RFA-TS-24-010: Persistent Environmental Toxicants in Veteran CNS Tissue: Identifying Exposures Determining Higher ALS Risk

PROJECT SUMMARY/ABSTRACT United States veterans have at least twice the risk of developing amyotrophic lateral sclerosis (ALS) as compared to the civilian population. Nonetheless, the etiological factor(s) underlying the elevated risk of ALS in military veterans are unknown. In the general population, specific environmental and lifestyle factors are associated with increased ALS risk. For example, truck drivers, airline pilots and cabin attendants have an increased risk of ALS, indicating the potential relevance of exhaust fumes and aircrafts as disease-linked environmental exposures. Together, the noted disparity in ALS rates among veterans strongly suggests that there are also high-risk exposures selectively experienced by military personnel that are disproportionate to the general population. Over their years of service, veterans may encounter numerous neurotoxic exposures (e.g., burn pits, engine exhaust, firing ranges, contaminated military bases). In order to reliably characterize the pollutant exposure level of veterans, it is important to directly evaluate persistent toxicants in those biological samples capable of storing such toxicants relevant to disease. Therefore, under Funding Option A, we propose an innovative evaluation in veteran central nervous system (CNS) tissue of persistent neurotoxicant mixtures emitted by service-linked exposure sources. Based on the literature and our own preliminary studies, our proposed toxicants of interest include: metals/nonmetal elements, nanoparticles, dioxins, and polycyclic aromatic hydrocarbons. To identify their contribution to disease development, we will characterize and/or compare the concentrations and spatial tissue-subcellular distribution of persistent toxicants detected in the CNS tissue of veterans with ALS to that of non-neurologic veteran and non-veteran controls. We will statistically assess if any sets of detected toxicants exert synergistic toxicity. In addition, we will evaluate how gene expression may be spatially associated with these deposited toxicants (spatially resolved transcriptomics). As a population, veterans are believed to smoke and suffer more head trauma/concussions than the general population and we will account for such variables in our analyses. Together, we believe that this study will greatly increase our understanding of environmental toxicants that accumulate in military personnel over their years of service and potentially contribute to ALS pathogenesis. Potential impacts include mitigating neurotoxic exposures, and clarifying the underlying ALS pathophysiology for therapy development.