Lipid Metabolites and Arsenic Methylation in the Strong Heart Family Study: An Untargeted Metabolomics Approach

Background and Aim. There are no safe levels of arsenic (As) exposure. Inorganic As (iAs) is methylated into mono-methyl (MMA) and dimethyl (DMA) arsenicals; methylation to DMA facilitates urinary As elimination and potentially reduces As-related toxicity. Our goal is to identify metabolites associated with As methylation patterns, as measured by the As species (iAs%, MMA%, and DMA%), and As methylation indices (primary methylation index (PMI:MMA/iAs) and secondary methylation index (SMI:DMA/MMA) which are less influenced by As exposure levels. Methods. This study leveraged urinary As and untargeted lipid metabolite data from 1,838 participants in the Strong Heart Family Study, which recruited adult participants from 12 American Indian communities in Arizona, Oklahoma, and North/South Dakota in 2001–2003. Metabolite data was performed on plasma samples using a quadrupole time-of-flight mass spectrometer. We used linear regression models to evaluate the cross-sectional associations between lipid metabolites and As methylation patterns and Mummichog for metabolic pathways analysis. Results. 1543 (543 identified, 1000 unidentified) lipid metabolic features were included. From 1,088 lipid metabolites that were significantly associated (pFDR<0.05) with at least one As species in linear regression models, 531 were associated with all three species, and 541 overlapped with MMA%, DMA% and SMI. Pathway enrichment analyses of associated metabolites (p<0.1) with ≥3 significant lipid metabolites in the pathway showed effects in 12 pathways that were associated with As methylation markers. Although there were only 3 pathways that were associated with PMI, (lineolate, fatty acid activation, and carnitine shuttle metabolism), these same pathways were associated with all 5 measures of As methylation. Conclusions. We found that associations between As methylation indices and lipid metabolites predominantly affect the secondary methylation of As, from MMA to DMA along fatty acid metabolism pathways. Future work will investigate if these metabolites are also associated with adverse health outcomes. Keywords: Arsenic methylation, metabolomics