The effects of altering glutathione levels in the male reproductive tract will be studied. The proposed study will attempt to establish a link between chemical-induced reduction of glutathione in the male reproductive tract with increased susceptibility of spermatozoa to chemical-induced mutations. Glutathione is an important intracellular tripeptide that participates in a number of cellular functions, one of which has been a primary interest in toxicology: the detoxification of xenobiotics. The importance of glutathione as a protective mechanism has been clearly established, within the body (e.g. liver, kidney) but little attention has been given to the reproductive tract where chronic toxicity or chemical induced heritable changes could have serious consequences for future generations. These studies will determine whether or not a number of environmentally important toxicants are capable of lowering the glutathione levels of the male reproductive tract, and if so, whether this change will render the animal more susceptible to the action of germ cell mutagens. The enzymatic and non-enzymatic mechanisms which afford protection to the male germinal cell will be determined.

The specific aims of this project are to characterize chemical classes of compounds that are capable of perturbing testicular and/or epididymal glutathione, and to evaluate the biochemical and toxicological consequences of these changes. Investigations will be initiated to understand the mechanisms by which functional deficits are potentiated by perturbations in reproductive tract GSH. These will include the identification of adducts formed in vivo in rat spermatozoa DNA after adminitration of ethyl methansulfonate, a known alkylating agent, and to compare the pattern of adduct formation after GSH depletion. Studies will also investigate the role of GSH in other organs (e.g. liver) as a contributing factor to interactions between environmental toxicants that lead to alteration of reproductive toxicity.

R29ES005318

1989-07-01

1995-06-30