Summary Methylmercury (MeHg) is a potent neurotoxin, and recent studies indicate that inorganic arsenic(III) (iAs) is also neurotoxic. Although chemicals co-occur in the environment, the study of chemical mixtures is more recent. Heavy metals target the central nervous system, and co-exposure may result in synergistic neurotoxic impacts. However, the biological and molecular mechanisms underlying these joint effects are uncertain. The aim of our study is to investigate synergism between iAs and MeHg, using the zebrafish (Danio rerio) model system. Aim 1. Investigate the uptake and metabolism of iAs and MeHg in zebrafish. We anticipate that co-exposure to both chemicals will alter the proportion of arsenic species in the liver, compared to controls. Adult zebrafish will be exposed to environmentally relevant levels of MeHg (through diet) and sodium arsenite (through water) (six treatment groups). In the liver, mercury species and arsenic species will be compared between treatment groups, and sex-specific differences will be investigated. Accumulation of mercury and arsenic in adult tissues and organs will be visualized using laser ablation-ICP-MS. Aim 2. Determine the impacts of MeHg and iAs exposure in progeny, including neurobehavioral outcomes, and mechanisms of toxicity. Mercury and arsenic species will be determined in whole embryos [120 hours post fertilization (hpf)], exposed to both neurotoxicants through maternal transfer. In embryos (6-120 hpf) and adults [90 days post fertilization (dpf)], morphological and neurobehavioral endpoints will be assessed. Using RNA sequencing, we will conduct genome-wide transcriptomics of offspring brains (90 dpf), and identify signaling pathways, which are enriched or depleted due to co-exposure. Transcriptomic results will be compared between treatment groups and males/females. This study will advance our understanding of the mechanisms by which co-exposure to two chemicals, which frequently co-occur in the environment, contribute synergistically to offspring neurotoxicity.