We previously found that prenatal ethanol exposure (PEE) induced adrenal dysplasia in offspring, which was related to intrauterine maternal glucocorticoid overexposure. This study investigated the intergenerational genetic effect and sex differences of PEE-induced changes in the synthetic function of adrenal corticosterone in offspring, and to clarify the intrauterine origin programming mechanism. Wistar pregnant rats were gavaged with ethanol (4 g/kg bw/d) from gestation day (GD) 9–20, and F1 generation was born naturally. The F1 generation female rats in the PEE group were mated with normal male rats to produce F2 generation. Serum and adrenal glands of fetal rats and F1/F2 adult rats were collected at GD20 and postnatal week 28. PEE increased the serum corticosterone level, while diminishing the expression of adrenal steroid synthases of fetal rats. Moreover, PEE enhanced the mRNA expression of GR and HDAC1, but inhibited the mRNA expression of SF1 and reduced the H3K9ac level of P450scc in the fetal adrenal gland. In PEE adult offspring of F1 and F2 generation the serum corticosterone level, the H3K9ac level of P450scc and its expression were decreased in males but were increased in females. In NCI-H295R cells, cortisol reduced the production of endogenous cortisol, down-regulated SF1, and up-regulated HDAC1 expression by activating GR, and decreased H3K9ac level and expression of P450scc. In conclusion, PEE could induce adrenal dysplasia in offspring with sex differences and intergenerational genetic effects, and the adrenal insufficiency in male offspring was related to the induction of low functional genetic programming of P450scc by intrauterine high corticosterone through the GR/SF1/HDAC1 pathway.

我们之前发现产前乙醇暴露 (PEE) 会导致后代肾上腺发育不良，这与宫内母体糖皮质激素过度暴露有关。本研究探讨PEE引起后代肾上腺皮质酮合成功能变化的代际遗传效应和性别差异，阐明宫内起源程序化机制。从妊娠日 (GD) 9-20 给 Wistar 妊娠大鼠灌胃乙醇 (4 g/kg bw/d)，F1 代自然出生。PEE组F1代雌性大鼠与正常雄性大鼠交配产生F2代。在 GD20 和出生后第 28 周收集胎鼠和 F1/F2 成年大鼠的血清和肾上腺。 PEE 增加血清皮质酮水平，同时降低胎鼠肾上腺类固醇合成酶的表达。此外，PEE增强了GR和HDAC1的mRNA表达，但抑制了SF1的mRNA表达并降低了胎儿肾上腺中P450scc的H3K9ac水平。在 F1 和 F2 代 PEE 成年后代中，血清皮质酮水平、P450scc 的 H3K9ac 水平及其表达在雄性中降低，而在雌性中升高。在 NCI-H295R 细胞中，皮质醇通过激活 GR 减少内源性皮质醇的产生，下调 SF1 和上调 HDAC1 的表达，并降低 H3K9ac 水平和 P450scc 的表达。综上所述，PEE 可诱发具有性别差异和代际遗传效应的后代肾上腺发育不良，