Antiestrogenicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin and non-ortho-substituted polychlorinated biphenyls

Some mechanisms of toxicity of halogenated aromatic hydrocarbons (HAHs), including those of specific polychlorinated biphenyl (PCB) congeners, are mediated by the aromatic hydrocarbon receptor (AhR). 2,3,7,8-Tetrachlorodibenzo- p-dioxin (TCDD), a prototypical AhR agonist, elicits a wide range of biochemical and toxic responses, including antiestrogenic effects. TCDD is antiestrogenic both in vivo and in vitro, but the mechanisms of antiestrogenicity are not well understood. We studied antiestrogenic effects of PCBs and TCDD, using E₂-responsive human breast-tumor cells in culture as systems to delineate the mechanism(s) of antiestrogenicity.; Exposure of ZR-75-1 cells to TCDD or the non-ortho-substituted PCBs, 3,4,4′,5-tetrachlorobiphenyl (PCB 81) and 3,3 ′,4,4′,5-pentachlorobiphenyl (PCB 126), blocked the 17β-estradiol (E₂)-stimulated elevations in the levels of estrogen receptor-α (ER-α), progesterone receptor (PGR) and cathepsin D (CD) mRNAs, and elicited marked elevations in the levels of mRNAs encoding cytochromes P450 1A1 (CYP1A1), an E₂ 2-hydroxylase, and 1B1 (CYP1B1), an E₂ 4-hydroxylase. TCDD and non-ortho -substituted PCBs elicited elevated rates of E₂ metabolism, but environmentally prevalent mono-ortho-substituted PCBs were much less effective. Long-term estrogen-deprived T47D cells exhibited diminished inducibility of E₂ metabolism that was reversible by E₂, suggesting a self-regulation of E₂ metabolism.; Exposure of T47D cells to PCB 81, 3,3′,4,4 ′-tetrachlorobiphenyl (PCB 77), PCB 126, or 3,3′ ,4,4′,5,5′-hexachlorobiphenyl (PCB 169) inhibited E₂-stimulated preconfluent proliferation. PCB 169, a potent inhibitor of CYP1A1 and CYP1B1, only slightly reduced the inhibitory effects of TCDD on cell proliferation, even in the presence of high E ₂ concentrations.; E₂ and estrone (E₁) are interconverted in the liver. Cytochrome P4501A2 (CYP1A2), a liver enzyme, had the highest catalytic efficiency for E₁ hydroxylation. Both human cDNA-expressed CYP1A1 and CYP1A2 catalyzed mainly 2-hydroxylation of E₁ with minor 4-hydroxylation activities, while CYP1B1 catalyzed primarily E₁ 4- and 2-hydroxylation. CYP1A1 and 1B1, which favor E₂ as substrate, may catalyze estrogen metabolism in extrahepatic, estrogen-responsive tissues in which E₂ concentrations exceed those of E₁. The stimulation of estrogen metabolism and the inhibition of cell proliferation may be important mechanistic components of the antiestrogenicity of TCDD and non-ortho-substituted PCBs.