UC Davis

Bioactivation (via xenobiotic metabolism) of various persistent organic air pollutants is a significant yet under-researched component of their toxicity. This dissertation will discuss two classes of persistent organic pollutants, 1) polycyclic aromatic hydrocarbons and 2) polychlorinated biphenyls; model compounds of naphthalene and 3,3'-dichlorobiphenyl (PCB 11) have been chosen to represent these classes, respectively. The lung can be particularly susceptible to toxicity following bioactivation, as the lung itself has significant xenobiotic metabolism capabilities, as well as constant connections to other well-perfused organs like liver, another major site of xenobiotic metabolism. Bioactivation is a crucial precursor step to the toxicity of naphthalene, our model compound. Naphthalene is a known carcinogen in rodents, and has been recently proven to form stable DNA adducts (a mechanism that can promote tumorigenesis) at known tumor tissue sites, but its risk in humans is not well-understood. We have utilized a novel technique known as accelerator mass spectrometry to detect 14C-labeled naphthalene DNA adduct lesions, which are very difficult to detect by other means. We have found that naphthalene is capable of forming stable, persistent DNA adducts in mouse lung and liver following an in vivo oral exposure. The bioactivation of naphthalene is a complex process and it is important to understand which metabolites are capable of adducting to DNA in human risk assessment. By leveraging a murine airway explant system, combined with a mix of 14C-labeled naphthalene metabolites and enzyme knockout mouse lines, we have mapped out which key metabolites and enzymatic pathways are thought to contribute the most to naphthalene-DNA adduct formation. This will be crucial for translating to human risk assessment, as there are key species differences between human and rodent pathways. Bioactivation of organic air pollutants can also affect critical biological processes beyond carcinogenicity. Developmental toxicity is also a concern, as seen by our second model compound, PCB 11. Using a gestational and lactational exposure model at human-relevant doses, we have observed irregular airway development in offspring, believed to be contributed to by bioactivation of PCB 11 into reactive metabolites and subsequent alterations of important lung development stages, resulting in mucous metaplasia characteristics in the lung. This newly-observed phenotype will be explored further for potential mechanisms of action, with xenobiotic metabolism being a focus. As shown in our models, xenobiotic metabolism plays an important role in the toxicity of organic air pollutants, and should be taken into consideration when assessing exposure and risk.