Polychlorinated biphenyls (PCBs) suppress thyroid hormone (TH) receptor (TR) - mediated transcription by dissociating TR-TH response element (TRE) binding partially

Abstract

PCBs are known as environmental contaminants that cause various effects in many organs including the central nerve system. Some PCBs pass through blood brain barrier (BBB) to accumulate in brain and cause disruptions of brain development. Previously we reported that very low dose, as low as 10-10M of hydroxylated PCBs suppressed TR-mediated transcription. However, the mechanism of suppression by PCB is not clarified. To understand the mechanism, we first examined the effects of PCB on coactivator and coreppressor interaction with TR using mammalian two-hybrid assay in CV-1 cell and GST pull-down study. TR-mediated transcription stimulated by steroid receptor coactivator-1 (SRC-1) was suppressed by PCBs. However, the binding of SRC-1 to TR was not dissociated by PCBs. PCBs did not recruit nuclear receptor corepressor (N-CoR) to TR in the presence of T3. Next, we examined PCB effects on TR binding to TRE by electorophoretic mobility shift assay. TR/retinoid X receptor (RXR) heterodimer complex was partially dissociated from TRE in the presence of PCBs. These results indicate that PCB suppressed TR-mediated transcriptional activation by partial dissociation of TR/RXR heterodimer complex from TRE. [Jpn J Physiol 54 Suppl:S221 (2004)]