Trichloroethylene inhibits development of embryonic heart valve precursorsin vitro

Previous epidemiological studies with humans and laboratory studies with ch ickens and rats linked trichloroethylene (TCE) exposure to cardiac defects. Although the cardiac defects in humans and laboratory animals produced by TCE are diverse, a majority of them involves valvular and septal structures , Progenitors of the valves and septa are formed by an epithelial-mesenchym al cell transformation of endothelial cells in the atrioventricular (AV) ca nal and outflow tract areas of the heart. Based on these studies, we hypoth esized that TCE might cause cardiac valve and septa defects by specifically perturbing epithelial-mesenchymal cell transformation. We tested this hypo thesis using an in vitro chick-AV canal culture model. This study shows tha t TCE affected several elements of epithelial-mesenchymal cell transformati on. In particular, TCE blocked the endothelial cell-cell separation process that is associated with endothelial activation. Moreover, TCE inhibited me senchymal cell formation throughout the concentration range tested (50-250 ppm). In contrast, TCE had no effect on the cell migration rate of the full y formed mesenchymal cells. Finally, the expression of 3 proteins (selected as molecular markers of epithelial-mesenchymal cell transformation) was an alyzed in untreated and TCE-treated cultures. TCE inhibited the expression of the transcription factor Mox-1 and extracellular matrix (ECM) protein fi brillin 2. In contrast, TCE had no effect on the expression of cu-smooth mu scle actin, These data suggest that TCE may cause cardiac valvular and sept al malformations by inhibiting endothelial separation and early events of m esenchymal cell formation in the heart.