The teratogenicity and fetotoxicity of two polyhalogenated cyclic hydrocarbons (PCH) (endrin and lindane) will be studied and compared with that induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a highly potent teratogen, in the fetuses of pregnant C57BL/6J (TCDD responsive) and DBA/2J (TCDD non-responsive) mice. The mechanism(s) of fetotoxicity of these compounds is/are not known, although several mechanisms have been proposed for TCDD. The study will assess the abilities of TCDD, endrin and lindane to induce the formation of reactive oxygen species, and lipid peroxidation and DNA single strand breaks (SSB), which may be due to the formation of reactive oxygen species and/or free radicals, resulting in an oxidative stress in the fetuses of pregnant mice after the exposure. Mice will be exposed to selected doses of these compounds on sensitive days of gestation, and the abilities of biochemical and teratogenic effects to segregate with the Ah locus will be determined. The products which results form altered lipid metabolism (malondialdehyde, formaldehyde, acetaldehyde and acetone) in response to these xenobiotics are transported via maternal serum and also excreted by the fetuses into the amniotic fluid. The levels of these products will be determined in maternal serum and amniotic fluid, using high pressure liquid chromatography (HPLC). The protective effects of selected antioxidants, namely vitamin E succinate, ellagic acid, butylated hydroxyanisole (BHA) and vitamin C against fetotoxicity induced by these compounds will be assessed. The results will provide insight into the role of the Ah receptor in the fetotoxicity and teratogenicity of structurally diverse PCH. Furthermore, the relationship between tissue damaging effects including lipid peroxidation and DNA single strand breaks, which occur in response to reactive oxygen species production, and the fetotoxicity and teratogenicity of these xenobiotics will be determined.
