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The Journal of Physiology logoLink to The Journal of Physiology
. 2012 Aug 28;590(Pt 21):5529–5540. doi: 10.1113/jphysiol.2012.239426

Maternal corticosterone regulates nutrient allocation to fetal growth in mice

Owen R Vaughan 1, Amanda N Sferruzzi-Perri 1, Abigail L Fowden 1
PMCID: PMC3515836  PMID: 22930269

Abstract

Stresses during pregnancy that increase maternal glucocorticoids reduce birth weight in several species. However, the role of natural glucocorticoids in the mother in fetal acquisition of nutrients for growth remains unknown. This study aimed to determine whether fetal growth was reduced as a consequence of altered amino acid supply when mice were given corticosterone in their drinking water for 5 day periods in mid to late pregnancy (day, D, 11–16 or D14–19). Compared to controls drinking tap water, fetal weight was always reduced by corticosterone. At D16, corticosterone had no effect on materno-fetal transfer of [14C]methylaminoisobutyric acid (MeAIB), although placental MeAIB accumulation and expression of the Slc38a1 and Slc38a2 transporters were increased. However, at D19, 3 days after treatment ended, materno-fetal transfer of MeAIB was increased by 37% (P < 0.04). During treatment at D19, placental accumulation and materno-fetal transfer of MeAIB were reduced by 40% (P < 0.01), although expression of Slc38a1 was again elevated. Permanent reductions in placental vascularity occurred during the earlier but not the later period of treatment. Placental Hsd11b2 expression, which regulates feto-placental glucocorticoid bioavailability, was also affected by treatment at D19 only. Maternal corticosterone concentrations inversely correlated with materno-fetal MeAIB clearance and fetal weight at D19 but not D16. On D19, weight gain of the maternal carcass was normal during corticosterone treatment but reduced in those mice treated from D11 to D16, in which corticosterone levels were lowest. Maternal corticosterone is, therefore, a physiological regulator of the amino acid supply for fetal growth via actions on placental phenotype.

Key points

  • Stress during pregnancy leads to fetal growth restriction.

  • Natural glucocorticoids, such as corticosterone, are elevated by maternal stress and, hence, may mediate the effects of stress on fetal growth.

  • This study shows that increasing corticosterone levels in pregnant mice limits fetal growth by reducing the amino acid supply and density of blood vessels in the placenta.

  • The findings suggest that excess corticosterone may act to defend maternal resources during times of stress by constraining the placental allocation of nutrients to the fetus.

  • The results also provide a potential mechanism by which stresses during pregnancy can program intrauterine growth and development with consequences in later life.

Introduction

The natural glucocorticoids, cortisol and corticosterone, have diverse metabolic and cardiovascular effects that ensure survival through periods of adversity (Vegiopoulos & Herzig, 2007). In experimental animals, their concentrations rise in response to physiological and psychological stresses of environmental origin including excess light and/or heat, physical restraint, infection and dietary restriction of calories and protein (Ward & Weisz, 1984; Montano et al. 1991; Lesage et al. 2001; Asiaei et al. 2011; Belkacemi et al. 2011; Sferruzzi-Perri et al. 2011; Cottrell et al. 2012). In pregnant animals, there are also consequences of these environmental insults for the offspring both in utero and later in life, which may be the result of early life overexposure to natural glucocorticoids (Barbazanges et al. 1996; Gardner et al. 1997; Langley-Evans, 1997; Lesage et al. 2004; Asiaei et al. 2011). Certainly, administration of the more potent synthetic glucocorticoid, dexamethasone, to pregnant females reduces birth weight and causes abnormalities in the metabolic and/or cardiovascular phenotype of their adult offspring in rats, guinea pigs, sheep and humans (Benediktsson et al. 1993; Nyirenda et al. 1998; Banjanin et al. 2004; De Blasio et al. 2007; Khan et al. 2011). Glucocorticoids may, therefore, act as common transducers of environmental stresses in determining intrauterine growth and developmental programming of the offspring. However, to date, little is known about their mechanisms of action in utero or about whether natural glucocorticoids at concentrations seen in mothers during adverse conditions have similar effects on fetal growth and development.

In all eutherian mammals, intrauterine growth depends on the supply of nutrients from the mother. In turn, this is determined by the ability of the mother to partition resources to the gravid uterus and of the placenta to transfer these nutrients to the fetus. The amino acid supply and the activity of the System A family of neutral amino acid transporters (SNATs), in particular, appear to have an important role in regulating fetal growth. Activity of these transporters is low in the placentae of growth restricted human infants (Glazier et al. 1997; Shibata et al. 2008) and direct inhibition of System A transporters restricts fetal growth in the rat (Cramer et al. 2002). Expression and activity of these transporters also increase in the mouse placenta during late gestation, when fetal weight gain is at its most rapid (Coan et al. 2010; Audette et al. 2011). The SNATs are transcribed from three genes, Slc38a1, Slc38a2 and Slc38a4, all of which are expressed in rodent and human placenta (Constancia et al. 2005; Desforges et al. 2006). They facilitate accumulation of small neutral amino acids in the placenta by sodium-dependent active transport from the mother. From there, the amino acids are transported down their concentration gradient into the fetus for tissue accretion or oxidative metabolism. Gene expression and activity of the System A transporters in the rodent placenta are affected by maternal nutritional perturbations that raise glucocorticoid concentrations, such as reduced total caloric intake or alterations in the dietary content of protein, fat or sugar (Jones et al. 2009; Coan et al. 2010, 2011; Vaughan et al. 2012). Since the placenta expresses glucocorticoid receptors from early in gestation (Thompson et al. 2002; Speirs et al. 2004), these dietary-induced changes in placental transport may be mediated by the glucocorticoids. Direct administration of dexamethasone at clinical doses has been shown to restrict placental growth and alter System A activity in the human and mouse placenta (Baisden et al. 2007; Audette et al. 2010; Audette et al. 2011; Cuffe et al. 2011). However, the effects of natural glucocorticoids on maternal resource allocation and placental transport capacity remain unknown.

This study tested the hypothesis that natural glucocorticoids in the pregnant mouse reduce fetal growth by altering placental phenotype and, thus, the allocation of nutrients to the fetus from the mother. Specifically, the study examined the effect of increasing maternal corticosterone concentrations, within the physiological range, on maternal weight gain during pregnancy, feto-placental growth and the supply of amino acids to the mouse fetus via the System A family of transporters. In particular, the experiments were designed to determine whether System A-mediated transport to the fetus was reduced when maternal corticosterone concentrations were high. Dams were supplied with corticosterone in their drinking water for 5 days, either from day (D) 11 to D16 or D14 to D19 of pregnancy, corresponding with the periods of most rapid weight gain of the placenta and fetus, respectively (Coan et al. 2004). Feto-placental growth and System A amino acid transport were studied on the final day of glucocorticoid overexposure and 3 days after the cessation of the earlier treatment, to determine whether the effects of corticosterone persisted.

