EFFECTS OF RETINOIC ACID ON THE 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN-INDUCED DIFFERENTIATION OF IN-VITRO CULTURED HUMAN KERATINOCYTES

In order to study the interactive effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), polychlorinated dibenzofurans (PCDFs) and retinoic acid on terminal differentiation of primary cultured keratinocytes derived from human foreskins, the amount of [S-35]methionine-labelled proteins incorporated into cross-linked envelopes (CLEs) was determined. After isolation of the CLEs with sodium dodecyl sulfate, the amount of radioactivity collected on a filter was considered as a quantitative parameter for keratinocyte differentiation. Treatment of keratinocytes with different concentrations of TCDD resulted in a dose-dependent increase in differentiation, while only a minor decrease in differentiation occurred after treatment with retinoic acid. However, simultaneous application of 10(-8) TCDD and different concentrations of retinoic acid led to a dose-dependent decrease in CLE formation. PCDFs exerted an effect on CLE formation similar to that of TCDD but with different potencies. We conclude that (1) TCDD induces a dose-dependent induction of human keratinocyte differentiation, (2) retinoic acid is a potent antagonist of TCDD-induced keratinocyte differentiation, and (3) primary cultures of human keratinocytes can serve as a useful model system to study the interactive effects of xenobiotics and hormone-like substances on the regulation of differentiation.