Intergenerational genetic programming mechanism and sex differences of the adrenal corticosterone synthesis dysfunction in offspring induced by prenatal ethanol exposure.
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.
['Cao|Jiangang|J|', 'Chen|Yawen|Y|', 'Xia|Xuan|X|', 'Qu|Hui|H|', 'Ao|Ying|Y|', 'Wang|Hui|H|']
D000311:Adrenal Glands D000818:Animals D002460:Cell Line D003345:Corticosterone D000431:Ethanol D005260:Female D047109:Fetal Development D018507:Gene Expression Regulation, Developmental D006655:Histone Deacetylases D006854:Hydrocortisone D008297:Male D011247:Pregnancy D011297:Prenatal Exposure Delayed Effects D000072260:RNA Splicing Factors D051381:Rats D017208:Rats, Wistar D011965:Receptors, Glucocorticoid D012737:Sex Factors D013047:Specific Pathogen-Free Organisms
Sex differences Prenatal ethanol exposure Adrenal gland Cytochrome p450 cholesterol side-chain cleavage enzyme Intergenerational inheritance Steroid hormone synthesis function