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Maternally derived glucocorticoid inhibits adrenal development in offspring induced by prenatal dexamethasone exposure via IGF1
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  • Yawen Chen,
  • Xuan Xia,
  • Guanghui Chen,
  • Jiangang Cao,
  • Hui Wang
Yawen Chen
Wuhan University School of Basic Medical Sciences
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Xuan Xia
Wuhan University School of Basic Medical Sciences
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Guanghui Chen
Wuhan University School of Basic Medical Sciences
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Jiangang Cao
Wuhan University School of Basic Medical Sciences
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Hui Wang
Wuhan University School of Basic Medical Sciences
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Abstract

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.