosteroid-binding globulin (CBG) binding capacity determination. In newborn males, the plasma testosterone concentration was also measured.
Adrenals of the mothers as well as adrenals, thymus, testicles, and liver of the pups were quickly removed and weighed.
For in situ hybridization studies, entire heads of newborns and placentas were immediately frozen on dry ice and stored at -70 C until sectioning.
In situ hybridization
Sections of the placenta (12 µm) as well as coronal sections
of the head through the hypothalamus, the hippocampus, and the
pituitary gland were made with a cryostat at -20 C. The sections were
mounted onto twice gelatin-coated slides, dried on a slide warmer, and
kept at -70 C.
In situ hybridizations were performed as previously described (17) with slight modifications. The sections were warmed at room temperature and fixed in 4% formaldehyde in PBS (Dulbecco A, Oxoid, Dardilly, France), pH 7.2, for 5 min. After two washes in PBS, they were placed in 0.25% acetic anhydride in 0.1 M triethanolamine/0.9% NaCl, pH 8, for 10 min and delipided in ethanol and chloroform. Sections were hybridized for 16 h at 56 C in 50 µl of a mixture containing 10 mM Tris (pH 7.4), 1 mM EDTA, 600 mM NaCl, 50% formamide (vol/vol), 10% dextran sulfate (wt/vol), 25 µl/ml yeast transfer RNA, 1 x Denhardt’s solution, 0.1 M dithiothreitol, and 1.5 x 106 dpm radioactive probes under a glass coverslip. All subsequent steps were performed at room temperature unless otherwise specified. Coverslips were removed in 2 x SSC (1 x SSC is 0.15 M NaCl and 0.015 M sodium citrate, pH 7.2). The sections were washed in 2 x SSC for 30 min, treated with ribonuclease A (10 µg/ml in 2 x SSC) for 30 min at 37 C, and subsequently washed in 1 x SSC/10 mM ß-mercaptoethanol (ß-ME) twice for 10 min each time, in 0.5 SSC/10 mM ß-ME for 10 min, in 0.1 SSC/10 mM ß-ME for 10 min, in 0.1 SSC/10 mM ß-ME twice for 30 min each time at 65 C, and finally in 0.1 SSC/10 mM ß-ME for 10 min. The sections were dehydrated in a 70% ethanol solution and exposed to x-ray film (Biomax-MR, Kodak, Le Pontet, France), concomitantly with radioactive brain paste standards, for 1 h to 15 days to quantify the hybridization signal on the film autoradiograms. For microphotography, some sections (only for corticoliberin hybridization) were dipped in nuclear emulsion (1:2 in water, K5, Illford, Saint-Priest, France).
The corticoliberin probe was a 770-bp BamHI fragment of the rat corticoliberin gene (19) subcloned into pGem3 (supplied by Dr. L. Bain, University of Michigan, Ann Arbor, MI) and linearized with HindIII (antisense probe). The POMC probe was a 397-bp fragment of the rat POMC gene (20) subcloned into pSP64 and linearized with BamHI (antisense probe). The 11ßHSD2 probe was a 561-bp fragment of the 11ßHSD2 gene (21) subcloned into PCR-Script and linearized with NotI (antisense probe) or BamHI (sense probe). The mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) probes were, respectively, 513- and 674-bp fragments of rat complementary DNA clones encoding the 3'-regions of MR and GR messenger RNAs (mRNAs), subcloned, respectively, into pGEM4 and pGEM3 (supplied by Dr. J. Seckl, University of Edinburgh, Edinburgh, UK) and linearized respectively with HindIII and AvaI (antisense probes). Riboprobes were labeled using [35S]UTP (1300 Ci/mmol; NEN Life Science Products, Paris, France) and synthesized according to the previously detailed procedure (22). Controls included hybridization with sense probes; no specific hybridization signals were observed in these conditions.
