Maternally derived low glucocorticoid mediates adrenal developmental programming alteration in offspring induced by dexamethasone

Adverse environments during pregnancy can increase susceptibility to chronic diseases in adult offspring. The occurrence and development of fetal-originated diseases were associated with adrenal developmental programming and homeostasis alteration in offspring. Dexamethasone is widely used for preterm delivery-related pregnancy diseases, but the intrauterine programming alteration and its occurrence mechanism of prenatal dexamethasone exposure (PDE) on adrenal development in offspring have not been clarified. In this study, prenatal dexamethasone therapy could inhibit neonatal development and cause a low exposure of maternally derived glucocorticoid in clinic. Then, we established a rat model of PDE and observed a similar phenomenon. Further, the adrenal steroidogenic function was continuously inhibited in the PDE male offspring rats, accompanied by the decreased H3K27ac level of adrenal insulin-like growth factor 1 (IGF1) and its expression. Moreover, chronic stress in PDE adult offspring rats could reverse the changes of the above indicators through the high level of glucocorticoid. In combination with in vivo, in vitro and a series of interference experiments, we confirmed that the low level of endogenous glucocorticoids inhibited the adrenal IGF1 expression and steroidogenic function through the GRα/miR-370-3p/Sirt3 pathway. In summary, PDE could continuously inhibit the adrenal steroidogenic function in the male offspring, which is associated with the maternally derived low glucocorticoid-mediated the adrenal developmental programming alteration in offspring. This study provides a theoretical and experimental basis for explaining the adrenal development origin of PDE-induced adult chronic diseases. [Display omitted] •PDE leads to a low exposure of maternally derived glucocorticoid in the fetus through inhibiting maternal adrenal function.•The low level of endogenous glucocorticoids is the main cause of adrenal insufficiency in male offspring induced by PDE.•The positive programming of GC-IGF1 axis mediates adrenal insufficiency in PDE offspring, and there is a gender difference.