title: Perinatal bisphenol A exposure promotes dose-dependent alterations of the mouse methylome.
abstract: BACKGROUND
  Environmental factors during perinatal development may influence developmental plasticity and disease susceptibility via alterations to the epigenome. Developmental exposure to the endocrine active compound, bisphenol A (BPA), has previously been associated with altered methylation at candidate gene loci. Here, we undertake the first genome-wide characterization of DNA methylation profiles in the liver of murine offspring exposed perinatally to multiple doses of BPA through the maternal diet.
  
  
  RESULTS
  Using a tiered focusing approach, our strategy proceeds from unbiased broad DNA methylation analysis using methylation-based next generation sequencing technology to in-depth quantitative site-specific CpG methylation determination using the Sequenom EpiTYPER MassARRAY platform to profile liver DNA methylation patterns in offspring maternally exposed to BPA during gestation and lactation to doses ranging from 0 BPA/kg (Ctr), 50 μg BPA/kg (UG), or 50 mg BPA/kg (MG) diet (N = 4 per group). Genome-wide analyses indicate non-monotonic effects of DNA methylation patterns following perinatal exposure to BPA, corroborating previous studies using multiple doses of BPA with non-monotonic outcomes. We observed enrichment of regions of altered methylation (RAMs) within CpG island (CGI) shores, but little evidence of RAM enrichment in CGIs. An analysis of promoter regions identified several hundred novel BPA-associated methylation events, and methylation alterations in the Myh7b and Slc22a12 gene promoters were validated. Using the Comparative Toxicogenomics Database, a number of candidate genes that have previously been associated with BPA-related gene expression changes were identified, and gene set enrichment testing identified epigenetically dysregulated pathways involved in metabolism and stimulus response.
  
  
  CONCLUSIONS
  In this study, non-monotonic dose dependent alterations in DNA methylation among BPA-exposed mouse liver samples and their relevant pathways were identified and validated. The comprehensive methylome map presented here provides candidate loci underlying the role of early BPA exposure and later in life health and disease status.
authors.forename: Jung H
authors.initials: JH
authors.lastname: Kim
authors.forename: Maureen A
authors.initials: MA
authors.lastname: Sartor
authors.forename: Laura S
authors.initials: LS
authors.lastname: Rozek
authors.forename: Christopher
authors.initials: C
authors.lastname: Faulk
authors.forename: Olivia S
authors.initials: OS
authors.lastname: Anderson
authors.forename: Tamara R
authors.initials: TR
authors.lastname: Jones
authors.forename: Muna S
authors.initials: MS
authors.lastname: Nahar
authors.affiliation: Department of Environmental Health Sciences, University of Michigan, 1415 Washington Heights, Ann Arbor, Michigan, USA. ddolinoy@umich.edu.
authors.forename: Dana C
authors.initials: DC
authors.lastname: Dolinoy
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds / Q000633:toxicity*; D018899:CpG Islands; D019175:DNA Methylation / Q000187:drug effects*; D030541:Databases, Genetic; D004032:Diet; D005260:Female; D016678:Genome; D023281:Genomics; D059014:High-Throughput Nucleotide Sequencing; D007774:Lactation; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051379:Mice; D018995:Myosin Heavy Chains / Q000235:genetics; D024462:Myosin Type II / Q000235:genetics; D027361:Organic Anion Transporters / Q000235:genetics; D010636:Phenols / Q000633:toxicity*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011401:Promoter Regions, Genetic; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D018995:Myosin Heavy Chains; D024462:Myosin Type II; D027361:Organic Anion Transporters; D010636:Phenols; C483905:Myh14 protein, mouse; C109687:Slc22a12 protein, mouse; C006780:bisphenol A; D000098826:Bisphenol A Compounds