Dexamethasone is widely used to treat
preterm labor and related diseases. However, prenatal
dexamethasone treatment (
PDT) can cause multiorgan developmental toxicities in offspring. Our previous study found that the occurrence of fetal-originated diseases was associated with adrenal developmental programming alterations in offspring. Here, we investigated the effects of
PDT on adrenal function in offspring and its intrauterine programming mechanism. A rat model of
PDT was established to observe the alterations of adrenal steroidogenesis in offspring. Furthermore, we confirmed the sex differences of adrenal steroidogenesis and its molecular mechanism combined with in vivo and in vitro experiments.
PDT caused a decrease in adrenal steroidogenic function in fetal rats, but it was decreased in males and increased in females after birth. Meanwhile, the adrenal H3K14ac level and expression of 11β-hydroxysteroid
dehydrogenase 2 (11β-HSD2) in
PDT offspring were decreased in males and increased in females, suggesting that 11β-HSD2 might mediate sex differences in adrenal function. We further confirmed that
dexamethasone inhibited the H3K14ac level and expression of 11β-HSD2 through the GR/SP1/p300 pathway. After bilateral testectomy or
ovariectomy of adult
PDT offspring rats, adrenal 11β-HSD2 expression and steroidogenic function were both reduced. Using rat primary fetal adrenal cells, the differential expression of AR and ERβ was proven to be involved in regulating the sex difference in 11β-HSD2 expression. This study demonstrated the sex difference in adrenal steroidogenic function of
PDT offspring after birth and elucidated a
sex hormone receptor-dependent epigenetically regulating mechanism for adrenal 11β-HSD2 programming alteration.