Maternal Hypoxia Alters Glucocorticoid Regulation in Adult Female Offspring and Their Embryonic Progeny

Prenatal hypoxia is a clinically relevant adverse factor that may affect fetal development both directly and through activation of maternal glucocorticoid signaling. The placenta plays a central role in this process by regulating fetal exposure to maternal glucocorticoids, yet it remains unclear whether hypoxia-induced endocrine alterations can extend into the next generation and modify placental and fetal brain glucocorticoid regulation during embryogenesis. Here, we investigated whether maternal hypoxia programs the glucocorticoid phenotype of adult female offspring and whether this phenotype is associated with altered placental glucocorticoid signaling and fetal brain corticosterone exposure in their progeny.

Adult female rats prenatally exposed to maternal hypoxia (MH) were examined for 24-h plasma corticosterone rhythms. These females were then mated with control males, and embryonic tissues from their progeny (progeny of maternal hypoxic females, PMH) were collected at e14, e16, e18, and e20. Corticosterone concentrations were measured in amniotic fluid and fetal brain, whereas placental and fetal brain expression of glucocorticoid receptor-related genes and 11β-hydroxysteroid dehydrogenases was assessed by qRT-PCR and Western blotting.

MH females showed overall elevation of plasma corticosterone across the circadian cycle, with a higher fitted MESOR (Midline Estimating Statistic Of Rhythm, i.e. the rhythm-adjusted mean) and reduced rhythmic robustness. In PMH embryos, maternal and fetal placentas (MP and FP) displayed stage- and compartment-specific changes in Nr3c1 and Fkbp5 expression, accompanied by reduced FP Hsd11b2 mRNA at e14, but no change in HSD11B1 and HSD11B2 protein levels in the MP and FP throughout pregnancy. Amniotic fluid corticosterone was increased at e14, e16, and e20, whereas fetal brain corticosterone was elevated at e14 and e16. In fetal brain, Fkbp5 expression increased at e16 and e18, Dusp1 decreased at e20, and Hsd11b1 decreased at e16, whereas GR and HSD11B2 protein levels remained unchanged.

These findings indicate that maternal hypoxia is associated with persistent alteration of glucocorticoid regulation in adult female offspring and with developmental stage-specific remodeling of placental glucocorticoid handling and fetal brain glucocorticoid signaling in the next generation. Therefore, we conducted this pilot study to map circadian corticosterone profiles in female rats exposed to maternal hypoxia and to assess glucocorticoid regulation in their placenta and fetal brain during pregnancy. This approach provided a detailed, temporal understanding of intergenerational glucocorticoid programming.