Quantification of the hybridization signal
Four sections from each animals were analyzed. Hybridization
signals were quantified on the film autoradiograms. The optical density
of the hybridized signal was measured using a Biocom 200 (Biocom, Les
Ulis, France) image analysis system. For MR hybridization, optical
densities were measured in hippocampal CA1 and CA2/CA3 areas. For GR
hybridization, optical densities were measured in whole hippocampus
(CA1, CA2, CA3), because at this early postnatal stage it was difficult
to analyze all hippocampal subregions. Optical densities were converted
to disintegrations per min/mm2 tissue using the
radioactive brain paste standards according to the method of Young
et al. (23).
RIAs
B assay in plasma samples was preceded by extraction in
ethylacetate after delipidation in isooctane. The percent recovery of a
known amount of B was over 95%. B levels were determined by RIA, using
a highly specific B antiserum (UCB-Bioproducts, France), as
previously described (24), with a detection threshold of 1
ng/ml. The intra- and interassay variations were, respectively, 2.4%
and 4.4%.
ACTH levels were measured in unextracted plasma by RIA using an ACTH commercial kit (ACTHK-PR, Cis Bio International, France). The characteristics of the antiserum have been previously reported (25). The sensitivity of the assay was 10 pg/ml, and the intra- and interassay variations were, respectively, 4.3% and 11.7%.
Measurement of plasma CBG binding capacity
A modification of the method described by Hammond and
Lähteenmäki (26) was used. Briefly, to clean
plasma samples of endogenous B, plasma aliquots of 10 µl (mothers) or
60 µl (newborns) were added to, respectively, 1 or 1.2 ml
dextran-coated charcoal (DCC) suspension (0.125 g dextran T70 and
1.25 g Norit charcoal in 500 ml 0.05 M PBS containing
0.1% gelatin, pH 7.4) for 30 min at room temperature. The tubes were
then centrifuged at 4000 rpm for 10 min to sediment the DCC. The
supernatant of samples from newborns was used directly to determine CBG
binding capacities, whereas samples from mothers were further diluted
1:5 in PBS. Aliquots of 100 µl supernatant were incubated with 0.5
pmol [3H]corticosterone/100 µl supernatant
([1,2,6,7-3H]corticosterone, Amersham Pharmacia Biotech, Arlington Heights, IL; SA, 88.4 Ci/mmol) in
the absence or presence of unlabeled B at concentrations varying from
8.67–144.5 nM. The final volume of the incubation medium
was 0.3 ml. Parallel incubations containing, respectively, 700 and 200
µl PBS in the presence of labeled B were performed to determine,
respectively, total radioactive activity and nonspecific binding. After
mixing, a first incubation for 1 h at room temperature followed by
a second incubation in an ice water bath for 15 min were performed. A
suspension of DCC (500 µl/tube) was then added to the assay tubes.
After an incubation for 10 min at 4 C, the tubes were centrifuged at
4000 rpm for 15 min at 4 C. An appropriate volume of the supernatant
that contains CBG-bound fraction was mixed with 5 ml scintillation
counting liquid (Optiphase 2, EE&G Instruments, Evry, France) and
counted in an LKB ß-scintillation counter.
The apparent maximum binding capacity (Bmax) and dissociation constant (Kd) of CBG for B were individually evaluated from Scatchard plots (27).
Plasma free B concentrations were calculated (rather than directly measured) in both mothers and pups at the time of death and at birth, respectively, using the mass action equation previously described by Plymate et al. (28).
Statistical analysis
All data are presented as the mean ± SEM.
