Interactive mechanism of halogenated aromatic hydrocarbons on AH receptor signal transduction pathway

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Chen, Guosheng
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University of Guelph

Exposure to halogenated aromatic hydrocarbons (HAHs) invariably involves complex mixtures rather than individual congeners. 2,3,7,8-Tetrachlorodibenzo-' p'-dioxin (TCDD) is a prototype of HAHs, which appear to share a common mechanism of toxicity and biochemical responses through the aryl hydrocarbon receptor (AhR). Less potent HAHs antagonize the toxicity of the potent congeners. The Ah receptor mediated signal transduction pathway leading to the induction of cytochrome P4501A1 in primary rat hepatocytes was utilized to investigate the mechanism of AhR action at each stage for representative HAHs, and to identify the point of divergence in the mechanism between an AhR agonist and antagonist. Non-'ortho' PCBs 77 and 126, and mono-' ortho' PCB 156 were full agonists at the stage of 'CYP1A1' gene transcription and CYP1A1 protein induction and non-antagonism was observed in combination with TCDD at these two stages. Non-planar PCB 153 was a partial AhR agonist and antagonist. The commonly reported decrease of ethoxyresorufin-' O'-deethylase (EROD) activity by PCBs at high concentration and their antagonism with TCDD in the EROD assay were completely due to the inhibition of the enzyme activity. The applied aspect of this study was to assess the dioxin-like activity of widely used flame retardants, polybrominated diphenyl ethers (PBDEs). Nineteen PBDE congeners and three commercial mixtures were systematically investigated at each stage of the AhR signaling pathway. PBDEs were weak AhR agonists with AhR binding affinity 2 to 5 orders of magnitude less than TCDD. PBDEs 77, 119 and 126 were the most potent congeners to show AhR-DRE complex formation, P4501A1 mRNA and protein induction. The environmentally predominant congeners 47, 99 and three commercial mixtures were weak or inactive in AhR action. PBDE congeners acted as AhR antagonist for AhR-DRE complex formation but not at mRNA and protein induction stages. The abilities of PBDEs to induce EROD activity were studied in primary chicken and rat hepatocytes, cell lines from rainbow trout (RTL-W1), rat (H4IIE) and human (HepG2, Caco-2). In all the cell cultures, PBDEs showed similar rank order with relative potency (REP) around 10-4 or less, similar to reported mono-'ortho' PCBs or PAHs, which indicated that PBDEs are weak CYP1A1 inducers.

halogenated aromatic hydrocarbons, AH receptor, signal transduction pathway, flame retardants, polybrominated diphenyl ethers