Brain accumulation and toxicity of Mn(II) and Mn(III) exposures

Concern over the neurotoxic effects of chronic moderate exposures to manganese has arisen due to increased awareness of occupational exposures and to the use of methylcyclopentadienyl manganese tricarbonyl, a manganese-containing gasoline antiknock additive. Little data exist on how the oxidation state of manganese exposure affects toxicity. The objective of this study was to better understand how the oxidation state of manganese exposure affects accumulation and subsequent toxicity of manganese. This study utilized a rat model of manganese neurotoxicity to investigate how ip exposure to Mn(II)-chloride or Mn(III)-pyrophosphate at total cumulative doses of 0, 30, or 90 mg Mn/kg body weight affected the brain region distribution and neurotoxicity of manganese. Results indicate that Mn(III) exposures produced significantly higher blood manganese levels than equimolar exposures to Mn(II). Brain manganese concentrations increased in a dose-dependent manner, with Mn(III) exposures producing significantly higher (> 25%) levels than exposures to Mn(II) but with no measurable differences in the accumulation of manganese across different brain regions. Gamma amino butyric acid concentrations were increased in the globus pallidus (GP) with manganese exposure. Dopamine (DA) levels were altered in the GP, with the highest Mn(II) and Mn(III) exposures producing significantly different DA levels. In addition, transferrin receptor and H-ferritin protein expression increased in the GP with manganese exposure. These data substantiate the heightened susceptibility of the GP to manganese, and they indicate that the oxidation state of manganese exposure may be an important determinant of tissue toxicodynamics and subsequent neurotoxicity.