Statistical analysis was performed using multiple ANOVA, followed by
Dunnett’s test. Unpaired Student’s t test was also used
when appropriate. P < 0.05 was considered
significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). During this last week of gestation,
the mean body weight increase was 65 g (+23.4%; P
< 0.001). In contrast, in pregnant rats exposed to FR50 from E14 to
E21 of gestation, body weight was not significantly modified throughout
the last week of pregnancy (Fig. 1A). However, the increase in plasma B
concentrations was higher in FR50 mothers than in controls at E19
(P < 0.01) and E21 (P < 0.05; Fig. 1B). The maternal plasma B level increased during late gestational
stages in both control (at E21; P < 0.01) and FR50
rats (on days E19 and E21; P < 0.001; Fig. 1B). At
term, FR50 mothers showed an increase in their relative adrenal weight
[32.02 ± 1.20 mg/100 g body weight (n = 6) vs.
26.54 ± 1.72 (n = 6); P < 0.05] as well as
a reduced (P < 0.05) plasma CBG binding capacity
without a significant change in the Kd values
(Table 1). In contrast, the free plasma B
concentration at term was strongly increased in FR50 mothers
(P < 0.001) compared with controls (Table 1).
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) without significant changes in thymus,
testicles, or liver weights (data not shown). These newborns also
showed significant reductions (P < 0.001) in
corticoliberin mRNA in the paraventricular nucleus (PVN; Fig. 3, A and
B) as well as in ACTH in plasma (P < 0.001; Fig. 3D)
without any modification of POMC mRNA in the adenohypophysis (Fig. 3C).
Nevertheless, these pups from FR50 mothers showed higher plasma B
levels (P < 0.05) than controls at birth (Fig. 3E).
Two hours after birth, plasma B was decreased (P <
0.01) in pups from FR50 mothers, but was increased (P
< 0.001) in pups from control mothers (Fig. 3E). At this point in
postnatal life, plasma B was lower (P < 0.001) in FR50
pups than in controls (Fig. 3E). In newborns, maternal food restriction
did not significantly affect either Bmax or
Kd values for CBG (Table 1
). However, as pups
from FR50 mothers showed higher levels of plasma B than controls at
birth (P < 0.05; Fig. 3E) despite no changes in CBG
characteristics, the calculated free plasma B level was also
significantly increased (P < 0.05) in FR50 pups
(P < 0.05; Table 1).
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). Similarly, GR gene expression was
strongly reduced (P < 0.001) in the whole hippocampus
in these pups (Fig. 4B). However, GR expression was not affected by
maternal food restriction in the hypothalamic PVN, the adenopituitary,
and the amygdala (data not shown).
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), but a significant rise in plasma B
concentrations on days E19 and E21 (Fig. 5B). Such effects of food
restriction on both maternal body weight and circulating B were
comparable to those observed in FR50 intact rats (Figs. 1 and 5).
Adrenalectomy followed by B supplementation of the mother from E14 to
E21 maintained a basal plasma B level throughout the last week of
gestation and prevented the FR50-induced rise on days E19 and E21 (Fig. 5B), without affecting body weight evolution compared with
corresponding controls (Fig. 5A). At term, sham-ADX FR50 mothers showed
increased (P < 0.05) adrenal weight (34.95 ±
2.40 vs. 27.43 ± 2.16 mg/100 g BW; n = 5–6;
P < 0.05). At this stage, the characteristics of
maternal CBG (Bmax and Kd)
were not significantly affected by either surgery or food regimens
(Table 3). Sham-ADX mothers exposed to
food restriction showed at term both higher values for plasma B
(P < 0.01) and free B (P < 0.001)
than controls (Table 3).
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).
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B). However, adrenal atrophy was observed only in
newborns from sham-ADX FR50 mothers (P < 0.001; Table 2B). Maternal adrenalectomy with substitutive B supply prevented food
restriction-induced adrenal atrophy in pups (Table 2B) as well as food
restriction-induced reduction in PVN corticoliberin mRNA (Fig. 7A). Adenopituitary
POMC gene expression was unaffected in pups by either maternal surgery
or food regimens (Fig. 7B). However, pups from sham-ADX mothers or ADX
mothers exposed to food restriction showed weaker plasma ACTH levels
(P < 0.05 and P < 0.01, respectively)
than controls (Fig. 7C). Moreover, plasma ACTH levels in newborns from
adrenalectomized mothers were significantly higher (P
< 0.001 and P < 0.01 for control and FR50 pups,
respectively) than those in pups from sham-ADX mothers (Fig. 7C).
