Mechanisms of Methylmercury Induced Neuronal Toxicity

PROJECT SUMMARY Methylmercury (MeHg) is a potent neurotoxin affecting both the developing and mature central nervous system with apparent indiscriminate disruption of multiple homeostatic pathways. However, genetic and environmental modifiers contribute significant variability to neurotoxicity associated with human exposures. Furthermore, neurotoxic outcomes show evidence of persistence and latent effects long after exposure has subsided. MeHg neurotoxicity is associated with oxidative stress and impaired redox homeostasis, mitochondrial dysfunction, activation of cell stress pathways, alteration of proteostasis, calcium dysregulation, damage to neuronal processes and neuronal/synaptic dysfunction, to name a few. Though, these same pathological hallmarks are seen with exposure to many (perhaps even most) neurotoxicants and underlie degenerative and developmental disorders. Hence, while they serve as key outcomes of MeHg exposure and indicators of neurological damage, their connection to underlying targets of MeHg neurotoxicity and inter-relationships between each other are unknown. Compelling evidence identifies both dopaminergic (DAergic) and glutamatergic (GLUergic) neurons as targets of MeHg-induced persistent neurotoxicity. Here we seek to identify and understand persistent and latent effects of MeHg toxicity on biological pathways impacted by MeHg toxicity. Our goal is to understand the toxicological hierarchy and temporal susceptibility of key toxic outcome pathways and their perpetuation. This proposal leverages innovative technologies and the unique resources of its investigative team to build a highly translatable and mechanistic approach. The genetically tractable Caenorhabditis elegans (C. elegans) model system is ideally suited for discovering genetic and molecular mechanisms associated with neurotoxicity. The human induced pluripotent stem cell (hiPSC) model enables assessment of human genetic/pharmacological modifiers influencing neurotoxic outcomes and susceptibility along the ontogeny of defined neural lineages. Our overarching hypothesis is that persistent effects of MeHg are self-perpetuating via interdependent relationships of key biological pathways that sustain and regulate neurological function. We propose three aims, with each utilizing C. elegans and hiPSC neuronal models of DAergic and GLUergic neurons, to yield a highly complementary and robust scientific approach. To address the overarching hypothesis we have designed three highly meritorious Specific Aims, namely (1) to evaluate the temporal pattern of persistent and latent MeHg neurotoxicity following early and/or late developmental exposures by unbiased gene expression analysis, (2) to test the hypothesis that the latency periods and severity of persistent neurotoxic effects of MeHg are dependent on exposure timing, duration and total levels, and (3) to test the hypothesis that the latent/persistent effects of MeHg exposure on biological pathways are interrelated and inexorable.