The objectives of this project are to: 1) utilize human nd macaque granulosa, trophoblast and endometrial cells and macaque embryos to evaluate their function in response to the toxicant TCDD while being cultured in vitro and 2) to evaluate the cellular mechanisms by which primate reproductive cells sustain toxic damage. The products in the conditioned culture media to be evaluated in this project are the same biomarkers being evaluated in Projects I and II. Morphological and biological indicators of cell toxicity will also be evaluated. Parallel studies will be performed which utilize in vivo exposed tissues from the macaques being monitored in Project II. This strategy will enable us to monitor analogous biomarkers of toxicity in vitro and in vivo. The ability of TCDD to affect preimplantation development of primate embryos will be studied by measuring its effects on embryo cell number and incidence and rate of blastocyst formation, thus permitting the assessment of direct preimplantation effects on early embryo development that may be difficult to assess in Project II. The ultimate goal of this study is to develop in vitro methodology that will allow us to investigate the mechanism of cellular toxicity and organ system damage which results in toxic effects on embryonic tissue and/or compromised maternal support of the conceptus during implantation. These experiments not only will provide a comprehensive description of the mechanism of toxic action of TCDD, but also will establish the approach for subsequent studies of known or suspected reproductive toxicants.
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