Sex difference in adrenal developmental toxicity induced by dexamethasone and its intrauterine programming mechanism

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 11 beta-hydroxysteroid dehydrogenase 2 (11 beta-HSD2) in PDT offspring were decreased in males and increased in females, suggesting that 11 beta-HSD2 might mediate sex differences in adrenal function. We further confirmed that dexamethasone inhibited the H3K14ac level and expression of 11 beta-HSD2 through the GR/SP1/p300 pathway. After bilateral testectomy or ovariectomy of adult PDT offspring rats, adrenal 11 beta-HSD2 expression and steroidogenic function were both reduced. Using rat primary fetal adrenal cells, the differential expression of AR and ERB was proven to be involved in regulating the sex difference in 11 beta-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 11 beta-HSD2 programming alteration.

Automated summary

The study investigated the effects of prenatal dexamethasone treatment (PDT) on adrenal function in offspring, revealing sex differences in adrenal steroidogenic function after birth. It was found that dexamethasone inhibited the H3K14ac level and expression of 11 beta-HSD2 through the GR/SP1/p300 pathway, with sex hormone receptors involved in regulating the sex difference in 11 beta-HSD2 expression.