The broad goals of the proposed research are 1) To determine whether the halogenated hydrocarbons, trichloroethylene (TCE) and 1,1 dichloroethylene (DCE), or their metabolites are responsible for the increased incidence of congenital cardiac defects found in humans, and in rodent and avian models, when there is exposure to these compounds during development. 2) To identify the specific compound(s) responsible for such defects. 3) To determine the mechanism by which the causative agent acts on the developing heart.
The specific aims are to test the hypotheses: 1) That a metabolite of TCE or DCE (perhaps a common or similar metabolite) is responsible for the increased incidence of cardiac defects in exposed fetuses. 2) That metabolic activation of halogenated hydrocarbons occurs in fetal or maternal organs and that where it occurs can be determined by in vitro cultivation of heart slices or whole embryos for comparison with in vivo data. 3) That by in vivo or in vitro exposure to known radiolabeled metabolites of TCE, it can be determined which ones localize to the fetal heart, and are, therefore, likely candidates for causing teratogenic effects. 4) That TCE, DCE and/or their metabolites form protein adducts in the developing fetal heart, thus altering proper development and resulting in cardiac defects. 5) That the presence of the chlorine atom (regardless of number) on the hydrocarbon is the determining factor in teratogenicity. 6) That the breakdown products of TCE in soil can be identified by use of a lysimeter as a model of a dump site. Chlorinated metabolites of TCE/DCE and a non-chlorinated metabolite of DCE will be delivered into the uterus of pregnant female rats during organogenesis. If this provocative test is positive for cardiac teratogenicity, a drinking water exposure study will follow. To determine where metabolism of the active agents occurs and whether the mechanism of action is via protein adduct formation, in vivo dosing of pregnant rats (includes maternal metabolism) will be contrasted with in vitro dosing of whole rat embryos in culture (fetal metabolism) and in vitro culture of precision cut heart slices. Protein adduct formation as well as changes in programmed cell death in whole embryos will be analyzed. The teratogenic effects of TCE/DCE are significant health issues because of the widespread contamination of water supplies here and abroad with these agents. Some metabolic products of TCE/DCE are also products of chlorination of municipal water supplies that contain natural organic material. As a result, the American public is frequently exposed via drinking water to these chemicals which may be acting as teratogens in the developing heart.
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