UC Berkeley

We are exposed to increasing numbers of chemicals, most of which have incomplete toxicological characterization. As many diseases have environmental causes, we must understand the molecular mechanisms of toxicity these chemicals elicit. Traditional toxicity testing relies on assessing indirect phenotypic outcomes, and deconvoluting the mechanism underlying these effects is challenging. Understanding the direct chemical-protein interactions of environmental chemicals is crucial for revealing their mechanisms of action to link adverse health outcomes, predict potential toxicities, and inform safer design of future chemicals. This work demonstrates how integrated chemoproteomics and metabolomics platforms can identify direct protein targets of environmental chemicals and reveal their downstream biochemical effects. After describing the chemoproteomics and functional metabolomics technologies used here, I discuss an activity-based proteomics method used to reveal the proteome wide off-targets of the widely used insecticide chlorpyrifos in vivo in mice. Then, I show how a compound-specific bioorthogonal chemical probe comprehensively reveals protein targets of the organophosphorus flame retardant triphenylphosphate, which causes dyslipidemia upon exposure. Finally, I use a broad chemoproteomic approach to profile the cysteine reactivity of multiple environmental electrophiles and identify enzyme targets of the fungicide chlorothalonil involved in fatty acid oxidation. These studies demonstrate the power and utility of combining chemoproteomics technologies to reveal the protein targets of environmental chemicals with metabolomics platforms to elucidate the biochemical effects of inhibition. This approach generated novel mechanistic detail to inform mechanism and predict toxicities of existing chemicals, and can be used to optimize design of future chemicals to protect human and environmental health.