Bisphenol A Disrupts HNF4α-Regulated Gene Networks Linking to Prostate Preneoplasia and Immune Disruption in Noble Rats.
Exposure of humans to bisphenol A (BPA) is widespread and continuous. The effects of protracted exposure to BPA on the adult prostate have not been studied. We subjected Noble rats to 32 weeks of BPA (low or high dose) or 17β-estradiol (E2) in conjunction with T replenishment. T treatment alone or untreated groups were used as controls. Circulating T levels were maintained within the physiological range in all treatment groups, whereas the levels of free BPA were elevated in the groups treated with T+low BPA (1.06 ± 0.05 ng/mL, P < .05) and T+high BPA (10.37 ± 0.43 ng/mL, P < .01) when compared with those in both controls (0.1 ± 0.05 ng/mL). Prostatic hyperplasia, low-grade prostatic intraepithelial neoplasia (PIN), and marked infiltration of CD4+ and CD8+ T cells into the PIN epithelium (P < .05) were observed in the lateral prostates (LPs) of T+low/high BPA-treated rats. In contrast, only hyperplasia and high-grade PIN, but no aberrant immune responses, were found in the T+E2-treated LPs. Genome-wide transcriptome analysis in LPs identified differential changes between T+BPA vs T+E2 treatment. Expression of multiple genes in the regulatory network controlled by hepatocyte nuclear factor 4α was perturbed by the T+BPA but not by the T+E2 exposure. Collectively these findings suggest that the adult rat prostate, under a physiologically relevant T environment, is susceptible to BPA-induced transcriptomic reprogramming, immune disruption, and aberrant growth dysregulation in a manner distinct from those caused by E2. They are more relevant to our recent report of higher urinary levels BPA found in patients with prostate cancer than those with benign disease.
Department of Environmental Health (H.-M.L., S.-M.H., J.C., M.M., N.N.C.T.), Center for Environmental Genetics (H.-M.L., S.-M.H., J.C., M.M., N.N.C.T.), Cincinnati Cancer Center (S.-M.H., M.M., N.N.C.T.), University of Cincinnati College of Medicine, Cincinnati, Ohio 45267; and Cincinnati Veteran Affairs Hospital Medical Center (S.-M.H.), Cincinnati, Ohio 45220.
Hung-Ming
HM
Lam
Department of Environmental Health (H.-M.L., S.-M.H., J.C., M.M., N.N.C.T.), Center for Environmental Genetics (H.-M.L., S.-M.H., J.C., M.M., N.N.C.T.), Cincinnati Cancer Center (S.-M.H., M.M., N.N.C.T.), University of Cincinnati College of Medicine, Cincinnati, Ohio 45267; and Cincinnati Veteran Affairs Hospital Medical Center (S.-M.H.), Cincinnati, Ohio 45220.
Shuk-Mei
SM
Ho
Department of Environmental Health (H.-M.L., S.-M.H., J.C., M.M., N.N.C.T.), Center for Environmental Genetics (H.-M.L., S.-M.H., J.C., M.M., N.N.C.T.), Cincinnati Cancer Center (S.-M.H., M.M., N.N.C.T.), University of Cincinnati College of Medicine, Cincinnati, Ohio 45267; and Cincinnati Veteran Affairs Hospital Medical Center (S.-M.H.), Cincinnati, Ohio 45220.
Jing
J
Chen
Department of Environmental Health (H.-M.L., S.-M.H., J.C., M.M., N.N.C.T.), Center for Environmental Genetics (H.-M.L., S.-M.H., J.C., M.M., N.N.C.T.), Cincinnati Cancer Center (S.-M.H., M.M., N.N.C.T.), University of Cincinnati College of Medicine, Cincinnati, Ohio 45267; and Cincinnati Veteran Affairs Hospital Medical Center (S.-M.H.), Cincinnati, Ohio 45220.
Mario
M
Medvedovic
Department of Environmental Health (H.-M.L., S.-M.H., J.C., M.M., N.N.C.T.), Center for Environmental Genetics (H.-M.L., S.-M.H., J.C., M.M., N.N.C.T.), Cincinnati Cancer Center (S.-M.H., M.M., N.N.C.T.), University of Cincinnati College of Medicine, Cincinnati, Ohio 45267; and Cincinnati Veteran Affairs Hospital Medical Center (S.-M.H.), Cincinnati, Ohio 45220.
Neville Ngai Chung
NN
Tam
D000818:Animals; D001559:Benzhydryl Compounds / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004343:Drug Implants; D052244:Endocrine Disruptors / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D004958:Estradiol / Q000008:administration & dosage / Q000494:pharmacology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D051557:Hepatocyte Nuclear Factor 4 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020249:Hormone Replacement Therapy; D007157:Immunologic Surveillance / Q000187:drug effects*; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D060787:Neoplasm Grading; D009929:Organ Size / Q000187:drug effects; D010636:Phenols / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D011467:Prostate / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D019048:Prostatic Intraepithelial Neoplasia / Q000139:chemically induced* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000139:chemically induced* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D011919:Rats, Inbred Strains; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013739:Testosterone / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology; D066007:Toxicokinetics; D000098826:Bisphenol A Compounds
D001559:Benzhydryl Compounds; D004343:Drug Implants; D052244:Endocrine Disruptors; D004958:Estradiol; D051557:Hepatocyte Nuclear Factor 4; D010636:Phenols; D013739:Testosterone; C496594:Hnf4a protein, rat; C006780:bisphenol A; D000098826:Bisphenol A Compounds