Dioxin and retinoic acid receptor cross-talk in human keratinocytes

Interaction between dioxin receptor and retinoic acid receptor in cultured human keratinocytes was examined. Keratinocytes exposed to dioxins showed a decrease in all-irons- retinoic acid (RA)-induced transforming growth factor beta. In binding studies, exposure of cells to dioxin showed a concentration- and time-dependent decrease in RA binding to its receptors (RARs); apparent half-maximal effective concentration = InM. The dissociation constant (Kd) for R A was 0.13 nM in both exposed and control cultures. B_maxwas decreased (0.108 vs 0.195 pmol RA bound/mg nuclear protein). Examination of steady-state messenger RNA levels showed a time-dependent decrease in RAR-γ mRNA in the presence of dioxin, which correlates with the decrease in RA binding. Levels of mRNA for RAR-α present in these cells was unaffected. Analysis of nuclei from dioxinexposed cells showed no change in the level of transcription of RAR-γ mRNA. These data suggest that TCDD may exert its toxic action in human keratinocytes by directly modulating the action of retinoic acid receptors and that this effect is due in part to a decrease in the stability of RAR-γ mRNA.