Methods

Animals

All procedures were carried out in accordance with UK Home Office regulations under the Animals (Scientific Procedures) Act 1986. Pairs of virgin female C57BL6/J mice were placed with a stud male overnight. Mated females were identified by the presence of a copulatory plug the following morning, which was designated D1 of pregnancy. Pregnant females (n= 110 in total) were housed in groups of two to five in 12 h:12 h dark–light conditions and allocated to one of three treatment groups. Forty-three females drank corticosterone (cort, corticosterone 21-hemmisuccinate in tap water, 200 μg ml−1, Steraloids Inc., Newport, RI, USA) from sipper bottles either from D11 to D16 (n= 25; D1 body weight (mean ± SEM), 18.2 ± 0.2 g) or from D14 to D19 (n= 18; D1 body weight, 18.4 ± 0.3 g). Controls (n= 67; D1 body weight, 18.6 ± 0.2 g) drank tap water throughout the experiment. Studies of materno-fetal amino acid transport were made on the final day of the treatment, on D16 or D19. A subset of the dams given corticosterone from D11 to 16 was returned to tap water on D16 for 3 days and studied, post-treatment, at D19 (n= 8). Daily ad libitum food consumption (Rat and Mouse No. 3 Breeding, Special Diet Services, Witham, UK) was greater during the period, from D14 to D19, when dams were drinking corticosterone (5.2 ± 0.1 g day−1, n= 4 cages) than in controls (4.3 ± 0.1 g day−1, n= 8 cages, P < 0.05). Therefore, 8 of the 18 mice treated with corticosterone from D14 to 19 were pair-fed to control food intake (PF, n= 4 cages). Food intake in animals drinking corticosterone from D11 to D16 (4.3 ± 0.1 g day−1, n= 6 cages) was similar to that of controls (4.1 ± 0.2 g day−1, n= 15 cages) during and after treatment. Water intake was significantly higher in animals given corticosterone over either period (D11–D16: control, 7.2 ± 0.7 ml day−1; cort, 11.4 ± 1.2 ml day−1; P < 0.05; D14–D19: control, 8.0 ± 0.9 ml day−1; cort, 10.9 ± 0.8 ml day−1; pair-fed cort 14.7 ± 1.1 ml day−1; P < 0.05). Thus, the mean corticosterone dose was 83 ± 9 μg g−1 day−1 in dams treated from D11 to D16 and 81 ± 6 μg g−1 day−1 for those treated later in pregnancy.

Experimental procedures

Between 08.00 and 10.00 h on D16 or D19, unidirectional materno-fetal clearance of the System A transporter substrate [14C]methylaminoisobutryic acid (MeAIB) was measured as described previously (Sibley et al. 2004). Briefly, mice were anaesthetized with an intraperitoneal injection of fentanyl-fluanisone and midazolam in water (1:1:2, 10 μg ml−1, Janssen Animal Health, High Wycombe, UK). The jugular vein was exposed and a 100 μl bolus of MeAIB (NEN NEC-671, specific activity 1.86 GBq mmol−1) delivered. Up to 4 min later, a cardiac blood sample was taken into an EDTA-coated phial and the dam was killed by cervical dislocation (mean time in minutes after tracer injection: D16 control, 1.8 ± 0.2; D16 early cort, 2.3 ± 0.2; D19 control, 1.8 ± 0.1; D19 late cort, 2.1 ± 0.3; D19 late cort + PF, 2.0 ± 0.2; D19 post-cort, 1.9 ± 0.3). The uterus was removed and the maternal carcass weighed, along with individual fetuses and placentae. The placenta closest to the mean weight from each litter was halved and fixed in either paraformaldehyde or glutaraldehyde solution (both 4% in 0.1 m Hepes) for histological analysis; the remaining placentae were frozen in liquid nitrogen for analysis of gene expression. Following centrifugation of the blood samples, plasma was stored at −20°C.

Maternal plasma hormone and nutrient concentrations

Corticosterone concentration in maternal plasma was measured by radioimmunoassay according to manufacturer's instructions (MP Biomedicals, Santa Ana, CA, USA). The mean recovery of of exogenous corticosterone added to phosphate buffer solution or serum at 400 ng ml−1 was 100.7 ± 3.1%. Intra-assay and inter-assay coefficients of variation for three pools of quality controls were 7.3% (mean 193.9 ng ml−1) and 6.9% (mean 248.7 ng ml−1), respectively, and the lower detection limit of the assay was 7.7 ng ml−1. When sample corticosterone concentrations exceeded the accurate range of the assay, twofold dilutions were made of the sample and measurements repeated. α-Amino nitrogen concentration was determined colorimetrically in plasma using a previously published method (Evans et al. 1993). The coefficient of variation for pooled glycine standards was 4.9% (mean 443 μm).

Placental transport of [14C]methylaminoisobutyric acid

From each litter, all fetuses and two placentae (the heaviest and lightest) were homogenized and digested in Biosol (National Diagnostics, Hull, UK) at 55°C. The MeAIB content of maternal plasma and of the digestates of the fetuses and placentae were measured by liquid scintillation counting (Optiphase Hisafe and LKB Wallac 1216 Rackbeta, both Perkin Elmer, Cambridge UK). The coefficient of variation of replicate measurements of MeAIB content of individual samples was 8.0%. Unidirectional materno-fetal clearance per gram of placenta, and radioactivity accumulated per gram of fetus or placenta were calculated as described previously (Sibley et al. 2004).

Placental gene expression

Real-time PCR was used to determine the relative quantity of Slc38a mRNA in placentae from each treatment group. Furthermore, the expression of genes encoding the glucocorticoid metabolizing enzymes, 11β-hydroxysteroid dehydrogenase (11βHSD) types I and II (Hsd11b1 and Hsd11b2 respectively) and the glucocorticoid receptor, Nr3c1, was measured. Total RNA was extracted from the placenta second closest in weight to the mean of each litter (n= 6 per treatment group) using the RNeasy Plus Mini Kit (Qiagen, Crawley, UK). Extracted RNA (2.5 μg) was reverse transcribed to generate cDNA using Multiscribe Reverse Transcriptase (Applied Biosystems, Warrington, UK). Gene expression in each sample was analysed in duplicate using the Applied Biosystems 7500 Fast system. The following Taqman Gene Expression Assays (Applied Biosystems) were used: Slc38a1 (Mm00506391_m1), Slc38a2 (Mm00628416_m1), Slc38a4 (Mm00459056_m1), Hsd11b1 (Mm00476182_m1), Hsd11b2 (Mm01251104_m1), and Nr3c1, (Mm00433832_m1). The expression of each transcript was normalized to the geometric mean of Hprt1 (Mm00446968_m1) and Sdha (Mm01352366_m1) expression, which did not vary between experimental groups. Finally, relative expression was calculated using the ΔΔCt method.

