Background and Purpose: Dexamethasone is widely used in preterm labor and related diseases. However, prenatal dexamethasone exposure (PDE) can cause multi-organ developmental toxicities in offspring. Our previous study found the occurrence of fetal-originated diseases were associated with adrenal developmental programming alteration in offspring. Here, we investigated the effects of PDE on the adrenal function in offspring and its intrauterine programming mechanism. Experimental Approach: A rat model of PDE was established to observe the alteration of adrenal steroidogenesis in offspring. Further, we confirmed the gender difference of adrenal steroidogenesis and its molecular mechanism combined with in vivo and in vitro experiment. Key Results: PDE caused a decrease in adrenal steroidogenic function in fetal rats, but decreased in males and increased in females after birth. Meanwhile, the adrenal H3K14ac level and expression of 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2) in PDE offspring were decreased in males and increased in females, suggesting 11β-HSD2 might mediate gender difference of adrenal function. We further confirmed dexamethasone inhibited the H3K14ac level and expression of 11β-HSD2 through GR/SP1/p300 pathway. After bilateral testectomy or ovariectomy in adult PDE offspring rats, adrenal 11β-HSD2 expression and steroidogenic function were both reduced. Using rat primary fetal adrenal cells, the differential expression in AR and ERβ were proved to involve in regulating the gender difference of 11β-HSD2 expression. Conclusion and Implications: This study demonstrated the gender difference in adrenal steroidogenic function of PDE offspring after birth, and elucidates a sex hormone receptor-dependent epigenetically regulating mechanism for adrenal 11β-HSD2 programming alteration.

Background and Purpose: Adverse environments during pregnancy can increase susceptibility to chronic diseases in adult offspring, which might be related to intrauterine glucocorticoid-induced multi-organ developmental programming and homeostasis alterations. Dexamethasone is widely used for preterm delivery-related pregnancy diseases. Previous studies suggested that prenatal dexamethasone exposure (PDE) could cause developmental toxicity of adrenal gland in offspring and the underlying mechanism has not been elucidated. Experimental Approach: Wistar rats were subcutaneously injected with dexamethasone (0.2 mg/kg·d) during gestational day 9-20. The placentas and serum and adrenal samples were collected to identify the related indicators. In vitro, human adrenocortical cell lines (NCI-H295R) were treated with cortisol and dexamethasone to confirm the molecular mechanism, respectively. Key Results: PDE caused a low level of maternally derived glucocorticoid in male fetal blood. Furthermore, the serum corticosterone level, the H3K27ac and expression levels of the adrenal insulin-like growth factor 1 (IGF1), and steroidogenic function continuously decreased in the PDE male offspring rats. With chronic stress, the serum corticosterone level increased in the adult PDE offspring, while the above indicators were also increased correspondingly. In vitro, we further confirmed that the endogenous glucocorticoid positively programmed the adrenal IGF1 expression and steroidogenesis through the GRα/miR-370-3p/Sirt3 pathway. Conclusion and Implications: The low level of maternally derived glucocorticoid induced by PDE caused adrenal insufficiency of adult offspring rats through epigenetic positive programming of the glucocorticoid (GC)-IGF1 axis. This study firstly confirmed that exogenous glucocorticoids (dexamethasone) can alter the adrenal development programming and homeostasis in offspring by inhibiting maternal adrenal function.