Maternal glucocorticoids do not directly mediate the effects of maternal social stress on the fetus

• Published in: Journal of endocrinology Vol. 255; no. 3; pp. 143 - 158
• Main Authors: Sze, Ying, Fernandes, Joana, Kołodziejczyk, Zofia M, Brunton, Paula J
• Format: Journal Article
• Language: English
• Published: Bristol Bioscientifica Ltd 01.12.2022
• Subjects: placenta; prenatal stress; glucocorticoids; sex differences; pregnancy
• ISSN: 0022-0795; 1479-6805
• DOI: 10.1530/JOE-22-0226

Stress during pregnancy negatively affects the fetus and increases the risk for affective disorders in adulthood. Excess maternal glucocorticoids are thought to mediate fetal programming; however, whether they exert their effects directly or indirectly remains unclear. During pregnancy, protective mechanisms including maternal hypothalamic–pituitary–adrenal (HPA) axis hyporesponsiveness and placental 11β-hydroxysteroid dehydrogenase (11βHSD) type 2, which inactivates glucocorticoids, limit mother-to-fetus glucocorticoid transfer. However, whether repeated stress negatively impacts these mechanisms is not known. Pregnant rats were exposed to repeated social stress on gestational days (GD) 16–20 and several aspects of HPA axis and glucocorticoid regulation, including concentrations of glucocorticoids, gene expression for their receptors (Nr3c1, Nr3c2), receptor chaperones (Fkbp51, Fkbp52) and enzymes that control local glucocorticoid availability (Hsd11b1, Hsd11b2), were investigated in the maternal, placental and fetal compartments on GD20. The maternal HPA axis was activated following stress, though the primary driver was vasopressin, rather than corticotropin-releasing hormone. Despite the stress-induced increase in circulating corticosterone in the dams, only a modest increase was detected in the circulation of female fetuses, with no change in the fetal brain of either sex. Moreover, there was no change in the expression of genes that mediate glucocorticoid actions or modulate local concentrations in the fetal brain. In the placenta labyrinth zone, stress increased Hsd11b2 expression only in males and Fkbp51 expression only in females. Our results indicate that any role glucocorticoids play in fetal programming is likely indirect, perhaps through sex-dependent alterations in placental gene expression, rather than exerting effects via direct crossover into the fetal brain.