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.
Lorick
K L
KL
Department of Environmental Health Sciences, Tulane University School of Public Health and Tropical Medicine, New Orleans, Louisiana, USA.
Toscano
D L
DL
Toscano
W A
WA
D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004147:Dioxins / Q000494:pharmacology; D006801:Humans; D015603:Keratinocytes / Q000502:physiology*; D007700:Kinetics; D008907:Mink; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects / Q000502:physiology; D018168:Receptors, Retinoic Acid / Q000187:drug effects* / Q000235:genetics / Q000502:physiology*; D014212:Tretinoin / Q000378:metabolism / Q000494:pharmacology
D004147:Dioxins; D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D018168:Receptors, Retinoic Acid; D014212:Tretinoin