title: Neonatal exposure to estradiol/bisphenol A alters promoter methylation and expression of Nsbp1 and Hpcal1 genes and transcriptional programs of Dnmt3a/b and Mbd2/4 in the rat prostate gland throughout life.
abstract: Evidence supporting an early origin of prostate cancer is growing. We demonstrated previously that brief exposure of neonatal rats to estradiol or bisphenol A elevated their risk of developing precancerous lesions in the prostate upon androgen-supported treatment with estradiol as adults. Epigenetic reprogramming may be a mechanism underlying this inductive event in early life, because we observed overexpression of phosphodiesterase 4D variant 4 (Pde4d4) through induction of hypomethylation of its promoter. This epigenetic mark was invisible in early life (postnatal d 10), becoming apparent only after sexual maturation. Here, we asked whether other estrogen-reprogrammable epigenetic marks have similar or different patterns in gene methylation changes throughout life. We found that hypomethylation of the promoter of nucleosome binding protein-1 (Nsbp1), unlike Pde4d4, is an early and permanent epigenetic mark of neonatal exposure to estradiol/bisphenol A that persists throughout life, unaffected by events during adulthood. In contrast, hippocalcin-like 1 (Hpcal1) is a highly plastic epigenetic mark whose hypermethylation depends on both type of early-life exposure and adult-life events. Four of the eight genes involved in DNA methylation/demethylation showed early and persistent overexpression that was not a function of DNA methylation at their promoters, including genes encoding de novo DNA methyltransferases (Dnmt3a/b) and methyl-CpG binding domain proteins (Mbd2/4) that have demethylating activities. Their lifelong aberrant expression implicates them in early-life reprogramming and prostate carcinogenesis during adulthood. We speculate that the distinctly different fate of early-life epigenetic marks during adulthood reflects the complex nature of lifelong editing of early-life epigenetic reprogramming.
authors: Department of Environmental Health, College of Medicine, University of Cincinnati, Cincinnati, Ohio 45267, USA.
authors: Wan-yee
authors: WY
authors: Tang
authors: Lisa M
authors: LM
authors: Morey
authors: Yuk Yin
authors: YY
authors: Cheung
authors: Lynn
authors: L
authors: Birch
authors: Gail S
authors: GS
authors: Prins
authors: Shuk-mei
authors: SM
authors: Ho
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D001483:Base Sequence; D001559:Benzhydryl Compounds; D002135:Calcium-Binding Proteins / Q000235:genetics*; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects; D000090205:DNA Methyltransferase 3A; D017931:DNA Primers / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D000077209:Decitabine; D004958:Estradiol / Q000008:administration & dosage* / Q000633:toxicity*; D015870:Gene Expression / Q000187:drug effects; D024001:HMGN Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010636:Phenols / Q000008:administration & dosage* / Q000633:toxicity*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011467:Prostate / Q000187:drug effects* / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D000097584:DNA Methyltransferase 3B; D000098826:Bisphenol A Compounds
chemical_list: D001374:Azacitidine; D001559:Benzhydryl Compounds; D002135:Calcium-Binding Proteins; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D017931:DNA Primers; D004268:DNA-Binding Proteins; D000077209:Decitabine; D004958:Estradiol; D024001:HMGN Proteins; D009419:Nerve Tissue Proteins; D010636:Phenols; D034741:RNA, Small Interfering; D000097584:DNA Methyltransferase 3B; C469810:Hpcal1 protein, rat; C115368:MBD2 protein; C006780:bisphenol A; D000098826:Bisphenol A Compounds