Peroxisome proliferators (PPs) are a group of structurally diverse compounds that are extensively used by humans, even though they cause increases in peroxisomes, hepatocellular proliferation and liver cancer in rodents. It was recently shown that free radicals play a central role in signaling in Kupffer cells, which produce mitogens (e.g., TNFalpha) and trigger cell proliferation in response to PPs; still, whether an increase in oxidants leads to DNA damage, thus contributing to carcinogenesis is not proven. It is hypothesized that PPs cause formation of oxidative DNA adducts and induce repair of these lesions. In addition, we will test whether the ability to induce DNA damage and/or repair correlates with carcinogenic potency of these compounds. Both potent (i.e., WY-14,643, and gemfibrozil) and weak (i.e., diethylhexyl and di-isononyl phthalates) rodent carcinogens, which are critical for human risk assessment will be studied. First, taking advantage of recent improvements in analytical technology and carefully avoiding artifactual adduct formation, we will look at the number of DNA lesions known to result from oxidative stress (e.g., 8-oxo-deoxyguanosine, etheno DNA adducts, apurinic/apyrimidinic sites). Second, we will investigate whether DNA repair enzymes, a response to DNA damage, are increased by PPs and whether DNA repair mechanisms are in balance using recently developed assay for abasic sites. Finally, using key knockout mouse strains (i.e., PPARalpha and NADPH oxidase-deficient p47phox) we will explore whether Kupffer cells or peroxisomes in hepatocytes are the source of oxidants for DNA adduct formation. Collectively, these studies will fill critical gaps in our knowledge regarding the mechanisms of action of this class of compounds and will have important implications for mechanistically based risk assessment.
| Pogribny, Igor P; Tryndyak, Volodymyr P; Woods, Courtney G et al. (2007) Epigenetic effects of the continuous exposure to peroxisome proliferator WY-14,643 in mouse liver are dependent upon peroxisome proliferator activated receptor alpha. Mutat Res 625:62-71 |
