Detection of novel environmental risk factors in the recently identified ALS clusters in Central Virginia

About This Grant

ABSTRACT Amyotrophic lateral sclerosis (ALS) is a rare, neurodegenerative condition that results in rapidly progressive muscle weakness and, ultimately, death from respiratory failure within 2-5 years of symptoms onset. The VCU Department of Neurology runs the largest ALS clinic in the region and, over the past 4 years, began witnessing an uptick in incident ALS cases. In partnership with the ALS Association, we analyzed the spatial distribution of ALS in Virginia. We identified apparent spatial ALS clustering with the highest relative risk of 3.75 for developing ALS in these “hotspots.” It should be mentioned that ALS has a global incidence of 2 per 100,000. There is mounting evidence that ALS stems from a combination of genetic susceptibility, age-related cellular damage, and environmental exposure. We, therefore, investigated whether local environmental factors contributed to increased ALS risk in these “hotspots.” Analysis of drinking water samples from households of ALS patients from this cluster identified elevated levels of a plasticizer dtBHQ (2,5-ditert-butylhydroquinone). At this point, it is unknown how dtBHQ appears in drinking water in these regions, but a reported application of dtBHQ is in the coatings of water pipes. Nonetheless, the presence of dtBHQ is intriguing, given some reports that at high doses, dtBHQ can cause muscle weakness and damage motor endplates in rats. Next, we investigated whether low-level exposure to dtBHQ could cause motor impairment in laboratory animals. Using a Zebrafish model system, we found that dtBHQ at nanomolar concentrations decreased touch-evoked response and caused shortening of primary motor axons and reduced branching indicative of motor circuit dysfunction. These preliminary results led us to propose a central hypothesis that the presence of a plasticizer dtBHQ in the environment of ALS clusters activates molecular mechanisms that cause motor neuron toxicity, contributing to the elevated risk of ALS in these hotspots. We are applying under Funding Option B and our proposal meets both of the RFA-TS-25-036 funding objectives by identifying a potential environmental risk factor for ALS and investigating how this risk factor contributes to the pathophysiology of ALS. Thus, for this investigation, in Aim 1, we will investigate the environmental and occupational risk factors in our ALS clusters through deep qualitative interviews. We will also compare this data with the National ALS Registry Epidemiological data of registrants from Central Virginia and the National cohort. In Aim 2, we will collect water specimens from households in ALS clusters and analyze them for dtBHQ levels and the presence of other toxicants. In Aim 3, we will investigate whether sustained, low-level exposure to dtBHQ activates neurotoxic pathways that cause motor neuron toxicity and lead to the expression of ALS-like phenotype using zebrafish and mice as model systems. This study will provide new data on the presence of a novel environmental toxicant and its role in elevating the risk of ALS in humans.