Maternally derived glucocorticoid inhibits adrenal development in
offspring induced by prenatal dexamethasone exposure via IGF1
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.