Placental morphometry

The mouse placenta consists of the labyrinthine zone (Lz), responsible for nutrient transport, and junctional zone (Jz), which is endocrine in function, along with the maternal decidua basalis (Db) (Coan et al. 2004). As the rates of both active and passive transport mechanisms depend upon the surface density, as well as the absolute size of the Lz, placental structure was quantified by stereology in fixed tissue. Paraformaldehyde fixed placental halves (n= 6 per group) were embedded in paraffin wax and exhaustively sectioned (7 μm thickness) perpendicular to the chorionic plate then stained using a standard haematoxylin and eosin protocol. The fractional volumes of the three zones were determined by point counting (10× objective lens, Computer Assisted Stereological Toolbox v2.0 and BX-50 optical microscope, both Olympus, Ballerup, Denmark) on a systematic random sample of sections (Coan et al. 2004). Fractional volumes were arcsine transformed prior to statistical analysis. Fractional volumes were converted to absolute volumes in mm3 by multiplying by total placental volume, assuming a density of 1 mg mm−3 (Hewitt et al. 2006). Glutaraldehyde fixed placental halves were embedded in Spurr's epoxy resin and a single mid-line section taken (1 μm thickness) then stained with toluidine blue. Volumes of maternal and fetal blood vessels in the Lz, along with the surface area and thickness of the barrier, were determined at 100× magnification using stereological methods described previously (Coan et al. 2004).

Statistical analysis

All data are presented as means ± SEM. Separate statistical comparisons were made depending upon the gestational age at the study. When the raw data were not normally distributed, they were logarithmically transformed prior to analysis. At D16, control and corticosterone treated groups were compared by Student's unpaired t test. At D19 control, cort, cort + PF and post-cort groups were compared by one-way ANOVA with the Bonferroni post hoc test. Where data were collected for individual conceptuses, e.g. feto-placental weight and MeAIB transport, each measurement within a litter was considered a replicate; therefore, litter means were calculated such that the number of subjects was the number of litters. Pearson's product–moment correlation coefficient (r) was used to determine the linear dependence of maternal plasma corticosterone concentration, materno-fetal 14C-MeAIB clearance, and fetal and placental weight. Partial correlation analysis was performed according to the method of Snedecor (Snedecor & Cochran, 1967).

Results

Plasma corticosterone concentration and weight gain in pregnant mice

Corticosterone administration in the drinking water either from D11 to D16 or from D14 to D19 of pregnancy raised maternal plasma corticosterone concentration on the final day of treatment (P < 0.01, Table 1) to values similar to those seen in undernourished or light/heat stressed dams (Montano et al. 1991; Sferruzzi-Perri et al. 2011). However, in pair fed dams drinking corticosterone from D14 to D19, corticosterone concentrations were not significantly different from control values (Table 1, P > 0.05). Neither were corticosterone concentrations significantly different from controls on D19, post-treatment from D11 to D14 of pregnancy (Table 1, P > 0.05). Maternal α-amino nitrogen concentrations did not differ significantly with treatment at either age (P > 0.05, Table 1).

Table 1.

Maternal plasma corticosterone and α-amino nitrogen concentrations, maternal, fetal and placental weights, and litter sizes in control (Con) and corticosterone (Cort) treated mice at D16 and D19 of pregnancy

D19
D16 Cort
Con Cort Con Ad lib Pair fed Post cort
Corticosterone (ng ml−1) 632± 60 1142± 134 † 714± 41 a 1143± 176 b 764± 65 a 524± 53 a
α Amino nitrogen (μm) 764 ± 45 795 ± 39 704 ± 31 710 ± 40 649 ± 54 597 ± 34
Maternal weight (g)
 Total 29.5± 0.5 27.5± 0.3 † 34.3± 0.5 a 32.7± 1.0 a 30.6± 0.9 b 32.3± 0.7 a
 Total gain from D1 11.7± 0.6 9.6± 0.2 † 15.3± 0.4 a 14.7± 0.7 a 12.1± 0.6 b 13.2± 0.6 ab
 Carcass 23.2 ± 0.4 22.2 ± 0.3 23.0± 0.2 a 23.3± 0.9 a 21.8± 0.6 ab 21.4± 0.4 b
 Carcass gain from D1 5.1 ± 0.4 4.2 ± 0.2 4.2± 0.3 ab 5.2± 0.6 a 3.6± 0.8 ab 2.5± 0.3 b
Conceptus weight (mg)
 Fetus 390± 5 363± 6 † 1180± 12 a 992± 17 b 961± 32 b 1116± 30 c
 Placenta 101± 1 94± 2 † 88± 1 a 78± 1 b 76± 1 b 85± 2 a
 Fetus:Placenta 3.9 ± 0.1 3.9 ± 0.1 13.5 ± 0.3 12.8 ± 0.3 12.7 ± 0.3 13.0 ± 0.3
Litter size 6.9 ± 0.3 6.4 ± 0.2 6.6 ± 0.2 6.7 ± 0.3 6.1 ± 0.4 6.9 ± 0.4
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Data are means ± SEM. Mice drank tap water throughout (D16 Con, n= 30; D19 Con, n= 37) or were given corticosterone from D11 to D16 (D16 Cort, n= 16; D19 Post cort, n= 8) or from D14 to D19 (D19 Cort Ad lib, n= 10; D19 Cort Pair fed, n= 8). Figures in bold represent significant overall effect of treatment (P < 0.05). †Significant difference (P < 0.05) from age-matched control by Student's t test; a, b and c represent significantly different groups by one-way ANOVA with Bonferroni post hoc test. Overall mean and SEM for fetal and placental weight were calculated from litter means.

Relative to controls, total weight of the pregnant mouse but not its carcass weight after hysterectomy was less on D16 when it drank corticosterone from D11 (Table 1). Post-treatment, dams were not lighter overall but did have a lower carcass weight and gained less carcass weight from D1 of pregnancy, relative to D19 controls (Table 1). Dams drinking corticosterone up to D19 and fed ad libitum did not differ in either total or carcass weight from controls, despite the increased food intake, although carcass weight gain during pregnancy was greatest in this group (Table 1). Total weight at D19 and total weight gain from D1 of pregnancy were significantly less in the pair-fed dams drinking corticosterone, relative to controls. However, maternal carcass weight and carcass weight gain of the pair fed dams were not significantly different from the controls or the ad libitum fed corticosterone treated dams (Table 1).

Fetal and placental growth

Maternal corticosterone administration significantly reduced fetal and placental weight on the final day of treatment at both D16 and D19 (Table 1). At D16, maternal corticosterone administration reduced both fetal and placental weight by 7% compared to the corresponding control values (Table 1, P < 0.05). On D19, fetuses were more growth restricted by maternal corticosterone treatment and were 16% lighter than control values compared to a 11% reduction in placental weight (Table 1). Pair-feeding pregnant dams to control food intake did not alter the effect of corticosterone treatment from D14 to D19 on the weight of the fetus or placenta (Table 1). Post-treatment from D11 to D16, fetuses remained 5% lighter than controls at D19, while placental weight no longer differed from control values (Table 1). Maternal corticosterone treatment, therefore, altered the growth trajectory of both the fetus and placenta although the growth patterns differed between the fetal and placental tissues. There was no effect of treatment on the ratio of fetal to placental weight at either D16 or D19 (Table 1). Fetal weight was negatively correlated with maternal plasma corticosterone at D19 (Fig. 1A) but not D16 (r=−0.23, P > 0.05, n= 18). Placental weight was not correlated with maternal corticosterone concentration at either gestational age studied (D16, r=−0.20, P > 0.05, n= 18; D19, r=−0.187, P > 0.05, n= 51). The number of viable pups per litter was unaffected by maternal treatment (Table 1).

