Manganese-induced developmental neurotoxicity in the CD rat: Is oxidative damage a mechanism of action?

Inhalation of high concentrations of manganese (Mn) is associated with an e xtrapyramidal motor disorder in humans. Oxidative damage, mediated by incre ased levels of Mn in dopaminergic brain regions and mitochondria, is a hypo thesized mechanism of action for Mn-induced neuronal degeneration and loss. To test this proposed mechanism, developing CD rats, which may be at an in creased risk for Mn-induced neurotoxicity, were exposed orally to 0, 25, or 50 mg/kg/day of MnCl2 from postnatal day (PND) I to 49 Brain regional and mitochondrial Mn levels, brain regional reactive oxygen species (ROS) level s, and whole-brain nuclear and mitochondrial 8-OHdG levels were used to eva luate Mn-mediated oxidative damage. High-dose Mn exposure was associated wi th increased spontaneous motor activity on PND 21 and decreased body weight s on PND 49. On PND 21, Mn concentrations were increased in brain regions a nd mitochondrial fractions in both low- and high-dose groups. ROS levels we re 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 mi tochondrial 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, i ncreased motor activity, and decreased body weights but not in selective ac cumulation of Mn in the striatum or mitochondr ial fraction of any brain re gion or elevations in striatal ROS or whole-brain 8-OHdG levels. These find ings do not support the hypothesis that oxidative damage, as assessed by RO S and 8-OHdG levels, is a mechanism of action in Mn-induced developmental n eurotoxicity in the CD rat. (C) 1999 Inter Press, Inc.