Biomarkers of genotoxicity, oxidative stress, and genetic susceptibility related to ambient ozone exposure in humans

Animal toxicology studies and controlled acute human exposures first implicated the inflammatory response to ozone (O3), and subsequent oxidative stress, as the primary mechanism of damage to the respiratory system and mutagenicity. This dissertation contributes to the relatively sparse molecular epidemiology evidence exploring the relationship of the ambient O3-related changes in lung function with markers of oxidative stress, genotoxicity, and genetic susceptibility in a population of healthy young adults (N = 255). The three primary hypotheses were: (1) elevated O 3 exposure will induce cytogenetic and oxidative damage while decreasing antioxidant capacity, (2) genetic polymorphisms involved in antioxidant defense will modulate O3- related cytogenetic, oxidative damage, and lung function decrements, and (3) O3-induced cytogenetic damage, oxidative stress, and decreased antioxidant capacity will be associated with decreased lung function and may be further modified by genetic polymorphisms. University of California, Berkeley (UCB) students spending their summer in the Los Angeles (LA) area had increased cytogenetic damage, MN/1000 cells, compared to those in the San Francisco (SF) Bay area (p < 0.05). The LA subjects also had significantly higher 8-iso-PGF compared to those from SF (p = 0.02). Long-term O3 exposure (2 week, 1 month, and estimated lifetime) also had significant and independent effects on 8-iso-PGF levels. These results were confirmed by increased 8-iso-PGF and cytogenetic damage in a subset of individuals exposed experimentally to O3. GSTM1 null/NQO1 Pro 187Pro-combination genotype was significantly associated with increased 8-iso-PGF and risk of a decrease in FEF25-75 in females, while the GSTP1 variant allele (Val105) was significantly associated with increased 8-iso-PGF and greater risk of a decrease in FEF 75 in males. GSTM1 null, however, was associated with increased cytogenetic damage but not O3-related oxidative stress or lung function in either sex. These results suggest O3 exposure does induce cytogenetic damage, oxidative stress, and decreased lung function in healthy individuals; and that these responses are sex-specific. Furthermore, oxidative stress and lung function are modified by GSTP1 Val and GSTM1 null/NQO1 Pro, while cytogenetic damage is modulated by, GSTM1 null suggesting different mechanisms of action for these two responses.