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-ret inoic acid (trans-RA) binding to retinoic acid receptors (RARs) in cul tured human keratinocytes (SCC-12F) was investigated. TCDD and trans-R A elicited opposing actions on the production of biologically active T GF-beta. TCDD exposure caused concentration-and time-dependent decreas es in trans-RA binding to SCC-12F RARs. The apparent half-maximal effe ctive TCDD concentration = 1 nM. TCDD exerts its action via the aryl h ydrocarbon 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 dissociatio n constant (Kd) calculated from Eadie-Hofstee analysis of equilibrium binding for trans-RA was 0.13 nM: in both TCDD-exposed and control cul tures. Approximately half of the trans-RA binding sites were lost in T CDD-exposed cells (control = 0.195; TCDD = 0.108 pmol trans-RA bound/m g protein). The data suggest TCDD may exert its toxic action in human keratinocytes by directly modulating RAR action. (C) 1998 Academic Pre ss.