title: DNA hypermethylation of acetoacetyl-CoA synthetase contributes to inhibited cholesterol supply and steroidogenesis in fetal rat adrenals under prenatal nicotine exposure.
abstract: Prenatal nicotine exposure is a risk factor for intrauterine growth retardation (IUGR). Steroid hormones synthesized from cholesterol in the fetal adrenal play an important role in the fetal development. The aim of this study is to investigate the effects of prenatal nicotine exposure on steroidogenesis in fetal rat adrenals from the perspective of cholesterol supply and explore the underlying epigenetic mechanisms. Pregnant Wistar rats were administered 1.0mg/kg nicotine subcutaneously twice a day from gestational day (GD) 7 to GD17. The results showed that prenatal nicotine exposure increased IUGR rates. Histological changes, decreased steroid hormone concentrations and decreased cholesterol supply were observed in nicotine-treated fetal adrenals. In the gene expression array, the expression of genes regulating ketone metabolic process decreased in nicotine-treated fetal adrenals. The following conjoint analysis of DNA methylation array with these differentially expressed genes suggested that acetoacetyl-CoA synthetase (AACS), the enzyme utilizing ketones for cholesterol supply, may play an important role in nicotine-induced cholesterol supply deficiency. Moreover, the decreased expression of AACS and increased DNA methylation in the proximal promoter of AACS in the fetal adrenal was verified by real-time reverse-transcription PCR (RT-PCR) and bisulfite sequencing PCR (BSP), respectively. In conclusion, prenatal nicotine exposure can cause DNA hypermethylation of the AACS promoter in the rat fetal adrenal. These changes may result in decreased AACS expression and cholesterol supply, which inhibits steroidogenesis in the fetal adrenal.
authors.affiliation: Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, China.
authors.forename: Dong-Mei
authors.initials: DM
authors.lastname: Wu
authors.affiliation: Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: He
authors.affiliation: Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, China.
authors.forename: Liang-Peng
authors.initials: LP
authors.lastname: Ma
authors.affiliation: Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, China; Hubei Provincial Key Laboratory of Developmentally Originated Diseases, Wuhan 430071, China. Electronic address: pingjie@whu.edu.cn.
authors.forename: Jie
authors.initials: J
authors.lastname: Ping
mesh_terms: D000305:Adrenal Cortex Hormones / Q000096:biosynthesis*; D000311:Adrenal Glands / Q000187:drug effects* / Q000196:embryology / Q000201:enzymology; D000818:Animals; D002784:Cholesterol / Q000378:metabolism*; D003066:Coenzyme A Ligases / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation / Q000187:drug effects*; D044127:Epigenesis, Genetic / Q000187:drug effects*; D005260:Female; D005317:Fetal Growth Retardation / Q000139:chemically induced* / Q000201:enzymology / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic; D005865:Gestational Age; D018811:Maternal Exposure; D009538:Nicotine / Q000633:toxicity*; D018722:Nicotinic Agonists / Q000633:toxicity*; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D017208:Rats, Wistar
chemical_list: D000305:Adrenal Cortex Hormones; D018722:Nicotinic Agonists; D012333:RNA, Messenger; D009538:Nicotine; D002784:Cholesterol; D003066:Coenzyme A Ligases; C023747:acetoacetyl-CoA synthetase
keywords: Acetoacetyl-CoA synthetase (AACS); Cholesterol; DNA methylation; Fetal adrenal; Nicotine; Steroid hormones