2,3,7,8-Tetrachlorodibenzo-p-dioxin Alters Retinoic Acid Receptor Function in Human Keratinocytes

Actions of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on all-trans-retinoic acid (trans-RA) binding to retinoic acid receptors (RARs) in cultured human keratinocytes (SCC-12F) was investigated. TCDD and trans-RA elicited opposing actions on the production of biologically active TGF-beta. TCDD exposure caused concentration-and time-dependent decreases in trans-RA binding to SCC-12F RARs. The apparent half-maximal effective TCDD concentration = 1 nM. TCDD exerts its action via the aryl hydrocarbon receptor (AhR). TCDBF, a partial AhR agonist, reduced trans-RA binding, indicating AhR involvement (control = 0.33; TCDBF = 0.22; TCDD = 0.142 pmol trans-RA bound/mg nuclear protein), The dissociation constant (Kd) calculated from Eadie-Hofstee analysis of equilibrium binding for trans-RA was 0.13 nM: in both TCDD-exposed and control cultures. Approximately half of the trans-RA binding sites were lost in TCDD-exposed cells (control = 0.195; TCDD = 0.108 pmol trans-RA bound/mg protein). The data suggest TCDD may exert its toxic action in human keratinocytes by directly modulating RAR action. (C) 1998 Academic Press.