Androgen receptor activation by polychlorinated biphenyls: epigenetic effects mediated by the histone demethylase...

The exposure to environmental endocrine disrupting compounds (EDC), as polychlorinated biphenyls (PCBs), widely diffused in the environment may produce epigenetic changes that affect the endocrine system. We found that PCBs activate AR transcriptional activity and that this effect is potentiated by the demethylase Jarid1b, a histone demethylase that catalyzes the removal of trimethylation of lysine 4 on histone H3 (H3K4me3), induced by PCB. The aim of the present study was to investigate the effect of the treatment of cultured cells (HEK293) with a mixture of the most diffused environmental PCBs and, also with dihydrotestosterone (DHT), on the functional interaction between AR and Jarid1b. Although the effect induced by DHT on the AR transactivation was considerably higher, the PCB mixture produced an AR-mediated transactivation in a dose-dependent manner. Cotransfection with plasmids expressing Jarid1b and various AR isoforms containing polyglutamine tracts (polyQ tracts) of different lengths showed that Jarid1b potentiates the AR transcriptional activity induced by PCBs but only with the shortest AR isoform. The potentiating effect of Jarid1b on the AR is mediated by a direct interaction of the enzyme with the AR promoter. In fact, utilizing constructs containing AR promoters with a different length and a luciferase reporter gene, we showed that the effect of PCBs, but not of DHT, needs the presence of Jarid1b and of at least two DNA binding sites for Jarid1b.