Maternal corticosterone regulates nutrient allocation to fetal growth in mice

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 [(14)C]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.

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

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).

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

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.

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

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 ΔΔC_t method relative to Hprt1 and Sdha.

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

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 ΔΔC_t method relative to Hprt1 and Sdha.