Affiliation: School of Medicine, Curriculum in Toxicology
Air pollution is a global public health problem. The induction of oxidative stress, or the cellular response to avoid cytotoxicity due to an increase in reactive oxygen species or decrease in antioxidants, is frequently cited as a mechanism of toxicity for air pollutants. In addition to the role of oxidative stress in disease, there is growing evidence that oxidative processes including the generation of reactive oxygen species is essential for normal cellular function. This dissertation provides evidence that the reactive oxygen species, hydrogen peroxide, is a key mediator in air pollutant-induced adverse cellular responses. First, it is demonstrated that the divalent metal, zinc, induces hydrogen peroxide-dependent adaptive gene expression in human airway epithelial cells. This builds upon previous work to establish that zinc-induced pro-oxidant effects and electrophilic activity are both critical in its mechanism of toxicity. We next show that the organic component, 1,2-naphthoquinone, increases protein sulfenylation of regulatory proteins via hydrogen peroxide. This is the first report that protein sulfenylation is effected by an environmentally relevant exposure, establishing a potential new mechanism of toxicity as well as a new biomarker for future studies. Finally, two approaches to utilize readouts of oxidative stress in a translational manner are discussed. Specifically, the biological basis of a genetic risk factor of a susceptible population to air pollution is explored using a primary human airway epithelial cell culture. We report that there is an intimate relationship between hydrogen peroxide and glutathione in the air pollutant-induced outcomes, and that the genetic risk factor, GSTM1-null, enhances the effect of 1,2-NQ to induce the novel readout protein sulfenylation. Furthermore, we were able to use a live cell imaging analysis of oxidative stress to rank the toxicity of fibers of importance to respiratory toxicity and show that asbestos fibers obtained from the Libby Montana Superfund Site have similar toxicity to that of crocidolite asbestos fibers. Together the data suggests a vital and important role of hydrogen peroxide in air pollutant-induced adverse responses and provides the basis to use redox-based readouts as biomarkers to improve public health.