title: DNA methylome changes by estradiol benzoate and bisphenol A links early-life environmental exposures to prostate cancer risk.
abstract: Developmental exposure to endocrine-disrupting chemicals (EDCs), 17β-estradiol-3-benzoate (EB) and bisphenol A (BPA), increases susceptibility to prostate cancer (PCa) in rodent models. Here, we used the methylated-CpG island recovery assay (MIRA)-assisted genomic tiling and CpG island arrays to identify treatment-associated methylome changes in the postnatal day (PND)90 dorsal prostate tissues of Sprague-Dawley rats neonatally (PND1, 3, and 5) treated with 25 µg/pup or 2,500 µg EB/kg body weight (BW) or 0.1 µg BPA/pup or 10 µg BPA/kg BW. We identified 111 EB-associated and 86 BPA-associated genes, with 20 in common, that have significant differentially methylated regions. Pathway analysis revealed cancer as the top common disease pathway. Bisulfite sequencing validated the differential methylation patterns observed by array analysis in 15 identified candidate genes. The methylation status of 7 (Pitx3, Wnt10b, Paqr4, Sox2, Chst14, Tpd52, Creb3l4) of these 15 genes exhibited an inverse correlation with gene expression in tissue samples. Cell-based assays, using 5-aza-cytidine-treated normal (NbE-1) and cancerous (AIT) rat prostate cells, added evidence of DNA methylation-mediated gene expression of 6 genes (exception: Paqr4). Functional connectivity of these genes was linked to embryonic stem cell pluripotency. Furthermore, clustering analyses using the dataset from The Cancer Genome Atlas revealed that expression of this set of 7 genes was associated with recurrence-free survival of PCa patients. In conclusion, our study reveals that gene-specific promoter methylation changes, resulting from early-life EDC exposure in the rat, may serve as predictive epigenetic biomarkers of PCa recurrence, and raises the possibility that such exposure may impact human disease.
authors.affiliation: a Department of Environmental Health , University of Cincinnati College of Medicine , Cincinnati , OH , USA.|b Center for Environmental Genetics, University of Cincinnati College of Medicine , Cincinnati , OH , USA.
authors.forename: Ana
authors.initials: A
authors.lastname: Cheong
authors.affiliation: a Department of Environmental Health , University of Cincinnati College of Medicine , Cincinnati , OH , USA.|b Center for Environmental Genetics, University of Cincinnati College of Medicine , Cincinnati , OH , USA.
authors.forename: Xiang
authors.initials: X
authors.lastname: Zhang
authors.affiliation: a Department of Environmental Health , University of Cincinnati College of Medicine , Cincinnati , OH , USA.
authors.forename: Yuk-Yin
authors.initials: YY
authors.lastname: Cheung
authors.affiliation: a Department of Environmental Health , University of Cincinnati College of Medicine , Cincinnati , OH , USA.|b Center for Environmental Genetics, University of Cincinnati College of Medicine , Cincinnati , OH , USA.
authors.forename: Wan-Yee
authors.initials: WY
authors.lastname: Tang
authors.affiliation: a Department of Environmental Health , University of Cincinnati College of Medicine , Cincinnati , OH , USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: c Department of Urology , College of Medicine, University of Illinois at Chicago , Chicago , IL , USA.
authors.forename: Shu-Hua
authors.initials: SH
authors.lastname: Ye
authors.affiliation: a Department of Environmental Health , University of Cincinnati College of Medicine , Cincinnati , OH , USA.|b Center for Environmental Genetics, University of Cincinnati College of Medicine , Cincinnati , OH , USA.|d Cincinnati Cancer Center , Cincinnati , OH , USA.
authors.forename: Mario
authors.initials: M
authors.lastname: Medvedovic
authors.affiliation: a Department of Environmental Health , University of Cincinnati College of Medicine , Cincinnati , OH , USA.|b Center for Environmental Genetics, University of Cincinnati College of Medicine , Cincinnati , OH , USA.|d Cincinnati Cancer Center , Cincinnati , OH , USA.
authors.forename: Yuet-Kin
authors.initials: YK
authors.lastname: Leung
authors.affiliation: c Department of Urology , College of Medicine, University of Illinois at Chicago , Chicago , IL , USA.|e University of Illinois Cancer Center , Chicago , IL , USA.
authors.forename: Gail S
authors.initials: GS
authors.lastname: Prins
authors.affiliation: a Department of Environmental Health , University of Cincinnati College of Medicine , Cincinnati , OH , USA.|b Center for Environmental Genetics, University of Cincinnati College of Medicine , Cincinnati , OH , USA.|d Cincinnati Cancer Center , Cincinnati , OH , USA.|f Cincinnati Veteran Affairs Hospital Medical Center , Cincinnati , OH , USA.
authors.forename: Shuk-Mei
authors.initials: SM
authors.lastname: Ho
mesh_terms: D000395:Air Pollutants, Occupational / Q000633:toxicity*; D000818:Animals; D001559:Benzhydryl Compounds / Q000633:toxicity*; D045744:Cell Line, Tumor; D018899:CpG Islands; D019175:DNA Methylation; D004781:Environmental Exposure; D044127:Epigenesis, Genetic; D004958:Estradiol / Q000031:analogs & derivatives* / Q000633:toxicity; D005260:Female; D056426:Genetic Loci; D006801:Humans; D008297:Male; D010636:Phenols / Q000633:toxicity*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016019:Survival Analysis; D000098826:Bisphenol A Compounds
chemical_list: D000395:Air Pollutants, Occupational; D001559:Benzhydryl Compounds; D004958:Estradiol; D010636:Phenols; C074283:estradiol 3-benzoate; C006780:bisphenol A; D000098826:Bisphenol A Compounds
keywords: Developmental origin of health and disease (DOHaD); Ingenuity®; NimbleGen rat DNA methylation promoter array; Pathway Analysis (IPA®); Sprague Dawley rats; The Cancer Genome Atlas (TCGA); early-life reprogramming; endocrine-disrupting chemicals (EDCs); epigenetics; methylated-CpG island recovery assay (MIRA); stem cell pluripotency