Inhibition of retinoic-acid-induced gene expression by 2,3,7,8-tetrachlorodibenzo-p-dioxin.

The polychlorinated aromatic hydrocarbon 2,3,7,8-tetrachlorodibenzo-p-dioxin, commonly referred to as dioxin or TCDD, has been shown to cause cleft palate in mice. TCDD displays an interesting interaction with another cleft palate teratogen, retinoic acid (RA): when mice are treated with TCDD and RA simultaneously, palatal clefts can be observed in 100% of offspring of mothers at dose levels far below those required for either agent to produce clefting if given singly. This synergy strongly suggests that the pathways controlled by these agents converge at one or more points in cells of the developing palate. In this study, we examined the effects of TCDD on induction of the type II cellular retinoic acid binding protein (CRABP-II) and the retinoic acid receptor beta (RAR beta) by RA in murine embryonic palate mesenchyme (MEPM) cells. While TCDD alone had no effect on basal levels of expression of either gene, the induction of both genes by RA was strongly inhibited by TCDD. These results represent the first evidence for a direct molecular interaction between the RA and TCDD-mediated signaling pathways.