Sodium arsenite requires redox sensitization to cause developmental dopaminergic neurotoxicity in Caenorhabditis elegans

Abstract

Environmental pollutants can disrupt mitochondrial function through many pathways and mitochondrial dysfunction is often linked to neurotoxicity, particularly of dopaminergic neurons. However, there are many mechanisms of mitochondrial toxicity. Remarkably, despite the centrality of the Krebs cycle to mitochondrial bioenergetics, there is very limited evidence regarding whether pollutants that inhibit the Krebs cycle can cause neurotoxicity. We exposed Caenorhabditis elegans through its whole development to Krebs cycle inhibitors sodium arsenite and fluoroacetic acid, and evaluated neuronal morphology and function as well as dopaminergic ATP levels and redox state. Both chemicals impaired growth and reproduction, but neither caused morphological damage nor functional deficits in dopaminergic, glutamatergic, or cholinergic neurons at concentrations causing mild organismal toxicity. Sodium arsenite, but not fluoroacetic acid, decreased dopaminergic ATP levels; neither caused significant changes in mitochondrial redox state. However, developmental exposure to sodium arsenite caused dopaminergic neurotoxicity when mitochondrial quality control or redox stress response was compromised by loss of pink-1/PINK1 or sod-2/SOD2, by co-exposure to rotenone, antimycin A, or buthionine sulfoximine, or secondary challenge to 6-hydroxydopamine. These conditions also led to dopamine-associated behavioral deficits. Thus, developmental exposure to sodium arsenite required an additional mitochondrial or redox stress challenge to cause dopaminergic neurotoxicity, and we did not find evidence that inhibition of the Krebs cycle broadly defined causes developmental neurotoxicity.