Discovery of Heavy Metal Neurotoxicity as a Suicide Biomarker via Multimodal Profiling and Behavioral Endophenotyping

Overview

Every 40 seconds, suicide steals a life, emphasizing the need to elucidate biological underpinnings. Despite psychological research, suicide's pathogenisis remains poorly understood. This study presents a multi-scale investigation of heavy metals, as inducers of neurobehavioral suicide risk, integrating organismal modeling, transcriptomic profiling, and computational epidemiology. C. elegans and Drosophila melanogaster were evaluated across experiments of motivation, focus, sleep, and social isolation, with behaviors quantified through optic flow using the Lucas-Kanade algorithm. Heavy-metal-treated worms exhibited a 49% reduction in focus, (p=0.000145) and lost climbing ability. They also showed a 78% failure rate in motivational tasks with a 27-fold increase in recovery time (p=0.011). Exposed flies failed to achieve deep sleep mimicking human insomnia. Freezing, absent in controls, occurred in 80% of exposed flies. Supplementation with L-glutamic acid reversed this phenotype, implicating neurotransmitter involvement. RNA-sequencing of heavy-metal-exposed Drosophila identified 313 significant differentially expressed genes (edgeR, FDR0.05), showing suppression of 1) the polyamine biosynthesis gene amd, ortholog of the SAT1 pathway, the most replicated postmortem suicide finding in human brains, and 2) ple (tyrosine hydroxylase), an enzyme in dopamine synthesis. At the population level, a GraphSAGE neural network (R2=0.447) identified water and air pollution as top suicide predictors independant from socioeconomic status, and a NHANES analysis (n=25,179) showed heavy metal exposure associated with 63% higher depression risk (p<1e-24). Together, these results suggest that heavy metal exposure is a significant and unrecognized biological contributor to suicide risk, and can potentially reform suicide prevention efforts.