PBCs environmental pollution and epigenome: a new role for androgen receptor-dependent modulation?

Epigenome is an important target of environmental effects, modulating disease susceptibility during the whole life. In our previous studies we have demonstrated that prenatal exposure to polychlorinated biphenyls (PCBs), an important class of endocrine disruptors, alters in liver some histone post-translational modifications (H3K4me3/H4K16Ac) and the expression of the corresponding modulating enzymes (Jarid1b/SirtT1) and reduces the androgen receptor (AR) levels1. Furthermore, it is known that steroid receptors could act also as co-regulator of histone modification enzymes. It is also remarkable that AR and Jarid1b (demethylating enzyme) interact each other and that Jarid1b is able to potentiate the transcriptional activity of AR2. The AR down-regulation, shown by our data, is not directly related to the reduction of H3K4me3 levels in the AR promoter, as our ChIP experiments have indicated1. The observed AR reduction might be related to the down-regulation of AR induced by its own activation3. The aim of this work was to characterize the complex scenario of AR involvement in regulating histone modifications. First of all, we investigated if a reconstituted mixture of PCBs is able to modulate AR transcriptional activity; we observed that PCBs are able to induce AR mediated transcription in a dose dependent way and that Jarid1b presence potentiates the PCB effect on AR transcriptional activity. Furthermore we showed that the localization of PCB- activated AR is influenced by Jarid1b presence. Finally, using AR promoter fused with a reporter gene, we found that PCBs are able to auto-downregulate AR, especially at the presence of Jarid1b. In conclusion it is possible to hypothesize that AR modulation exerted by PCB pass through chromatin structure remodelling. It remains to clarify if AR is involved in mediating PCB induced disruption of Jarid1b.