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.

Grant Number: 5R01ES007331-31
NIH Institute/Center: NIH
Principal Investigator: Michael Aschner