Figure 1. Interdependence of fetal weight, materno-fetal clearance of [14C]methylaminoisobutyric acid (MeAIB) and maternal plasma corticosterone at D19 of pregnancy.

Figure 1

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Mice drank tap water throughout (open circles) or were given corticosterone from D11 to D16 (diamonds) or from D14 to D19 (Ad lib, filled circles; Pair fed, grey circles). Each point represents one dam; litter means are displayed for fetal weight and MeAIB clearance. Corticosterone concentrations presented on logarithmic scale. All significant Pearson correlations: r=−0.53, P < 0.001, n= 51 dams (A); r=−0.47, P= 0.001, n= 45 dams (B); r= 0.62, P < 0.001, n= 45 (C).

Transplacental amino acid transport

Maternal corticosterone treatment from D11 had no effect on unidirectional materno-fetal clearance or fetal accumulation of MeAIB on D16 (Fig. 2). However, placental MeAIB accumulation was 35% greater in corticosterone treated than control litters at this age (P < 0.05, Fig. 2). At D19, following maternal corticosterone treatment from D14, unidirectional MeAIB clearance and accumulation of MeAIB in the placenta and fetus were all 40–50% less than in controls, irrespective of maternal food intake (P < 0.05, Fig. 2). In contrast, in D19 dams post-treatment from D11 to D16, unidirectional clearance and fetal accumulation of MeAIB were increased by 38% relative to controls (P < 0.05), although placental MeAIB accumulation did not differ from control values (Fig. 2). When all the data were combined, irrespective of treatment at each gestational age studied, materno-fetal MeAIB clearance was negatively correlated with maternal corticosterone and positively correlated with fetal weight at D19 (Fig. 1B and C) but not at day 16 (P > 0.05, both cases). Thus, part of the association between fetal weight and maternal corticosterone at D19 (Fig. 1A) may have been due to the accompanying changes in placental amino acid clearance. Partial correlation of the three variables showed that maternal corticosterone and materno-fetal MeAIB clearance both significantly influenced fetal weight at D19 but that clearance had the more pronounced effect (partial correlation coefficients: corticosterone held constant, 0.500, P < 0.001; MeAIB clearance held constant, −0.342, P= 0.023).

Figure 2. Materno-fetal transport of [14C]methylaminoisobutyric acid (MeAIB) in control (Con) and corticosterone (Cort) treated mice at D16 and D19 of pregnancy.

Figure 2

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Data are means ± SEM. Mice drank tap water throughout (D16 Con, n= 12; D19 Con, n= 22) or were given corticosterone from D11 to D16 (D16 Cort, n= 8; D19 Post cort, n= 7) or from D14 to D19 (D19 Cort Ad lib, n= 7; D19 Cort Pair fed, n= 8). †Significant difference (P < 0.05) from age-matched control by Student's t test; a, b and c, represent significantly different groups by one-way ANOVA with Bonferroni post hoc test.

Placental Slc38a expression

When corticosterone was administered from D11 to D16, the relative expression in the placenta of Slc38a1 and Slc38a2, but not Slc38a4, was increased at D16 (P < 0.05, Fig. 3). However, when corticosterone was given closer to term, expression of Slc38a1 alone was increased in the ad libitum fed but not in the pair fed group relative to the controls (P < 0.05, Fig. 3). Corticosterone-induced changes in Slc38a expression did not persist to D19 after the cessation of treatment on D16 (Fig. 3). Corticosterone-induced changes in placental Slc38a expression, therefore, paralleled placental [14C]MeAIB accumulation at D16, but not at D19, and were unrelated to unidirectional materno-fetal clearance or fetal accumulation of MeAIB at both ages.

Figure 3. Relative expression of Slc38a genes in control and corticosterone treated placentae.

Figure 3

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Data are means ± SEM relative to age-matched control group. n= 6 placentae per group. Mice drank tap water throughout (D16 Con, D19 Con) or were given corticosterone from D11 to D16 (D16 Cort; D19 Post cort) or from D14 to D19 (D19 Cort Ad lib; D19 Cort Pair fed). †Sgnificant difference (P < 0.05) from age-matched control by Student's t test; a and b represent significantly different groups by one-way ANOVA with Bonferroni post hoc test. Gene expression was determined by the ΔΔCt method relative to Hprt1 and Sdha.

Placental morphology

The volumes of the different zones within the placenta did not differ from control values in corticosterone overexposed placentae at D16 (Table 2), even though they weighed less. On D19, following corticosterone treatment from D14, Lz absolute volume did not differ from control values in the placentae of ad libitum fed mice but was smaller in the placentae of those pair-fed than controls (P < 0.05, Table 2). The volume of fetal capillaries within the Lz was 55% less in corticosterone exposed than in control placentae on D16. Similarly, at D19 there was a significant effect of treatment on fetal capillary volume, which was lowest in dams given corticosterone from D11 to D16 when expressed as a percentage of total Lz volume. There were, however, no glucocorticoid-dependent differences in Lz surface area at either gestational age that could explain the differences in amino acid transport or transporter expression (Table 2). Barrier thickness was not affected by maternal treatment either.

Table 2.

Morphology of placentae of control (Con) and corticosterone (Cort) treated mice at D16 and D19 of pregnancy

D19
D16 Cort
Con Cort Con Ad lib Pair fed Post cort
Volume (mm3)
 Lz 50 ± 3 43 ± 1 49± 2a 44± 1 ab 40± 2 b 50± 2 a
 Jz 33 ± 2 34 ± 2 22 ± 1 22 ± 1 19 ± 2 26 ± 2
 Db 16 ± 2 16 ± 1 14 ± 1 11 ± 0.4 13 ± 1 11 ± 1
 MBS 9 ± 1 9 ± 0.4 9 ± 0.4 9 ± 1 8 ± 1 9 ± 1
 FC 9± 1 4± 0.04 † 10± 2 a 9± 1 a 5± 0.3 a 6± 1 a
 Troph. 34 ± 2 30 ± 1 35 ± 2 27 ± 1 27 ± 3 34 ± 4
Volume (%)
 Lz 50 ± 2 47 ± 1 58 ± 2 57 ± 1 56 ± 2 58 ± 2
 Jz 34 ± 2 37 ± 2 26 ± 2 29 ± 1 26 ± 3 30 ± 2
 Db 16 ± 2 17 ± 1 17 ± 1 15 ± 1 18 ± 1 13 ± 1
 MBS 17± 1 20± 1 † 17 ± 1 20 ± 1 21 ± 2 20 ± 3
 FC 17± 1 9± 1 † 19± 3 a 20± 1 a 13± 1 ab 12± 1 b
 Troph. 66± 1 71± 2 † 64 ± 2 60 ± 1 66 ± 3 69 ± 4
Surface Area (cm2)
 MBS 19 ± 3 16 ± 0.1 26 ± 2 24 ± 1 23 ± 2 22 ± 2
 FC 14 ± 1 11 ± 2 19 ± 2 18 ± 2 14 ± 2 14 ± 1
 Mean 17 ± 2 14 ± 1 22 ± 2 21 ± 2 18 ± 1 18 ± 1
 Th (μm) 3.2 ± 0.04 3.2 ± 0.05 2.5 ± 0.1 2.4 ± 0.1 2.7 ± 0.2 2.7 ± 0.1
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Mean ± SEM stereological measurements. Mice drank tap water throughout (D16 Con, n= 6; D19 Con, n= 4) or were given corticosterone from D11 to D16 (D16 Cort, n= 6; D19 Post cort, n= 6) or from D14 to D19 (D19 Cort Ad lib, n= 7; D19 Cort Pair fed, n= 4). Figures in bold represent significant overall effect of treatment (P < 0.05). †Significant difference (P < 0.05) from age-matched control by Student's t test; a, b and c represent significantly different groups by one-way ANOVA with Bonferroni post hoc test. Lz, labyrinthine zone; Jz, junctional zone; Db, decidua basalis; MBS, maternal blood space; FC, fetal capillary; Troph., trophoblast; Th, harmonic mean thickness.

