SEQUELA OF WY-14, 643-INDUCED OXIDATIVE STRESS

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Peroxisome proliferators are a group of structurally diverse compounds that cause an increase in both the number and size of peroxisomes, elevate rates of cell proliferation and cause liver cancer in rodents. Although the mechanism of carcinogenesis is not known, two main hypotheses have been proposed. One views oxidative stress as a critical event in the carcinogenic process, while the other contends that elevated and sustained cell replication is responsible for the induction of tumors. The latter is considered to be the main mechanism of promotion, although, the role of oxidative stress in initiation is controversial. However, these two hypotheses are not mutually exclusive. In exciting new experiments, we showed that at least one of the base excision repair enzymes is upregulated by chronic administration of WY-14,643, a model peroxisome proliferator. This led us to the hypothesis that peroxisome proliferators induce both increased formation of oxidative DNA adducts and repair of these lesions. Furthermore, we hypothesize that oxidative stress is involved in signaling pathways for cell proliferation leading to higher probabilities of mutation, promotion and progression. We will utilize frozen tissues from the NTP study to investigate following questions: 1) Do peroxisome proliferators induce the formation of oxidative and/or etheno DNA adducts in rodent liver? 2) Does DNA repair play a role in peroxisome proliferator- induced carcinogenesis? 3) Are increases in free radicals following chronic exposure to peroxisome proliferators consistent with oxidants as a signaling mechanism for cell proliferation? We predict that the poor correlation between hepatic oxidative DNA lesions and carcinogenic potency of peroxisome proliferators is due to the limited number of DNA adducts that has been studied and the induction of DNA repair. State-of-the-art equipment and techniques developed in this laboratory will allow us to look at a broad spectra of DNA adducts, the activity of multiple DNA repair enzymes, markers of oxidative stress, and a signal transduction pathway for cell proliferation. We expect to find a good correlation between hepatocarcinogenic potency of peroxisome proliferators and their ability to produce oxidants using a responsive species (rat) and a nonresponsive species (hamster). The unique design of the NTP study will allow us to examine our hypotheses using tissues from WY-14,643- exposed rates and hamsters by comparing different doses and time points. The strengths of this novel application lie in the evaluation of specific hypotheses designed to fill critical gaps in our knowledge regarding the mechanism(s) of action of this important but poorly understood class of compounds. This research also will have important implications for mechanistically based risk assessment.