Plasma corticosterone levels were increased in newborns from sham-ADX
FR50 mothers (P < 0.05) as well as in pups from ADX-C
mothers (P < 0.01; Table 3). CBG binding
characteristics (Bmax and
Kd) were not significantly affected in newborns
by either maternal surgery or food regimens (Table 3).
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). GR gene expression in the whole
hippocampus of pups was not affected by either maternal surgery or food
regimens (Fig. 8B).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In adult rats, food restriction increases HPA axis activity and disrupts the normal daily rhythm in circulating B, which shows high levels maintained throughout the day (35, 36, 37). However, the mechanisms by which food restriction activates the HPA axis are not fully known. They could imply an increase in ACTH synthesis and secretion (37) as well as an enhancement of adrenal sensitivity to ACTH (38).
To our knowledge, the present data indicate for the first time that pregnant rats exposed to undernutrition performed by 50% food restriction during the last week of gestation show activation of their HPA axis, as suggested by the increase in both plasma B levels and relative adrenal weight. Similarly, maternal dietary protein restriction throughout gestation has been shown to activate the HPA axis (39). According to the present data, food restriction during the last week of gestation decreases at term the plasma CBG level and consequently increases the free B concentration in the maternal compartment. CBG was usually reported to limit the free fraction of B and then to protect B from degradation by P-450 enzymes in the liver (40). Nevertheless, the role of CBG remains contentious. CBG could act as a sump, binding and inactivating B, or could act as a B carrier. The nonsignificant effect of food restriction on maternal CBG in sham-adrenalectomized mothers was unexpected. It could be related to an unusual variability of this small experimental group (n = 4).
B is a highly lipophilic molecule that can cross the placenta from the mother to the fetus and vice versa (41, 42, 43). Indeed, the fetus can contribute to the maternal B pool after day 18 of gestation when the mother has been adrenalectomized (42). However, the placental transfer of B is regulated by the placental enzyme 11ßHSD2, which converts glucocorticoids (cortisol and B) to inactive 11-dehydro metabolites (13, 14) and thus protects the fetuses from an excess of maternal glucocorticoids. As we reported in the present study, a decrease in 11ßHSD2 mRNA in the placenta of pregnant rats subjected to food restriction producing a reduction of enzyme activity could overexpose fetuses to high levels of B from maternal origin. Such hypothesis is fully consistent with increased circulating levels of B in newborns from food-restricted mothers. On the other hand, the adrenal atrophy observed in these fetuses is correlated to a reduction of plasma ACTH levels as well as a decrease in corticoliberin mRNA in the PVN. Decreased levels of MR and GR mRNAs in the hippocampus are consistent with high circulating levels of B at term in pups from food-restricted mothers. Indeed, a stress-induced elevation of B was reported to down- regulate glucocorticoid receptors in the hippocampus and/or the hypothalamus of the adult (44). These data suggest that the hypoactivity of the fetal HPA axis can be related to the negative feedback control exerted by high circulating levels of B arising from the maternal compartment. Such feedback has been previously demonstrated in rat fetuses at the end of gestation (16). Low activity of the HPA axis in newborns from mothers exposed to reduced food intake is also suggested by the lack of increasing circulating levels of B 2 h after birth, whereas such an increase is observed in control pups. Our data are in agreement with low placental 11ßHSD2 activity observed in babies with small birth weights (15) and with an increased cortisol level in human growth-retarded fetuses (10). Moreover, an attenuation of the 11ßHSD2 activity was also reported in rats in response to maternal dietary protein restriction (39).
