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Antagonism of aryl hydrocarbon receptor-dependent induction of CYP1A1 and inhibition of IgM expression by di-ortho-substituted polychlorinated biphenyls.

Abstract：

:Halogenated aromatic hydrocarbons (HAHs) are ubiquitous environment contaminants that produce many of their toxic effects by binding to the aryl hydrocarbon receptor (AhR). However, several investigations have demonstrated that certain polychlorinated biphenyl (PCB) congeners, principally di-ortho-chlorinated PCB congeners, or mixtures containing multiple di-ortho-chlorinated PCBs, inhibit AhR-mediated responses induced by other toxic HAHs. Most relevant to the present study are past reports demonstrating antagonism by these uniquely acting PCB congeners on AhR agonist-mediated inhibition of humoral immune responses. The mechanism responsible for antagonism of AhR agonists by certain PCBs is presently unknown. The present study evaluated the antagonist activity of several di-ortho-substituted PCB congeners [PCB47 (2,2',4,4'), PCB52 (2,2',5,5'), PCB128 (2,2',3,3',4,4'), and PCB153 (2,2',4,4',5,5')] when present in combination with AhR agonists [TCDD (2,3,7,8,-tetrachlorodibenzo-p-dioxin), PCB126 (3,3',4,4',5), and PCB77 (3,3',4,4')] on CYP1A1 induction and inhibition of lipopolysaccharide (LPS)-induced immunoglobulin production in the CH12.LX B cell line. In contrast to non-ortho-substituted PCB (PCB77), which showed additive effects on CYP1A1 induction in combination with TCDD, all of the di-ortho-substituted PCBs examined produced antagonism. Di-ortho-substituted PCB (PCB52) also antagonized TCDD- or PCB126- mediated inhibition of IgM secretion and immunoglobulin heavy chain mRNA expression in the LPS-activated B cells. In addition, PCB52 inhibited TCDD-induced AhR DNA binding to a dioxin-responsive element. Collectively, these results suggest that the mechanism responsible for antagonism by di-ortho-substituted PCB congeners of AhR agonist-mediated CYP1A1 induction and inhibition of antibody responses in B cells occurs through interference with agonist activation of the cytosolic AhR complex.

journal_name

Toxicol Appl Pharmacol

journal_title

Toxicology and applied pharmacology

authors

Suh J,Kang JS,Yang KH,Kaminski NE

doi

10.1016/s0041-008x(02)00040-6

subject

Has Abstract

pub_date

2003-02-15 00:00:00

pages

11-21

issue

eissn

0041-008X

issn

1096-0333

pii

S0041008X02000406

journal_volume

187

pub_type

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Antagonism of aryl hydrocarbon receptor-dependent induction of CYP1A1 and inhibition of IgM expression by di-ortho-substituted polychlorinated biphenyls.