Differential expression of placental 11β-HSD2 induced by high maternal glucocorticoid exposure mediates sex differences in placental and fetal development

A variety of adverse environmental factors during pregnancy cause maternal chronic stress. Caffeine is a common stressor, and its consumption during pregnancy is widespread. Our previous study showed that prenatal caffeine exposure (PCE) increased maternal blood glucocorticoid levels and caused abnormal development of offspring. however, the placental mechanism for fetal development inhibition caused by PCE-induced high maternal glucocorticoid has not been reported. This study investigated the effects of PCE: induced high maternal glucocorticoid level on placental and fetal development by regulating placental 11 beta-hydroxysteroid dehydrogenase 2 (11 beta-HSD2) expression and its underlying mechanism. First, human placenta and umbilical cord blood samples were collected from women without prenatal use of synthetic glucocorticoids. We found that placental 11 beta-HSD2 expression was significantly correlated with umbilical cord blood corrisol level and birth weight in male newborns but not in females. Furthermore, we established a rat model of high maternal glucocorticoids induced by PCE (caffeine, 60 mg/kgd, ig), and found that the expression of 11 beta-HSD2 in male PCE placenta was decreased and negatively correlated with the maternal/fetal/placental corticosterone levels. Meanwhile, we found abnormal placental structure and nutrient transporter expression. In vitro, BeWo cells were used and confirm that 11 beta-HSD2 mediated inhibition of placental nutrient transporter expression induced by high levels of glucocorticoid. Finally, combined with the animal and cell experiments, we further confirmed that high maternal glucocorticoid could activate the GR-C/EBP alpha-Egr1 signaling pathway, leading to decreased expression of 11 beta-HSD2 in males. However, there was no significant inhibition of placental 11 beta-HSD2 expression, placental and fetal development in females. In summary, we confirmed that high maternal glucocorticoids could regulate placental 11 beta-HSD2 expression in a sex-specific manner, leading to differences in placental and fetal development. This study provides the theoretical and experimental basis for analyzing the inhibition of fetoplaccntal development and its sex difference caused by maternal stress.

Automated summary

This study demonstrates that high maternal glucocorticoids can regulate the expression of placental 11β-HSD2 in a sex-specific manner, resulting in differences in placental and fetal development.