According to the present data, maternal food restriction reduces 11ßHSD2 mRNA in the placenta at term independently of low or high maternal B level during late gestation. Then, we postulate that maternal B is not the main factor that mediates the reduction in placental 11ßHSD2 expression associated with intrauterine growth retardation. Direct effects of malnutrition or indirect ones via disturbances in maternal metabolism could also be implicated in the reduction of placental 11ßHSD2 expression.
Numerous data suggest that in both humans and animals, relatively low glucocorticoid excess during pregnancy induces IUGR and increases the risk of hypertension in adulthood (45). Indeed, treatment of pregnant rats with carbenoxolone, an 11ßHSD2 inhibitor, or with dexamethasone causes a reduction of birth weight and produces permanent hypertension in offspring (46, 47). However, this latter treatment may induce a robust, rather than a modest, exposure of fetuses to glucocorticoids, as carbenoxolone softens placental inactivation of B. On the contrary, dexamethasone, which is a poor substrate for the 11ßHSD2 (12), when administered to the mother can easily cross the placental barrier and spread to the fetal circulation. Moreover, increased B supply to the fetus from food-restricted mothers is not the only or the main factor that induces reduction in body growth, as in our study fetuses from ADX, sham, or intact mothers developed similar hypotrophy despite variations in maternal and fetal circulating B levels. IUGR induced by maternal food restriction could be related, rather, to disruption of placental transfer of nutrients and/or disturbance of their use by fetal tissues.
The lack of adrenal atrophy at term in fetuses from adrenalectomized mothers exposed to food restriction is consistent with the higher plasma ACTH levels observed in such fetuses. Moreover, as plasma B levels in fetuses from adrenalectomized mothers are similarly increased independently of the available food, we can speculate that the activity of the HPA axis is not directly depressed by the undernutrition. Discrepancies in some biological parameters between pups from operated or intact mothers that concern particularly hippocampal mRNA of GRs could be related to long-lasting effect of maternal surgery. Such data are in agreement with activation of the fetal HPA axis in response to adrenalectomy, which withdraws negative feedback exerted by maternal B (42, 43).
The present data suggest that food restriction of the pregnant rat during the last week of gestation induces both atrophy and hypoactivity of adrenals in fetuses at term. These alterations are dependent on B arising from the mother. Both the increase in circulating B in the maternal compartment and the expected reduction of placental 11ßHSD2 activity favor glucocorticoid transfer to the fetus and thereafter disturb the fetal HPA axis.
The long-term consequences of prenatal undernutrition on both the HPA axis responsiveness to stress and related behaviors can be expected in these rats, as it was reported for adults after exposition to prenatal stress (48, 49). Moreover, we showed in this animal model, which is largely used to study the long-term consequences of IUGR, i.e. permanent hypertension and insulin resistance in adulthood (6, 7, 8, 50), that fetuses are overexposed to high levels of maternal glucocorticoids. As these adrenal hormones have powerful programming properties during the perinatal period, we can speculate that long-term disturbances observed in offspring may be in part mediated by maternal glucocorticoid excess. Consistent with this hypothesis is the fact that hypertension in rats induced by maternal dietary protein restriction can be prevented by pharmacological blockade of glucocorticoid biosynthesis in the pregnant dam and her offspring, but reversed by concomitant B supply (51). Thus, the correlation between low birth weight and some adulthood diseases could be in part related to the adverse glucocorticoid environment in utero during the early postnatal period. Perinatal disturbances of the HPA axis could program or imprint the development of tissues and organs, producing later dysfunctions and diseases, as reported for blood pressure in the adult offspring of rats exposed to dexamethasone in the last week of pregnancy (52).
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Acknowledgments |
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Footnotes |
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2 These authors contributed equally to this work.
Received September 26, 2000.
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References |
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tal exposure to a low-protein diet, in the rat, is prevented by
pharmacological blockade of maternal glucocorticoid synthesis. J
Hypertens 15:537–544[CrossRef][Medline]
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