Placental expression of Hsd11b1, Hsd11b2 and Nr3c1

Hsd11b1 mRNA levels were not affected by maternal treatment at either age (Fig. 4). In contrast, expression of Hsd11b2, which inactivates corticosterone, was related to treatment at D19 but not D16 (Fig. 4). At D19, placental Hsd11b2 expression was highest in the ad lib fed dams treated with corticosterone from D14 to D19 and lowest in the dams post-treatment from D11 to D16 (Fig. 4), the groups that had the highest and lowest maternal corticosterone concentrations, respectively (Table 1). Expression of the glucocorticoid receptor, Nr3c1, did not differ with treatment at either gestational age studied (Fig. 4).

Figure 4. Expression of genes regulating glucocorticoid bioavailability in control and corticosterone treated placentae.

Figure 4

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Data are means ± SEM relative to age-matched control group. n= 6 per group. Mice drank tap water throughout (D16 Con, D19 Con) or were given corticosterone from D11 to D16 (D16 Cort; D19 Post cort) or from D14 to D19 (D19 Cort Ad lib; D19 Cort Pair fed). †Significant difference (P < 0.05) from age-matched control by Student's t test; a and b, represent significantly different groups by one-way ANOVA with Bonferroni post hoc test. Gene expression was determined by the ΔΔCt method relative to Hprt1 and Sdha.

Discussion

This study demonstrates for the first time that the natural glucocorticoid, corticosterone, at physiological concentrations in the mother regulates fetal nutrient acquisition and growth, in part, by actions on the nutrient transport capacity of the placenta. Fetuses of corticosterone treated dams always weighed less than normal, even when maternal food intake increased in response to treatment during late pregnancy. This corticosterone induced fetal growth restriction was associated with morphological and functional changes in placental phenotype that depended on gestational age at the time of treatment. In particular, there were changes in the placental accumulation and clearance the amino acid analogue, MeAIB, transported by the System A amino acid transporters. Changes in placental transcription of the glucocorticoid receptor did not explain the differing outcomes of corticosterone treatment over the two gestational age ranges. Despite the known catabolic actions of the glucocorticoids (Vegiopoulos & Herzig, 2007), dams maintained weight gain of their own tissues at the expense of fetal and placental growth during corticosterone treatment, but resources were diverted to the gravid uterus at the expense of the maternal carcass in late gestation following treatment earlier in pregnancy. Maternal corticosterone, therefore, appears to have an important role in regulating nutrient allocation between the maternal tissues and the gravid uterus in the mouse.

On the fifth day of corticosterone treatment at day 16, fetal growth was reduced in proportion to placental weight, a proxy measure of the total nutrient supply. There was also a proportionate reduction in the growth of the endocrine and transport zones of the placenta in the corticosterone treated dams. However, accumulation of MeAIB by the small D16 corticosterone treated placenta was increased relative to controls in association with up-regulated expression of the Slc38a1 and Slc38a2 isoforms of the System A amino acid transporters. Previous studies in rodent placentae have shown that expression of these two Slc38a isoforms is responsive to environmental cues and up-regulated by undernutrition, protein deprivation and natural growth restriction of the placenta (Coan et al. 2008, 2010, 2011). However, the corticosterone induced increases in placental System A activity did not result in increased amino acid transport to the fetus or maintenance of normal fetal growth at D16. The increased uptake of amino acids by the corticosterone treated placenta may have been used to maintain its own growth during the period of treatment when it would normally have been growing maximally (Coan et al. 2004). Certainly, 3 days after cessation of treatment, placentae of dams drinking corticosterone from D11 to D16 were no longer growth restricted relative to D19 controls.

Although placental weight normalized post corticosterone treatment, fetal growth restriction and the reduced fetal vascularity of the labyrinthine zone persisted at D19. Similarly, short term maternal treatment with synthetic glucocorticoids causes a permanent deficit of labyrinthine blood vessels in the rat placenta (Hewitt et al. 2006). Reductions in placental blood flow as a result of these vascular defects may decrease transfer of oxygen and other flow limited substances essential for fetal growth during the later part of gestation. Certainly, failure of the mouse fetus to recover post-treatment, despite increased placental clearance and fetal accumulation of MeAIB by D19, suggests that the fetal growth trajectory is altered permanently by the earlier corticosterone insult. Initial upregulation of placental amino acid accumulation during treatment, followed subsequently by increased transfer to the fetus indicates that placental uptake and efflux of amino acids may be differentially regulated and temporally dissociated from the original stimulus. Indeed, the delay between the increases in placental and fetal MeAIB uptake seen with corticosterone treatment from D11 to D16 suggests that the placenta may be responding not only to maternal corticosterone but also to nutrient demand signals from the growth retarded fetus once maternal corticosterone concentrations have normalized. The delayed upregulation of amino acid transport to the fetus post-maternal corticosterone treatment may also explain, in part, the reduced carcass weight of the dam by D19. Compensatory upregulation of placental MeAIB clearance is also seen when the placental nutrient supply fails to meet the fetal drive for growth due to either natural intra-litter variability or genetic manipulation of feto-placental growth (Constancia et al. 2005; Coan et al. 2008).

