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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.

Authors: Tang, Wan-yee; Morey, Lisa M; Cheung, Yuk Yin; Birch, Lynn; Prins, Gail S; Ho, Shuk-mei

Published In Endocrinology, (2012 Jan)

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.

PubMed ID: 22109888 Exiting the NIEHS site

MeSH Terms: Animals; Animals, Newborn; Azacitidine/analogs & derivatives; Azacitidine/pharmacology; Base Sequence; Benzhydryl Compounds; Calcium-Binding Proteins/genetics*; DNA (Cytosine-5-)-Methyltransferases/genetics; DNA Methylation/drug effects; DNA Primers/genetics; DNA-Binding Proteins/genetics; Estradiol/administration & dosage*; Estradiol/toxicity*; Gene Expression/drug effects; HMGN Proteins/antagonists & inhibitors; HMGN Proteins/genetics*; Male; Nerve Tissue Proteins/genetics*; Phenols/administration & dosage*; Phenols/toxicity*; Promoter Regions, Genetic/drug effects; Prostate/drug effects*; Prostate/metabolism*; RNA, Small Interfering/genetics; Rats; Rats, Sprague-Dawley

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