Sex-Specific Differences in the Placental Unfolded Protein Response in a Rodent Model of Gestational Hypoxia

Abstract

Gestational hypoxia is a major contributor to fetal growth restriction (FGR) and perinatal morbidity and mortality and has been closely linked to the activation of the unfolded protein response (UPR) in the placenta. Recent studies on adverse pregnancy conditions show differential adaptive responses in pregnancies carrying male or female fetuses. Here, we use an established rat model of hypoxic pregnancy and FGR to test the hypothesis that chronic hypoxia promotes sexually dimorphic activation of the placental UPR. Our data showed that gestational hypoxia increased glucose regulatory protein 78 (GRP78) expression in male placentae, increased activating transcription factor 6 activation (ATF6) in female placentae, and did not induce changes in other UPR markers. In addition, gestational hypoxia reduced fetal weight only in males and ATF6 activation correlated with an increase in the fetal crown-rump-length/body weight ratio only in females. These results suggest sex-specific divergence in the placental adaptive response to gestational hypoxia, which may account for the sexual dimorphism observed in placental function and pregnancy outcomes in complicated pregnancies.

Keywords: Fetal growth restriction; Gestational hypoxia; Sexual dimorphism; Unfolded protein response.

Fig. 1

Values are mean ± S.E.M. for the relative ratio of GRP78/total protein (A), cleaved/total ATF6 (B), phosphorylated/total eIF2α (C), phosphorylated/total IRE1α (D), and NRLP3/total protein (E). Groups are male (M; ●) vs. female (F; ☐) and normoxia (N; red) vs. hypoxia (H; blue). The representative images of the whole membrane for total protein staining in (A) and (E) were vertically compressed to allow the intensity of all bands within the lanes to be visualized. Significant differences are P<0.05, two-way ANOVA with Sidak’s post hoc test.

Fig. 2

Values are mean ± S.E.M. for fetal weight (A) and fetal CRL/weight (B); the correlations of fetal weight and fetal CRL/weight with cleaved/total ATF6 in placentae from male (C and E) and female (D and F) fetuses. Groups are male (●) vs. female (☐) and normoxia (N; red) vs. hypoxia (H; blue). Significant differences are P<0.05, two-way ANOVA with Sidak’s post hoc test. Significant correlations (P<0.05) determined by Pearson’s correlation.