When corticosterone treatment was given later in gestation, the fetus was proportionately more growth restricted than the placenta. This was due, in part, to down-regulation of placental amino acid clearance. Similarly, administration of the long acting, highly potent synthetic glucocorticoid, dexamethasone, has been shown to reduce placental System A activity on D19 in mice in vivo (Audette et al. 2011). However, cortisol and dexamethasone increase System A activity of cultured human trophoblast cells and explants (Jones et al. 2006; Audette et al. 2010). In part, these differing observations may reflect the short and long term effects of glucocorticoid receptor stimulation as System A activity was measured 48 h and up to 5 days after glucocorticoid exposure in the in vitro and in vivo studies, respectively. They may also reflect temporal differences in the expression, translation and trafficking of functional amino acid transporters in response to glucocorticoids as dissociation between Slc38 gene expression and System A activity has been observed in this and previous studies of placental MeAIB transport (Jansson et al. 2006; Coan et al. 2011). When corticosterone treated dams were pair-fed to control intake, amino acid supply to the fetus was reduced even though plasma corticosterone concentration was not significantly different from control values. With reduced food availability, the noctural period of food and water intake may have finished earlier in the night in pair-fed compared to ad libitum fed dams treated with corticosterone with consequences for their circulating corticosterone concentrations measured at a fixed time period the following morning. Taken together, the current observations suggest that there may also be interactions between glucocorticoid concentrations and other signals of nutritional availability that impact on placental transport. Nevertheless, the inverse relationship observed between corticosterone concentrations and placental amino acid clearance when all D19 data were combined indicates that maternal corticosterone is a physiological inhibitor of System A amino acid transport to fetal mice during late gestation. The inhibitory effect of corticosterone on nutrient allocation to the fetus is consistent with weight gain of the maternal carcass being highest in the group of dams given the later treatment, in which corticosterone levels were raised at D19. Furthermore, since the post-treatment group had the lowest maternal corticosterone concentrations, up-regulation of placental MeAIB clearance at D19 after corticosterone treatment from D11 to D16 may directly reflect the disinhibition of System A activity as well as more indirect signals of fetal nutrient demand.

The greater reduction in fetal weight at D19 during corticosterone treatment from D14 may also have been due to maternal corticosterone crossing the placenta to have direct growth inhibitory effects on the fetus independent of changes in the nutrient supply. From D15 onwards of mouse pregnancy, there is a natural ontogenic decline in the placental level of 11βHSD2, which metabolizes maternal corticosterone to its inactive form (Condon et al. 1997; Thompson et al. 2002). Since this enzyme is rapidly saturated when maternal corticosterone concentrations rise (Staud et al. 2006), feto-placental bioavailability of maternal corticosterone is likely to be greater in late than mid gestation. This may explain the greater inhibitory effect of maternal corticosterone on both fetal growth and placental amino acid transport at D19 than D16. Partial correlation analyses of these variables at D19 showed that fetal weight was more dependent on placental MeAIB clearance than maternal corticosterone per se, which suggests that the effects of maternal corticosterone on fetal growth are mediated primarily via changes in placental amino acid transport rather than by direct actions on the D19 fetus. However, the differences in placental 11βHSD2 expression between the groups with the highest and lowest maternal corticosterone concentrations suggest that the D19 placenta may attempt to limit the inhibitory effects of maternal corticosterone by modifying expression of this enzyme accordingly.

In summary, maternal corticosterone reduces nutrient allocation to feto-placental growth at the time of exposure by changing the vascularity and amino transport characteristics of the mouse placenta. This may spare nutrients for maternal use during adverse conditions that raise maternal glucocorticoid concentrations. Indeed, effects of corticosterone were more pronounced near term when the fetal nutrient demands for growth are rising most rapidly in absolute terms. While the effects of glucocorticoids may be more important for maternal fitness in polytocous species, in which fetal mass represents a large proportion of the total weight of the pregnant dam, there is nonetheless a rise in cortisol in late pregnancy in monotocous species including sheep and humans that have smaller fetal to maternal mass ratios (Carr et al. 1981; Demey-Ponsart et al. 1982; Bell et al. 1991). Certainly, the current findings provide a potential mechanism to explain how stressful events during human pregnancy lead to reduced infant birthweight (Eskenazi et al. 2007; Khashan et al. 2008). As the effects of corticosterone on resource allocation in the present study persisted after exposure, altered placental function furthermore programmes fetal growth with potential consequences for offspring phenotype long after the initial insult (Fowden et al. 2008). Maternal corticosterone, therefore, acts as a signal of adversity to the placenta and provides a mechanism for the mother to constrain nutrient distribution to the gravid uterus during adverse conditions, a strategy that operates even in birds and reptiles (Love & Williams, 2008; Itonaga et al. 2012). Overall, maternal corticosterone may have an important role in the evolutionary conflict between mother and fetus over resource allocation, which improves the future reproductive fitness of the mother at the expense of the current offspring when prevailing environmental conditions are poor.

Acknowledgments

The authors would like to thank Nuala Daw, Chris Cardinal and Wendy Cassidy for technical assistance. The study was supported by a Centre for Trophoblast Research graduate studentship awarded to O.R.V.

Glossary

D

day of pregnancy

Db

decidua basalis

Jz

junctional zone

Lz

labyrinthine zone

MeAIB

[14C]methylaminoisobutyric acid

PF

pair-fed

SNAT

sodium-coupled neutral amino acid transporter

Author contributions

The experiments were conducted in the Department of Physiology, Development and Neuroscience of the University of Cambridge. O.R.V and A.L.F conceived and designed the experiments, collected, analysed and interpreted data, and drafted and critically revised the article for important intellectual content. A.N.S. collected, analysed and interpretated data, and drafted and revised the article. All authors approved the final version of the manuscript.

