RT Journal Article SR Electronic T1 Natural variation in C. elegans arsenic toxicity is explained by differences in branched chain amino acid metabolism JF bioRxiv FD Cold Spring Harbor Laboratory SP 373787 DO 10.1101/373787 A1 Stefan Zdraljevic A1 Bennett W. Fox A1 Christine Strand A1 Oishika Panda A1 Francisco J. Tenjo A1 Shannon C. Brady A1 Tim A. Crombie A1 John G. Doench A1 Frank C. Schroeder A1 Erik C. Andersen YR 2019 UL http://biorxiv.org/content/early/2019/02/07/373787.abstract AB We find that variation in the dbt-1 gene underlies natural differences in Caenorhabditis elegans responses to the toxin arsenic. This gene encodes the E2 subunit of the branched-chain α-keto acid dehydrogenase (BCKDH) complex, a core component of branched-chain amino acid (BCAA) metabolism. We causally linked a non-synonymous variant in the conserved lipoyl domain of DBT-1 to differential arsenic responses. Using targeted metabolomics and chemical supplementation, we demonstrate that differences in responses to arsenic are caused by variation in iso-branched chain fatty acids. Additionally, we show that levels of branched chain fatty acids in human cells are perturbed by arsenic treatment. This finding has broad implications for arsenic toxicity and for arsenic-focused chemotherapeutics across human populations. Our study implicates the BCKDH complex and BCAA metabolism in arsenic responses, demonstrating the power of C. elegans natural genetic diversity to identify novel mechanisms by which environmental toxins affect organismal physiology.