title: Manganese-induced developmental neurotoxicity in the CD rat: is oxidative damage a mechanism of action?
abstract: Inhalation of high concentrations of manganese (Mn) is associated with an extrapyramidal motor disorder in humans. Oxidative damage, mediated by increased levels of Mn in dopaminergic brain regions and mitochondria, is a hypothesized mechanism of action for Mn-induced neuronal degeneration and loss. To test this proposed mechanism, developing CD rats, which may be at an increased risk for Mn-induced neurotoxicity, were exposed orally to 0, 25, or 50 mg/kg/day of MnCl2 from postnatal day (PND) 1 to 49 Brain regional and mitochondrial Mn levels, brain regional reactive oxygen species (ROS) levels, and whole-brain nuclear and mitochondrial 8-OHdG levels were used to evaluate Mn-mediated oxidative damage. High-dose Mn exposure was associated with increased spontaneous motor activity on PND 21 and decreased body weights on PND 49. On PND 21, Mn concentrations were increased in brain regions and mitochondrial fractions in both low- and high-dose groups. ROS levels were elevated in cerebellum but not striatum. On PND 49, Mn concentrations in brain regions and mitochondrial fractions were increased only in the high-dose group. Mn exposure did not significantly alter 8-OHdG levels in either mitochondrial or nuclear DNA. Selective uptake of Mn by the striatum or mitochondrial fraction was not demonstrated at either time point. These data allow us to conclude that oral exposure to high levels of Mn in developing CD rats resulted in increased brain regional and mitochondrial Mn levels, increased motor activity, and decreased body weights but not in selective accumulation of Mn in the striatum or mitochondrial fraction of any brain region or elevations in striatal ROS or whole-brain 8-OHdG levels. These findings do not support the hypothesis that oxidative damage, as assessed by ROS and 8-OHdG levels, is a mechanism of action in Mn-induced developmental neurotoxicity in the CD rat.
authors.affiliation: Chemical Industry Institute of Toxicology, Research Triangle Park, NC, USA. brenneman@ciit.org
authors.forename: K A
authors.initials: KA
authors.lastname: Brenneman
authors.forename: R C
authors.initials: RC
authors.lastname: Cattley
authors.forename: S F
authors.initials: SF
authors.lastname: Ali
authors.forename: D C
authors.initials: DC
authors.lastname: Dorman
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000831:Animals, Newborn; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000737:chemistry / Q000302:isolation & purification; D004305:Dose-Response Relationship, Drug; D005260:Female; D008345:Manganese / Q000493:pharmacokinetics*; D020149:Manganese Poisoning; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009043:Motor Activity / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D010298:Parity; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014018:Tissue Distribution
chemical_list: D017382:Reactive Oxygen Species; D008345:Manganese; D004247:DNA