References

  1. Asiaei M, Solati J, Salari AA. Prenatal exposure to LPS leads to long-lasting physiological consequences in male offspring. Dev Psychobiol. 2011;53:828–838. doi: 10.1002/dev.20568. [DOI] [PubMed] [Google Scholar]
  2. Audette MC, Challis JR, Jones RL, Sibley CP, Matthews SG. Antenatal dexamethasone treatment in midgestation reduces system A-mediated transport in the late-gestation murine placenta. Endocrinology. 2011;152:3561–3570. doi: 10.1210/en.2011-0104. [DOI] [PubMed] [Google Scholar]
  3. Audette MC, Greenwood SL, Sibley CP, Jones CJP, Challis JRG, Matthews SG, Jones RL. Dexamethasone stimulates placental system A transport and trophoblast differentiation in term villous explants. Placenta. 2010;31:97–105. doi: 10.1016/j.placenta.2009.11.016. [DOI] [PubMed] [Google Scholar]
  4. Baisden B, Sonne S, Joshi RM, Ganapathy V, Shekhawat PS. Antenatal dexamethasone treatment leads to changes in gene expression in a murine late placenta. Placenta. 2007;28:1082–1090. doi: 10.1016/j.placenta.2007.04.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Banjanin S, Kapoor A, Matthews SG. Prenatal glucocorticoid exposure alters hypothalamicpituitary-adrenal function and blood pressure in mature male guinea pigs. J Physiol. 2004;558:305–318. doi: 10.1113/jphysiol.2004.063669. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Barbazanges A, Piazza PV, Le Moal M, Maccari S. Maternal glucocorticoid secretion mediates long-term effects of prenatal stress. J Neurosci. 1996;16:3943–3949. doi: 10.1523/JNEUROSCI.16-12-03943.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Belkacemi L, Jelks A, Chen CH, Ross MG, Desai M. Altered placental development in undernourished rats: role of maternal glucocorticoids. Reprod Biol Endocrinol. 2011;9:105. doi: 10.1186/1477-7827-9-105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Bell ME, Wood CE, Keller-Wood M. Influence of reproductive state on pituitary-adrenal activity in the ewe. Domest Anim Endocrinol. 1991;8:245–254. doi: 10.1016/0739-7240(91)90060-w. [DOI] [PubMed] [Google Scholar]
  9. Benediktsson R, Lindsay RS, Noble J, Seckl JR, Edwards CR. Glucocorticoid exposure in utero: new model for adult hypertension. Lancet. 1993;341:339–341. doi: 10.1016/0140-6736(93)90138-7. [DOI] [PubMed] [Google Scholar]
  10. Carr BR, Parker CR, Jr, Madden JD, MacDonald PC, Porter JC. Maternal plasma adrenocorticotropin and cortisol relationships throughout human pregnancy. Am J Obstet Gynecol. 1981;139:416–422. doi: 10.1016/0002-9378(81)90318-5. [DOI] [PubMed] [Google Scholar]
  11. Coan PM, Angiolini E, Sandovici I, Burton GJ, Constancia M, Fowden AL. Adaptations in placental nutrient transfer capacity to meet fetal growth demands depend on placental size in mice. J Physiol. 2008;586:4567–4576. doi: 10.1113/jphysiol.2008.156133. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Coan PM, Ferguson-Smith AC, Burton GJ. Developmental dynamics of the definitive mouse placenta assessed by stereology. Biol Reprod. 2004;70:1806–1813. doi: 10.1095/biolreprod.103.024166. [DOI] [PubMed] [Google Scholar]
  13. Coan PM, Vaughan OR, McCarthy J, Mactier C, Burton GJ, Constancia M, Fowden AL. Dietary composition programmes placental phenotype in mice. J Physiol. 2011;589:3659–3670. doi: 10.1113/jphysiol.2011.208629. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Coan PM, Vaughan OR, Sekita Y, Finn SL, Burton GJ, Constancia M, Fowden AL. Adaptations in placental phenotype support fetal growth during undernutrition of pregnant mice. J Physiol. 2010;588:527–538. doi: 10.1113/jphysiol.2009.181214. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Condon J, Ricketts ML, Whorwood CB, Stewart PM. Ontogeny and sexual dimorphic expression of mouse type 2 11β-hydroxysteroid dehydrogenase. Mol Cell Endocrinol. 1997;127:121–128. doi: 10.1016/s0303-7207(97)04000-8. [DOI] [PubMed] [Google Scholar]
  16. Constancia M, Angiolini E, Sandovici I, Smith P, Smith R, Kelsey G, Dean W, Ferguson-Smith A, Sibley CP, Reik W, Fowden A. Adaptation of nutrient supply to fetal demand in the mouse involves interaction between the Igf2 gene and placental transporter systems. Proc Natl Acad Sci U S A. 2005;102:19219–19224. doi: 10.1073/pnas.0504468103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Cottrell EC, Holmes MC, Livingstone DE, Kenyon CJ, Seckl JR. Reconciling the nutritional and glucocorticoid hypotheses of fetal programming. FASEB J. 2012;26:1866–1874. doi: 10.1096/fj.12-203489. [DOI] [PubMed] [Google Scholar]
  18. Cramer S, Beveridge M, Kilberg M, Novak D. Physiological importance of system A-mediated amino acid transport to rat fetal development. Am J Physiol Cell Physiol. 2002;282:C153–160. doi: 10.1152/ajpcell.2002.282.1.C153. [DOI] [PubMed] [Google Scholar]
  19. Cuffe JS, Dickinson H, Simmons DG, Moritz KM. Sex specific changes in placental growth and MAPK following short term maternal dexamethasone exposure in the mouse. Placenta. 2011;32:981–989. doi: 10.1016/j.placenta.2011.09.009. [DOI] [PubMed] [Google Scholar]
  20. De Blasio MJ, Dodic M, Jefferies AJ, Moritz KM, Wintour EM, Owens JA. Maternal exposure to dexamethasone or cortisol in early pregnancy differentially alters insulin secretion and glucose homeostasis in adult male sheep offspring. Am J Physiol Endocrinol Metab. 2007;293:E75–82. doi: 10.1152/ajpendo.00689.2006. [DOI] [PubMed] [Google Scholar]
  21. Demey-Ponsart E, Foidart JM, Sulon J, Sodoyez JC. Serum CBG, free and total cortisol and circadian patterns of adrenal function in normal pregnancy. J Steroid Biochem. 1982;16:165–169. doi: 10.1016/0022-4731(82)90163-7. [DOI] [PubMed] [Google Scholar]
  22. Desforges M, Lacey HA, Glazier JD, Greenwood SL, Mynett KJ, Speake PF, Sibley CP. SNAT4 isoform of system A amino acid transporter is expressed in human placenta. Am J Physiol Cell Physiol. 2006;290:C305–312. doi: 10.1152/ajpcell.00258.2005. [DOI] [PubMed] [Google Scholar]
  23. Eskenazi B, Marks AR, Catalano R, Bruckner T, Toniolo PG. Low birthweight in New York City and upstate New York following the events of September 11th. Hum Reprod. 2007;22:3013–3020. doi: 10.1093/humrep/dem301. [DOI] [PubMed] [Google Scholar]
  24. Evans PC, Ffolliott-Powell FM, Harding JE. A colorimetric assay for amino nitrogen in small volumes of blood: reaction with β-naphthoquinone sulfonate. Anal Biochem. 1993;208:334–337. doi: 10.1006/abio.1993.1056. [DOI] [PubMed] [Google Scholar]
  25. Fowden AL, Forhead AJ, Coan PM, Burton GJ. The placenta and intrauterine programming. J Neuroendocrinol. 2008;20:439–450. doi: 10.1111/j.1365-2826.2008.01663.x. [DOI] [PubMed] [Google Scholar]
  26. Gardner DS, Jackson AA, Langley-Evans SC. Maintenance of maternal diet-induced hypertension in the rat is dependent on glucocorticoids. Hypertension. 1997;30:1525–1530. doi: 10.1161/01.hyp.30.6.1525. [DOI] [PubMed] [Google Scholar]
