Gender difference in adrenal developmental toxicity induced by
dexamethasone and its intrauterine programming mechanism
Abstract
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.