Endocrine disruptors provoke differential modulatory responses on androgen receptor and pregnane and xenobiotic receptor: potential implications in metabolic disorders

Abstract

A systematic comparison of the impact of some potential endocrine disruptors (EDs) on modulation of androgen receptor (AR) and pregnane and xenobiotic receptor (PXR) function was conducted in a multi-step analysis. Promoter-reporter-based transcription assays were performed in conjunction with receptor dynamic studies in living cells that helped implicating the suspected EDs for their deleterious effects. We demonstrate that most of the selected EDs not only inhibit AR transcriptional activity, but also alter its subcellular dynamics. Conversely, some of these anti-androgenic compounds were potent activator of xeno-sensing nuclear receptor, PXR. Interestingly, agonist-activated AR that associates with the mitotic chromatin fails to achieve this association when bound to anti-androgenic EDs. Conclusively, most EDs (except BCH) behaved like pure antagonist for AR while as agonist for PXR. Subsequent experiments with DDT treatment in mice model indicated that in testis AR and its regulated genes PEM and ODC levels are down-regulated, whereas in liver of same mice PEM is up-regulated while AR and ODC remain unchanged. On the contrary, PXR and its regulated genes CYP3A11 and MDR1 levels in mice liver were up-regulated while in testis PXR remained unchanged, CYP3A11 up-regulated and MDR1 were down-regulated. Based on a novel "Biopit" concept it is speculated that long-term exposure to endocrine disrupting chemicals may influence the epigenetic profile of target cells via transcription factors thereby making them vulnerable to onset of chemically induced endocrine-related malignancies or metabolic disorders.