  27. Glazier JD, Cetin I, Perugino G, Ronzoni S, Grey AM, Mahendran D, Marconi AM, Pardi G, Sibley CP. Association between the activity of the system A amino acid transporter in the microvillous plasma membrane of the human placenta and severity of fetal compromise in intrauterine growth restriction. Pediatr Res. 1997;42:514–519. doi: 10.1203/00006450-199710000-00016. [DOI] [PubMed] [Google Scholar]
  28. Hewitt DP, Mark PJ, Waddell BJ. Glucocorticoids prevent the normal increase in placental vascular endothelial growth factor expression and placental vascularity during late pregnancy in the rat. Endocrinology. 2006;147:5568–5574. doi: 10.1210/en.2006-0825. [DOI] [PubMed] [Google Scholar]
  29. Itonaga K, Jones SM, Wapstra E. Do gravid females become selfish? Female allocation of energy during gestation. Physiol Biochem Zool. 2012;85:231–242. doi: 10.1086/665567. [DOI] [PubMed] [Google Scholar]
  30. Jansson N, Pettersson J, Haafiz A, Ericsson A, Palmberg I, Tranberg M, Ganapathy V, Powell TL, Jansson T. Down-regulation of placental transport of amino acids precedes the development of intrauterine growth restriction in rats fed a low protein diet. J Physiol. 2006;576:935–946. doi: 10.1113/jphysiol.2006.116509. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Jones HN, Ashworth CJ, Page KR, McArdle HJ. Cortisol stimulates system A amino acid transport and SNAT2 expression in a human placental cell line (BeWo) Am J Physiol Endocrinol Metab. 2006;291:E596–603. doi: 10.1152/ajpendo.00359.2005. [DOI] [PubMed] [Google Scholar]
  32. Jones HN, Woollett LA, Barbour N, Prasad PD, Powell TL, Jansson T. High-fat diet before and during pregnancy causes marked up-regulation of placental nutrient transport and fetal overgrowth in C57/BL6 mice. FASEB J. 2009;23:271–278. doi: 10.1096/fj.08-116889. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Khan AA, Rodriguez A, Kaakinen M, Pouta A, Hartikainen AL, Jarvelin MR. Does in utero exposure to synthetic glucocorticoids influence birthweight, head circumference and birth length? A systematic review of current evidence in humans. Paediatr Perinat Epidemiol. 2011;25:20–36. doi: 10.1111/j.1365-3016.2010.01147.x. [DOI] [PubMed] [Google Scholar]
  34. Khashan AS, McNamee R, Abel KM, Pedersen MG, Webb RT, Kenny LC, Mortensen PB, Baker PN. Reduced infant birthweight consequent upon maternal exposure to severe life events. Psychosom Med. 2008;70:688–694. doi: 10.1097/PSY.0b013e318177940d. [DOI] [PubMed] [Google Scholar]
  35. Langley-Evans SC. Hypertension induced by foetal exposure to a maternal low-protein diet, in the rat, is prevented by pharmacological blockade of maternal glucocorticoid synthesis. J Hypertens. 1997;15:537–544. doi: 10.1097/00004872-199715050-00010. [DOI] [PubMed] [Google Scholar]
  36. Lesage J, Blondeau B, Grino M, Breant B, Dupouy JP. Maternal undernutrition during late gestation induces fetal overexposure to glucocorticoids and intrauterine growth retardation, and disturbs the hypothalamo-pituitary adrenal axis in the newborn rat. Endocrinology. 2001;142:1692–1702. doi: 10.1210/endo.142.5.8139. [DOI] [PubMed] [Google Scholar]
  37. Lesage J, Del-Favero F, Leonhardt M, Louvart H, Maccari S, Vieau D, Darnaudery M. Prenatal stress induces intrauterine growth restriction and programmes glucose intolerance and feeding behaviour disturbances in the aged rat. J Endocrinol. 2004;181:291–296. doi: 10.1677/joe.0.1810291. [DOI] [PubMed] [Google Scholar]
  38. Love OP, Williams TD. The adaptive value of stress-induced phenotypes: effects of maternally derived corticosterone on sex-biased investment, cost of reproduction, and maternal fitness. Am Nat. 2008;172:E135–149. doi: 10.1086/590959. [DOI] [PubMed] [Google Scholar]
  39. Montano MM, Wang MH, Even MD, vom Saal FS. Serum corticosterone in fetal mice: sex differences, circadian changes, and effect of maternal stress. Physiol Behav. 1991;50:323–329. doi: 10.1016/0031-9384(91)90073-w. [DOI] [PubMed] [Google Scholar]
  40. Nyirenda MJ, Lindsay RS, Kenyon CJ, Burchell A, Seckl JR. Glucocorticoid exposure in late gestation permanently programs rat hepatic phosphoenolpyruvate carboxykinase and glucocorticoid receptor expression and causes glucose intolerance in adult offspring. J Clin Invest. 1998;101:2174–2181. doi: 10.1172/JCI1567. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Sferruzzi-Perri AN, Vaughan OR, Coan PM, Suciu MC, Darbyshire R, Constancia M, Burton GJ, Fowden AL. Placental-specific Igf2 deficiency alters developmental adaptations to undernutrition in mice. Endocrinology. 2011;152:3202–3212. doi: 10.1210/en.2011-0240. [DOI] [PubMed] [Google Scholar]
  42. Shibata E, Hubel CA, Powers RW, von Versen-Hoeynck F, Gammill H, Rajakumar A, Roberts JM. Placental system A amino acid transport is reduced in pregnancies with small for gestational age (SGA) infants but not in preeclampsia with SGA infants. Placenta. 2008;29:879–882. doi: 10.1016/j.placenta.2008.07.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Sibley CP, Coan PM, Ferguson-Smith AC, Dean W, Hughes J, Smith P, Reik W, Burton GJ, Fowden AL, Constancia M. Placental-specific insulin-like growth factor 2 (Igf2) regulates the diffusional exchange characteristics of the mouse placenta. Proc Natl Acad Sci U S A. 2004;101:8204–8208. doi: 10.1073/pnas.0402508101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Snedecor GW, Cochran WG. Statistical Methods. Ames: Iowa State College Press; 1967. [Google Scholar]
  45. Speirs HJ, Seckl JR, Brown RW. Ontogeny of glucocorticoid receptor and 11β-hydroxysteroid dehydrogenase type-1 gene expression identifies potential critical periods of glucocorticoid susceptibility during development. J Endocrinol. 2004;181:105–116. doi: 10.1677/joe.0.1810105. [DOI] [PubMed] [Google Scholar]
  46. Staud F, Mazancova K, Miksik I, Pavek P, Fendrich Z, Pacha J. Corticosterone transfer and metabolism in the dually perfused rat placenta: effect of 11β-hydroxysteroid dehydrogenase type 2. Placenta. 2006;27:171–180. doi: 10.1016/j.placenta.2005.01.001. [DOI] [PubMed] [Google Scholar]
  47. Thompson A, Han VK, Yang K. Spatial and temporal patterns of expression of 11β-hydroxysteroid dehydrogenase types 1 and 2 messenger RNA and glucocorticoid receptor protein in the murine placenta and uterus during late pregnancy. Biol Reprod. 2002;67:1708–1718. doi: 10.1095/biolreprod.102.005488. [DOI] [PubMed] [Google Scholar]
  48. Vaughan OR, Sferruzzi-Perri AN, Coan P, Fowden A. Environmental regulation of placental phenotype: implications for fetal growth. Reprod Fertil Dev. 2012;24:1–17. doi: 10.1071/RD11909. [DOI] [PubMed] [Google Scholar]
  49. Vegiopoulos A, Herzig S. Glucocorticoids, metabolism and metabolic diseases. Mol Cell Endocrinol. 2007;275:43–61. doi: 10.1016/j.mce.2007.05.015. [DOI] [PubMed] [Google Scholar]
  50. Ward IL, Weisz J. Differential effects of maternal stress on circulating levels of corticosterone, progesterone, and testosterone in male and female rat fetuses and their mothers. Endocrinology. 1984;114:1635–1644. doi: 10.1210/endo-114-5-1635. [DOI] [PubMed] [Google Scholar]

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