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Principal Investigator: STUART A BATTERMAN
Organization: UNIVERSITY OF MICHIGAN AT ANN ARBOR
Fiscal Year: 2024
Award: $653,107
Funding agency: National Institute of Environmental Health Sciences
ABSTRACT
Amyotrophic lateral sclerosis (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 and progression; we have shown that measured and reported pesticide exposures strongly increase ALS risk and that high levels of persistent organic pollutants (POPs) decrease ALS survival in ALS subjects in Michigan. Therefore, there is a need to delineate the “ALS exposome,” defined as the lifetime of environmental exposures that contributes to ALS risk. In this proposal, our objectives are to improve our ALS exposome model by enhancing insight into pollutant mixtures associated with ALS accounting for genetic risk, identifying periods of susceptibility to exposures, correlating toxin measurements in easily assessable biofluids with epidemiologic data, and identifying whether these environmental toxins are absorbed into the central nervous system (CNS) in order to improve insight into the gene-time-environment hypothesis in ALS. Our central hypothesis is that identifying environmental pollutants in biofluids and CNS tissues will advance models of ALS pathogenesis. In Aim 1, we will better characterize the ALS exposome by measuring environmental toxins in biological samples obtained longitudinally from ALS subjects from the University of Michigan ALS Patient Repository and age- and sex-matched controls across the State of Michigan to yield insight into the pollutant mixtures that contribute to disease risk and survival, accounting for genetic susceptibility via polygenic risk scores. In Aim 2, we will evaluate residential and occupational histories for association with ALS risk and survival, while also correlating exposure histories to toxin measures from Aim 1, to gain comprehensive insight into exposure mixtures and time windows critical for ALS
risk. Finally, in Aim 3, we will quantitate environmental toxins and heavy metals in ALS and control CNS tissues, and link peripheral alterations with observed changes in ALS CNS tissue and critical exposure windows to thereby ascertain environmental risk factors that potentially contribute to ALS pathogenesis. Overall, successful completion of these aims will have an important positive translational impact by identifying ALS disease risk factors associated with occupational and environmental exposures, while accounting for genetic susceptibility. This proposal will therefore expand our understanding of the ALS exposome in the context of genetic risk, identify toxins that pose a public health risk, identify occupations linked to exposures, and establish a framework to test for these exposures in other neurodegenerative diseases. This understanding of the ALS exposome will support much-needed public health interventions to target modifiable disease risk factors in this
lethal disorder.
Terms: <ALS patients><Accounting><Affect><Age><Amyotrophic Lateral Sclerosis><Amyotrophic Lateral Sclerosis Motor Neuron Disease><Amyotrophic Lateral Sclerosis patients><Autopsy><BMI><BMI percentile><BMI z-score><Biological><Biological Monitoring><Body Tissues><Body mass index><Brain><Brain Nervous System><CNS Nervous System><Central Nervous System><Complex><Data><Degenerative Neurologic Disorders><Disease><Disease Progression><Disorder><Ecologic Monitoring><Ecological Monitoring><Encephalon><Environment><Environmental Exposure><Environmental Factor><Environmental Monitoring><Environmental Pollutants><Environmental Risk Factor><Environmental Toxin><Environmental and Occupational Exposure><Epidemiological data><Epidemiology data><Exposure to><Gehrig's Disease><Genes><Genetic><Genetic Predisposition><Genetic Predisposition to Disease><Genetic Risk><Genetic Susceptibility><Genetic propensity><Geography><Goals><Heavy Metals><Heterogeneity><History><Hobbies><Inherited Predisposition><Inherited Susceptibility><Jobs><Link><Lou Gehrig Disease><Maps><Measurement><Measures><Medulla Spinalis><Metabolic><Michigan><Modeling><Nerve Degeneration><Nervous System Degenerative Diseases><Neural Degenerative Diseases><Neural degenerative Disorders><Neuraxis><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic Degenerative Conditions><Neuron Degeneration><OCP exposure><Occupational><Occupational Exposure><Occupations><Organophosphates><PCBs><Pathogenesis><Patients><Peripheral><Pesticides><Phenotype><Physical activity><Polychlorinated Biphenyls><Polychlorobiphenyl Compounds><Population><Predisposition><Professional Positions><Public Health><Quetelet index><Recording of previous events><Reporting><Risk><Risk Factors><Sampling><Spinal Cord><Survey Instrument><Surveys><Susceptibility><Testing><Time><Tissues><Toxic Environmental Agents><Toxic Environmental Substances><Toxin><Trace metal><Trauma><Universities><Work><absorption><ages><biologic><biomonitoring><chlorinated hydrocarbon pesticide><cohort><compare to control><comparison control><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><demographics><depository><disease prevention><disease risk><disorder prevention><disorder risk><environmental contaminant><environmental risk><environmental testing><environmental toxicant><epidemiologic data><genetic etiology><genetic mechanism of disease><genetic vulnerability><genetically predisposed><histories><improved><innovate><innovation><innovative><insight><interest><malleable risk><modifiable risk><necropsy><neural degeneration><neurodegeneration><neurodegenerative><neurodegenerative illness><neurological degeneration><neuronal degeneration><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><organochlorine pesticide><organochlorine pesticide exposure><outreach><persistent organic pollutants><pesticide exposure><pleiotropic effect><pleiotropism><pleiotropy><pollutant><polybrominated biphenyl ether><polybrominated diphenyl ether><polychlorobiphenyl><polygenic risk score><postmortem><public health intervention><recruit><repository><sex><translational impact><uptake><workplace exposure>