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

Abstract

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 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.

Utero-placental expression and functional implications of HSD11B1 and HSD11B2 in canine pregnancy

“…In fact, in the rat, the bioactivity of HSD11B1 could not be measured in the placenta at different stages of pregnancy, despite being detectable at the mRNA level [68]. Furthermore, maternal stress in mice was associated with increased expression of HSD11B2 in the placenta, but did not affect HSD11B1 [69]. Nevertheless, the possible weak involvement of HSD11B1 in the canine placenta still needs to be further confirmed.…”

Sex differences in offspring risk and resilience following 11β-hydroxylase antagonism in a rodent model of maternal immune activation

“…It has been proposed that chronic maternal restraint stress decreases 11βHSD2 activity, allowing elevated levels of glucocorticoids to pass through the placenta, enter the fetus, and disrupt brain development by affecting fetal glucocorticoid receptors (Welberg et al, 2000Mairesse et al, 2007Jensen Peña et al, 2012). While studies on this effect in maternal psychological stress models remain inconclusive (Sze et al, 2022), lipopolysaccharide (LPS)-induced MIA downregulates 11βHSD2 mRNA (Straley et al, 2014;Núñez Estevez et al, 2020), leading to disruptions in glucocorticoid metabolism and subsequent changes in glucocorticoid and corticotropin-releasing hormone (CRH) receptor expression in offspring (Núñez Estevez et al, 2020;Connors et al, 2014;Zhao et al, 2020). These central changes were accompanied by sex-specific alterations in social behaviors, including reduced social preference and impaired social discrimination.…”