ABSTRACT ALS is a progressive and fatal neurodegenerative disease with complex unknown pathogenesis. Recent evidence supports a gene-time-environment hypothesis whereby environmental exposures trigger neurodegeneration when superimposed on a genetic risk profile. Supporting this premise, long-term adverse environmental exposures are linked to ALS risk, environmental pollutant exposures strongly correlate with ALS prevalence, and we have shown that persistent organic pollutants (POPs), in particular measured organochlorine pesticide and reported pesticides, exposures strongly increase ALS risk in a subset of ALS patients from Michigan. Therefore, there is a critical need to understand how the “ALS exposome,” defined as the lifetime of environmental exposures, contributes to ALS risk and drives disease pathogenesis. In this proposal, we will harness the power of advanced metabolomics analyses to gain insight into the effect that environmental exposures, such as residential and occupational exposures, have on the metabolome. As metabolites reflect the impact of exogenous exposures on cellular processes, metabolomics has emerged as the new frontier in exposome research. Our objective is to identify the metabolomics signatures that associate with POP exposures and historical exposure risk factors, and associate with ALS progression. Our central hypothesis is that POP exposures will lead to conserved metabolomic signatures in both plasma and central nervous system (CNS) tissues. In Aim 1, we will use longitudinal plasma from ALS participants from our unique University of Michigan ALS Patient Repository (UMAPR) with high versus low concentrations of POPs, as well as plasma from geographically dispersed healthy control subjects, to better characterize how POP exposures impact the metabolome. In Aim 2, we will evaluate whether metabolomic signatures are shared in ALS subjects with similar occupational and residential exposure risks and whether these signatures diverge in subjects with disparate risks in order to yield insights into causal mechanisms from prior epidemiologic studies. Finally, in Aim 3, we will determine whether metabolomic signatures in ALS subject plasma are present in post-mortem brain and spinal cord tissue and correlate with exposures. Overall, completion of these aims will establish a comprehensive and rigorous dataset of metabolomic signatures associated with exposures to POPs, as well as residential and occupational exposure risk histories across the disease course, to provide insight into the influence of exposures on the onset and progression of ALS. These outcomes will have an important positive translational impact by identifying modifiable factors that can mitigate the risk of developing ALS, uncovering associated metabolic changes that represent biomarkers, and guiding future studies on new pathophysiologic disease mechanisms.