Bisphenol A disrupts HNF4-regulated gene networks linking to prostate preneoplasia in Noble rats

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 17-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 4 (HNF4) 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.

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