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Bisphenol A disrupts HNF4α-regulated gene networks linking to prostate preneoplasia in Noble rats

ABSTRACT: Exposure of humans to bisphenol A (BPA) is widespread and continuous. We previously showed that perinatal exposure to BPA increased prostate cancer risk in adult rats. Yet the effects of protracted, exposure to BPA during adulthood have not been studied. In this study, we subjected Noble rats to 32 weeks of co-treatment with testosterone (T) and BPA (low- or high-dose) or T and 17β-estradiol (E2) via Silastic capsule implants. Circulating T levels were comparable in all treatment groups, whereas the levels of free BPA were elevated in the groups that received T+low BPA (1.06 ± 0.05 ng/ml, P<0.05) and T+high BPA (10.37 ± 0.43 ng/ml, P<0.01) when compared with those in controls (0.1 ± 0.05 ng/ml). T+low/high BPA induced prostatic hyperplasia, low-grade prostatic intraepithelial neoplasia (PIN), and intraepithelial infiltration of T-lymphocytes only in the lateral prostates (LPs), whereas T+E2 induced high-grade PIN in this prostatic lobe. Genome-wide transcriptome analysis identified differential changes in the LPs of T+BPA and T+E2 treatments, with aberrant expression of multiple genes in the regulatory network controlled by the transcription factor hepatic nuclear factor 4α (HNF4α) specifically in BPA- but not E2-treated LPs. These findings suggest that the adult rat prostate is susceptible to transcriptomic reprogramming by BPA associated with the development of prostate pathology in a manner distinct from that of E2. The relevance of these data to the previous report demonstrating an association between high urinary levels of BPA and prostate cancer needs to be studied further.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE66633 | GEO | 2015/03/07

SECONDARY ACCESSION(S): PRJNA277505

REPOSITORIES: GEO

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Project description:Bisphenol A (BPA) is primarily used to make polycarbonate plastic, with a global capacity of production exceeding 8 million tons per year. Biomonitoring studies with human urine, blood and tissue samples suggest that humans are subjected to widespread and continuous exposure to BPA. It has been well established that early life exposure to BPA predisposes the prostate gland to carcinogenesis later in life. However, it remains unknown if BPA exposure during adulthood induces benign or neoplastic pathology in the prostate. The main objective of the present study is to determine the effects of BPA exposures during adulthood on the prostate and to characterize the global transcriptional reprogramming underlying endocrine disruption by BPA. We elevated circulating levels of free BPA in Noble rats to the human-relevant internal dose range with BPA-filled Silastic implants while maintaining the physiological levels of testosterone (T) with T-filled implants. Cotreatment with T and 17β-estradiol (E2) was our reference regimen which induced preneoplastic and cancereous lesions. The T + low/high dose of BPA induced prostatic hyperplasia, low-grade prostate intraepithelial neoplasia (LGPIN) and intraepithelial infiltration of T-lymphocytes specifically in the lateral prostate (LP). Using microarray analysis, we delineated specific impacts of low and high dose of BPA (with the T-support) on the gene expression program in LPs. Hierarchical clustering revealed that the endocrine disrupting effects of T + low dose of BPA showed partial resemblance to those of T + high dose of BPA and T+E2. In contrast, the influence of T+ high dose of BPA on the LP transcriptome was completely different from those of T + E2. Further, IPA analysis of specific T+ low or high BPA gene signature identified a transcription factor, HNF4α, as a regulatory hub affecting a number of differentially expressed genes by BPA exposures. These findings suggest that the adult rat prostate is still venerable to the endocrine disrupting effects of BPA. Perhaps chronic exposure to low dose of BPA provides a niche comprising heightened cell proliferation, inflammatory responses and disrupted gene expression program, which favor the onset and development of prostatic benign or malignant diseases in men. Rat lateral prostates were collected from untreated control and treated groups [Testosterone (T) + Estradiol (E2), T + low dose Bisphenol A (low BPA) and T + high BPA] for RNA extraction and hybridization on Affymetrix microarrays. We sought to identify transcriptional signature of BPA exposures in the lateral prostate gland.

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Bisphenol A disrupts HNF4α-regulated gene networks linking to prostate preneoplasia in Noble rats

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