TY - JOUR T1 - Cross-species metabolomic analysis of DDT and Alzheimer’s disease-associated tau toxicity JF - bioRxiv DO - 10.1101/2021.06.14.448355 SP - 2021.06.14.448355 AU - Vrinda Kalia AU - Megan M. Niedzwiecki AU - Joshua M. Bradner AU - Fion K. Lau AU - Meghan L. Bucher AU - Katherine E. Manz AU - Zoe Coates Fuentes AU - Kurt D. Pennell AU - Martin Picard AU - Douglas I. Walker AU - William T. Hu AU - Dean P. Jones AU - Gary W. Miller Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/06/15/2021.06.14.448355.abstract N2 - Background The formation of hyperphosphorylated tau (p-tau) protein tangles in neurons is a pathological marker of Alzheimer’s disease (AD). Exposure to the pesticide dichlorodiphenyltrichloroethane (DDT) has been associated with increased risk of AD.Objectives To determine if there was a connection between DDT exposure and tau toxicity we investigated whether exposure to DDT can exacerbate tau protein toxicity in C. elegans. In addition, we examined the association between p-tau protein and metabolism in a human population study and in a transgenic C. elegans strain neuronally expressing a mutant tau protein fragment that is prone to aggregation.Methods In the human population study, we used a metabolome-wide association framework to determine the association between p-tau measured in the cerebrospinal fluid (CSF) and metabolomic features measured in both plasma (n = 142) and CSF (n = 78) using high-resolution metabolomics (HRM). Using the same HRM method, we determined changes in metabolomic features in the transgenic C. elegans strain compared to its control strain. Metabolites associated with p-tau in both species were analyzed for overlap. We also examined the effect of DDT and aggregating tau protein on growth, swim behavior, mitochondrial function, metabolism, learning, and lifespan in C. elegans.Results Plasma and CSF-derived features associated with p-tau level were related to drug, amino acid, fatty acid and mitochondrial metabolism pathways. Five metabolites overlapped between plasma and C. elegans, and 4 between CSF and C. elegans. DDT exacerbated the inhibitory effect of aggregating tau protein on growth and basal respiration. In the presence of aggregating tau protein, DDT induced more curling and was associated with reduced levels of amino acids but increased levels of uric acid and adenosylselenohomocysteine. Developmental exposure to DDT blunted the lifespan reduction caused by aggregating tau protein.Conclusion The model organism C. elegans can complement human studies by providing a means to study mechanisms of environmental toxicants. Specifically, our C. elegans data show that DDT exposure and tau protein aggregation both inhibit mitochondrial function and DDT exposure can exacerbate the mitochondrial inhibitory effects of tau protein aggregation providing a plausible explanation for the observed human associations.Competing Interest StatementThe authors have declared no competing interest. ER -