Air pollutants and pesticides, two major and widespread environmental exposures, have been shown to increase the risk of various health outcomes such as birth outcomes, cardiovascular diseases, neurodevelopmental disorders, and neurodegenerative diseases. The cumulative toxic effects of chronic air pollution and pesticide exposures are mediated through various biological processes, such as oxidative stress and inflammation, epigenetic alterations, mitochondrial dysfunction, altered intercellular communication, altered microbiome communities, and impaired nervous system function. Mapping the exogeneous exposures to endogenous responses facilitates the ability to identify the nongenetic drivers of health and disease, and ultimately lead to more effective and efficient disease prevention. In this dissertation, we investigate metabolomic and epigenomic signals associated with traffic-related air pollution and chronic ambient pesticide exposures to better understand pathogenic mechanisms underlying chronic health effects.We first investigated perturbations of the maternal serum metabolome in response to traffic-related air pollution. We retrieved stored mid-pregnancy serum samples from 160 mothers who lived in the Central Valley of California known for high air particulate levels. We estimated prenatal traffic-related air pollution exposure (carbon monoxide, nitric oxides, and particulate matter less than 2.5 microns) during the first trimester using the California Line Source Dispersion Model, version 4 (CALINE4) based on residential addresses recorded at birth. We used liquid chromatography-high resolution mass spectrometry (LC-HRMS) to obtain untargeted metabolic profiles. Multivariate and univariate analyses were conducted to select metabolomic features associated with air pollution exposure and pathway analyses identified biologic pathways related to air pollution exposure. In total, we identified 432 metabolomic features that discriminated between the high (n=98) and low air pollution exposed group (n=62). Pathway enrichment analysis for features associated with air pollution indicated that in maternal serum oxidative stress and inflammation related pathways were altered, including linoleate, leukotriene, and prostaglandin pathways.
We also investigated perturbations in the serum metabolome for organophosphates (OPs), organochlorines (OCs), and pyrethroids (PYRs), all pesticides that have been widely used in the agricultural regions of the Central Valley of California. We conducted high-resolution metabolomic profiling of serum samples from 176 older adults and estimated each participant’s chronic ambient pesticide exposure (from 1974 to year of blood draw) to OPs, OCs, and PYRs with a geographic information system (GIS)-based model. We identified metabolites and metabolic pathways associated with one or multiple pesticide classes, including mitochondrial energy metabolism, fatty acid and lipid metabolism, and amino acid metabolism. Utilizing an integrative network approach, we found that disturbances in the fatty acid beta-oxidation pathway are shared across all three pesticide classes.
Lastly, to investigate the systematic biological responses to chronic ambient OP exposure, we cross-sectionally integrated the methylome and metabolome measured in blood samples collected from older adults living in the Central Valley of California (n=176). Similarly, cumulative OP exposure over a ten-year period was estimated using a GIS-based model. The single-omics analyses showed both epigenomic and metabolomic signatures of OP as being enriched in the glycosphingolipid (GSL) biosynthesis pathway. Besides this common pathway, the metabolome and epigenome also exhibited distinct responses to OPs, with differently methylated CpGs being involved in intracellular membrane transport, cell adhesion, and carcinogenesis; and OP-related metabolites being involved in aromatic amino acids metabolism, neurotransmitter precursors, oxidative stress, and mitochondria function. Moreover, we illustrate possible interactions between these two molecular layers through metabolic processes and nutrient-sensing pathways when we integrated the epigenomic and metabolomic signals.
In summary, our studies linked macro-level population exposures to micro-level biologic responses affecting the metabolome and the epigenome, to provide insight into molecular mechanisms underlying the chronic toxicity of air pollution and pesticide exposure and their interaction with health outcomes, thereby providing much-needed information for the prediction, prevention, and treatment of a variety of diseases.
