title: Exposure to mitochondrial genotoxins and dopaminergic neurodegeneration in Caenorhabditis elegans.
abstract: Neurodegeneration has been correlated with mitochondrial DNA (mtDNA) damage and exposure to environmental toxins, but causation is unclear. We investigated the ability of several known environmental genotoxins and neurotoxins to cause mtDNA damage, mtDNA depletion, and neurodegeneration in Caenorhabditis elegans. We found that paraquat, cadmium chloride and aflatoxin B1 caused more mitochondrial than nuclear DNA damage, and paraquat and aflatoxin B1 also caused dopaminergic neurodegeneration. 6-hydroxydopamine (6-OHDA) caused similar levels of mitochondrial and nuclear DNA damage. To further test whether the neurodegeneration could be attributed to the observed mtDNA damage, C. elegans were exposed to repeated low-dose ultraviolet C radiation (UVC) that resulted in persistent mtDNA damage; this exposure also resulted in dopaminergic neurodegeneration. Damage to GABAergic neurons and pharyngeal muscle cells was not detected. We also found that fasting at the first larval stage was protective in dopaminergic neurons against 6-OHDA-induced neurodegeneration. Finally, we found that dopaminergic neurons in C. elegans are capable of regeneration after laser surgery. Our findings are consistent with a causal role for mitochondrial DNA damage in neurodegeneration, but also support non mtDNA-mediated mechanisms.
authors.affiliation: Nicholas School of the Environment, Duke University, Durham, North Carolina, United States of America.
authors.forename: Claudia P
authors.initials: CP
authors.lastname: González-Hunt
authors.affiliation: Nicholas School of the Environment, Duke University, Durham, North Carolina, United States of America.
authors.forename: Maxwell C K
authors.initials: MC
authors.lastname: Leung
authors.affiliation: Nicholas School of the Environment, Duke University, Durham, North Carolina, United States of America.
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Bodhicharla
authors.affiliation: Nicholas School of the Environment, Duke University, Durham, North Carolina, United States of America.
authors.forename: Madeline G
authors.initials: MG
authors.lastname: McKeever
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina, United States of America.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Arrant
authors.affiliation: Nicholas School of the Environment, Duke University, Durham, North Carolina, United States of America.
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Margillo
authors.affiliation: Nicholas School of the Environment, Duke University, Durham, North Carolina, United States of America.
authors.forename: Ian T
authors.initials: IT
authors.lastname: Ryde
authors.affiliation: Center for Applied Genomics and Technology, Duke University, Durham, North Carolina, United States of America.
authors.forename: Derek D
authors.initials: DD
authors.lastname: Cyr
authors.affiliation: Department of Genetics, Program in Cellular Neuroscience, Neurodegeneration, and Repair, Yale University School of Medicine, New Haven, Connecticut, United States of America.
authors.forename: Sara G
authors.initials: SG
authors.lastname: Kosmaczewski
authors.affiliation: Department of Genetics, Program in Cellular Neuroscience, Neurodegeneration, and Repair, Yale University School of Medicine, New Haven, Connecticut, United States of America.
authors.forename: Marc
authors.initials: M
authors.lastname: Hammarlund
authors.affiliation: Nicholas School of the Environment, Duke University, Durham, North Carolina, United States of America.
authors.forename: Joel N
authors.initials: JN
authors.lastname: Meyer
mesh_terms: D018663:Adrenergic Agents / Q000633:toxicity; D000818:Animals; D017173:Caenorhabditis elegans / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D004249:DNA Damage / Q000187:drug effects*; D004272:DNA, Mitochondrial / Q000235:genetics; D004298:Dopamine / Q000633:toxicity; D015259:Dopamine Agents / Q000633:toxicity; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000473:pathology*; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics / Q000473:pathology*; D009153:Mutagens / Q000633:toxicity*; D009410:Nerve Degeneration / Q000188:drug therapy / Q000473:pathology*; D016627:Oxidopamine / Q000633:toxicity; D010269:Paraquat / Q000633:toxicity
chemical_list: D018663:Adrenergic Agents; D004272:DNA, Mitochondrial; D015259:Dopamine Agents; D009153:Mutagens; D016627:Oxidopamine; D010269:Paraquat; D004298:Dopamine