Preferential epigenetic programming of estrogen response after in utero xenoestrogen (bisphenol-A) exposure.
Bisphenol-A (BPA) is an environmentally ubiquitous estrogen-like endocrine-disrupting compound. Exposure to BPA in utero has been linked to female reproductive disorders, including endometrial hyperplasia and breast cancer. Estrogens are an etiological factor in many of these conditions. We sought to determine whether in utero exposure to BPA altered the global CpG methylation pattern of the uterine genome, subsequent gene expression, and estrogen response. Pregnant mice were exposed to an environmentally relevant dose of BPA or DMSO control. Uterine DNA and RNA were examined by using methylated DNA immunoprecipitation methylation microarray, expression microarray, and quantitative PCR. In utero BPA exposure altered the global CpG methylation profile of the uterine genome and subsequent gene expression. The effect on gene expression was not apparent until sexual maturation, which suggested that estrogen response was the primary alteration. Indeed, prenatal BPA exposure preferentially altered adult estrogen-responsive gene expression. Changes in estrogen response were accompanied by altered methylation that preferentially affected estrogen receptor-α (ERα)-binding genes. The majority of genes that demonstrated both altered expression and ERα binding had decreased methylation. BPA selectively altered the normal developmental programming of estrogen-responsive genes via modification of the genes that bind ERα. Gene-environment interactions driven by early life xenoestrogen exposure likely contributes to increased risk of estrogen-related disease in adults.-Jorgensen, E. M., Alderman, M. H., III, Taylor, H. S. Preferential epigenetic programming of estrogen response after in utero xenoestrogen (bisphenol-A) exposure.
Yale University School of Medicine, New Haven, Connecticut, USA.
Elisa M
EM
Jorgensen
Yale University School of Medicine, New Haven, Connecticut, USA.
Myles H
MH
Alderman
Yale University School of Medicine, New Haven, Connecticut, USA hugh.taylor@yale.edu.
Hugh S
HS
Taylor
D000818:Animals; D001559:Benzhydryl Compounds / Q000633:toxicity*; D044127:Epigenesis, Genetic / Q000187:drug effects*; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D010636:Phenols / Q000633:toxicity*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D000098826:Bisphenol A Compounds
D001559:Benzhydryl Compounds; D047628:Estrogen Receptor alpha; D004967:Estrogens; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins; D010636:Phenols; C092119:Hoxa10 protein, mouse; C006780:bisphenol A; D000098826:Bisphenol A Compounds
ERα binding; endocrine disruptor; methylation; uterus