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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 glutathione system is comprised of glutathione and several key enzymes: glutathione-S-transferases, glutathione reductase, glutathione peroxidase, and gamma-glutamyl transpeptidase. The activity of these enzymes can affect tissue levels of glutathione and therefore will be studied to determine the effects of the selected toxicants of the glutathione status of the male reproductive tract. Glutathione and its related enzymes contain a number of reduced sulfhydryls, and the activity of the entire system is essentially linked to the nucleophilic nature and activity of the thiol group. Therefore, the toxicants that will be tested were chosen because they are chemicals that either 1) have a great affinity for sulfhydryl groups in biological systems or 2) the parent compound or one of its intermediate metabolites are reactive electrophiles that will react with GSH and the sulfhydryl groups on the enzymes of the GSH system. Germ cell mutations represent potentially one of the most serious consequences of exposure to environmental toxicants due to induction of heritable defects transmissible to progeny. The enzymatic and non- enzymatic mechanisms which afford protection to the male germinal cell will be determined.

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