Evidence that 2,3,7,8-tetrachlorodibenzo-p-dioxin and thyroid hormones act through different mechanisms in human keratinocytes.
It has been proposed [J. D. McKinney, J. Fawkes, S. Jordan, K. Chae, S. Oatley, R. E. Coleman, and W. Briner (1985). Environ. Health Perspect. 61, 41-53] that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) produces toxic responses through persistent occupancy of nuclear thyroxine (T4) receptors, and that maintenance of receptor occupancy by supraphysiologic concentrations of thyroid hormones mimics TCDD toxicity [L. H. Hong, J. D. McKinney, and M. I. Luster (1987). Biochem. Pharmacol., 36, 1361-1365]. TCDD induces hyperkeratinization in cultured normal human epidermal cells and the human keratinocyte line, SCC-12F. This response is associated with a decrease in high-affinity epidermal growth factor (EGF) receptors. These cell systems were used as models to compare the actions of TCDD with those of triiodothyronine (T3) and T4 on human target cells. Keratinocytes were treated simultaneously with T3 and T4 in a 4:1 molar ratio (T3/T4; Hong et al., 1987) and levels of EGF binding and 7-ethoxycoumarin O-deethylase activity (a marker for cytochrome P1-450 induction) were measured. T3/T4 (at concentrations up to 10 microM T3/2.5 microM T4) and T3 or T4 alone (0.1 to 10 microM) did not produce the hyperkeratinization, the decrease in EGF binding, or the increase in ECOD activity that are characteristic of TCDD exposure. Nonresponsiveness to T3/T4 was not due to metabolism of these hormones by the keratinocytes. T3 and T4 did not compete with [3H]TCDD for binding to cytosolic Ah receptor from C57BL6 mouse liver, SCC-12F, or normal human epidermal cells. TCDD and an active stereoisomer, 2,3,7,8-tetrachlorodibenzofuran, did not compete with [125I]T3 or [125I]T4 for binding to nuclear receptors from SCC-12F cells or C57BL6 mouse liver. Taken together, these data demonstrate that the actions of TCDD and thyroid hormones are mediated by distinct mechanisms in human keratinocytes.
D015660:7-Alkoxycoumarin O-Dealkylase; D001853:Bone Marrow / Q000187:drug effects; D002478:Cells, Cultured; D004147:Dioxins / Q000633:toxicity*; D004817:Epidermis / Q000187:drug effects*; D066246:ErbB Receptors / Q000187:drug effects; D006801:Humans; D007633:Keratins; D008675:Metamorphosis, Biological / Q000187:drug effects; D010105:Oxygenases / Q000032:analysis; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D018336:Receptors, Aryl Hydrocarbon; D011955:Receptors, Drug / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000187:drug effects; D013963:Thyroid Hormones / Q000378:metabolism / Q000633:toxicity*
D004147:Dioxins; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D011955:Receptors, Drug; D011988:Receptors, Thyroid Hormone; D013963:Thyroid Hormones; D007633:Keratins; D010105:Oxygenases; D015660:7-Alkoxycoumarin O-Dealkylase; D066246:ErbB Receptors