2,3,7,8-tetrachlorodibenzo- p-dioxin augments the modulation of gene expression mediated by the thyroid hormone receptor

Abstract

Previously, we reported on genes whose expression was highly modulated by T3 in the HeLaTR cells that stably expressed the thyroid hormone receptor (TR). In this study, we examined the effects of 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) on TR-mediated gene expression. In the HeLaTR cells, T3 induced the expression of the reporter gene in a thyroid hormone responsible element (TRE)-dependent manner. When the cells were cultured in the presence of T3, the addition of TCDD but not 4-hydroxy-2′,3,4′,5,6′-pentachlorobiphenyl (PCB-OH), bisphenol A (BPA), or di(2-ethylhexyl)phthalate (DEHP) to the culture media further enhanced the T3-induced expression of the reporter gene. RT-PCR revealed that mRNA levels of 4-1BB, fmfc, PSCA, PSG7, RANTES, and TRAF1, which were highly increased by T3, were further elevated in cells exposed to T3 and TCDD. Also, the mRNA level of BMP6, which was decreased by T3, further declined in the cells exposed to both T3 and TCDD. In contrast to the effect of TCDD, PCB-OH suppressed the modulation of these gene expressions by T3. Neither TCDD nor PCB-OH alone affected the expression of 4-1BB, fmfc, PSCA, PSG7, RANTES, TRAF1, or BMP6. These results indicate that TCDD augments the cellular responses to T3 by hyperactivating TR-mediated gene expression, whereas PCB-OH suppresses cellular responses to T3 by negatively regulating it. Based on these findings, enzyme-linked immunosorbent assay (ELISA) for the PSCA protein in the HeLaTR cells was established. Such assays will be useful to monitor the effects of endocrine disrupting chemicals (EDCs) on TR-mediated gene expression.