The proposed studies will examine the effect of selected groundwater contaminants (the volatile organic chemicals initially studied in the previous three years of this grant) and polychlorinated biphenyls on specific mechanisms of action relating to the reproductive process. This will include direct effects on the sperm, egg, and embryo as they proceed through the preimplantation stages of pregnancy, during implantation and embryonic development and effects exerted at the time of labor and parturition. These studies will build on our existing research program and will utilize in vitro methods of cell and tissue culture including techniques for in vitro fertilization. Since some of the in vitro methods proposed are applied for the first time in toxicity studies, additional in vivo assay methods will be carried out to verify the in vitro approach and findings. Several of the proposed test chemicals have been implicated in reproductive dysfunction in occupationally exposed workers, yet little is known about the etiology. Specifically, these studies will: 1) complete in vivo and in vitro evaluation of the VOCs previously studied and expanded this work to the PCBs; 2) develop in vitro assay methods using microsurgically divided embryos to characterize effects on individual embryonic cells; 3) use the above methods to determine specific mechanistic action of the VOCs and PCBs on reproduction and mechanisms of cell-cell communication; 4) determine the fertility of offspring exposed to PCBs in utero and through puberty; 5) in vitro testing, not only of the chemicals in question but also biodegradation products; 6) determine the effects of test chemicals on sperm intracellular calcium concentrations and hydrogen peroxide production; 7) application of computer-aided image analysis for effects on sperm motion analysis; 8) chemical effects on sperm capacitation; 9) effects on myometrial gap junctional communication in vitro; 10) effect of in vitro exposure of uterine strips to the test chemicals on contractility; and 11) mechanisms of myometrial gap junctional communication effects as it relates to labor induction.
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