title: Methylmercury impairs canonical dopamine metabolism in rat undifferentiated pheochromocytoma (PC12) cells by indirect inhibition of aldehyde dehydrogenase.
abstract: The environmental neurotoxicant methylmercury (MeHg) disrupts dopamine (DA) neurochemical homeostasis by stimulating DA synthesis and release. Evidence also suggests that DA metabolism is independently impaired. The present investigation was designed to characterize the DA metabolomic profile induced by MeHg, and examine potential mechanisms by which MeHg inhibits the DA metabolic enzyme aldehyde dehydrogenase (ALDH) in rat undifferentiated PC12 cells. MeHg decreases the intracellular concentration of 3,4-dihydroxyphenylacetic acid (DOPAC). This is associated with a concomitant increase in intracellular concentrations of the intermediate metabolite 3,4-dihydroxyphenylaldehyde (DOPAL) and the reduced metabolic product 3,4-dihydroxyethanol. This metabolomic profile is consistent with inhibition of ALDH, which catalyzes oxidation of DOPAL to DOPAC. MeHg does not directly impair ALDH enzymatic activity, however MeHg depletes cytosolic levels of the ALDH cofactor NAD(+), which could contribute to impaired ALDH activity following exposure to MeHg. The observation that MeHg shunts DA metabolism along an alternative metabolic pathway and leads to the accumulation of DOPAL, a reactive species associated with protein and DNA damage, as well as cell death, is of significant consequence. As a specific metabolite of DA, the observed accumulation of DOPAL provides evidence for a specific mechanism by which DA neurons may be selectively vulnerable to MeHg.
authors.affiliation: *Neuroscience Program, Department of Pharmacology and Toxicology, Department of Biochemistry and Molecular Biology, College of Osteopathic Medicine and Department of Neurology and Ophthalmology, Michigan State University, East Lansing, Michigan 48824 tiernan8@msu.edu.
authors.forename: Chelsea T
authors.initials: CT
authors.lastname: Tiernan
authors.affiliation: *Neuroscience Program, Department of Pharmacology and Toxicology, Department of Biochemistry and Molecular Biology, College of Osteopathic Medicine and Department of Neurology and Ophthalmology, Michigan State University, East Lansing, Michigan 48824.
authors.forename: Ethan A
authors.initials: EA
authors.lastname: Edwin
authors.affiliation: *Neuroscience Program, Department of Pharmacology and Toxicology, Department of Biochemistry and Molecular Biology, College of Osteopathic Medicine and Department of Neurology and Ophthalmology, Michigan State University, East Lansing, Michigan 48824 *Neuroscience Program, Department of Pharmacology and Toxicology, Department of Biochemistry and Molecular Biology, College of Osteopathic Medicine and Department of Neurology and Ophthalmology, Michigan State University, East Lansing, Michigan 48824.
authors.forename: Hae-Young
authors.initials: HY
authors.lastname: Hawong
authors.affiliation: *Neuroscience Program, Department of Pharmacology and Toxicology, Department of Biochemistry and Molecular Biology, College of Osteopathic Medicine and Department of Neurology and Ophthalmology, Michigan State University, East Lansing, Michigan 48824.
authors.forename: Mónica
authors.initials: M
authors.lastname: Ríos-Cabanillas
authors.affiliation: *Neuroscience Program, Department of Pharmacology and Toxicology, Department of Biochemistry and Molecular Biology, College of Osteopathic Medicine and Department of Neurology and Ophthalmology, Michigan State University, East Lansing, Michigan 48824 *Neuroscience Program, Department of Pharmacology and Toxicology, Department of Biochemistry and Molecular Biology, College of Osteopathic Medicine and Department of Neurology and Ophthalmology, Michigan State University, East Lansing, Michigan 48824 *Neuroscience Program, Department of Pharmacology and Toxicology, Department of Biochemistry and Molecular Biology, College of Osteopathic Medicine and Department of Neurology and Ophthalmology, Michigan State University, East Lansing, Michigan 48824.
authors.forename: John L
authors.initials: JL
authors.lastname: Goudreau
authors.affiliation: *Neuroscience Program, Department of Pharmacology and Toxicology, Department of Biochemistry and Molecular Biology, College of Osteopathic Medicine and Department of Neurology and Ophthalmology, Michigan State University, East Lansing, Michigan 48824 *Neuroscience Program, Department of Pharmacology and Toxicology, Department of Biochemistry and Molecular Biology, College of Osteopathic Medicine and Department of Neurology and Ophthalmology, Michigan State University, East Lansing, Michigan 48824.
authors.forename: William D
authors.initials: WD
authors.lastname: Atchison
authors.affiliation: *Neuroscience Program, Department of Pharmacology and Toxicology, Department of Biochemistry and Molecular Biology, College of Osteopathic Medicine and Department of Neurology and Ophthalmology, Michigan State University, East Lansing, Michigan 48824 *Neuroscience Program, Department of Pharmacology and Toxicology, Department of Biochemistry and Molecular Biology, College of Osteopathic Medicine and Department of Neurology and Ophthalmology, Michigan State University, East Lansing, Michigan 48824.
authors.forename: Keith J
authors.initials: KJ
authors.lastname: Lookingland
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D004298:Dopamine / Q000378:metabolism*; D007529:Isoflavones / Q000494:pharmacology; D008767:Methylmercury Compounds / Q000633:toxicity*; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D009243:NAD / Q000378:metabolism; D016716:PC12 Cells; D010673:Pheochromocytoma / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D012402:Rotenone / Q000494:pharmacology
chemical_list: D007529:Isoflavones; D008767:Methylmercury Compounds; D012402:Rotenone; D009243:NAD; C004742:daidzein; D000444:Aldehyde Dehydrogenase; D004298:Dopamine
keywords: PC12 cell; aldehyde dehydrogenase; dopamine metabolism; methylmercury-induced neurotoxicity