Manganese oxidation state and its implications for toxicity.

Manganese (Mn) is ubiquitous in mammalian systems and is essential for proper development and function, though it can also be toxic at elevated exposures. While essential biologic functions of Mn depend on its oxidation state [e.g., Mn(II), Mn(III)], little is known about how the oxidation state of elevated Mn exposures affect cellular uptake, and function/toxicity. Here we report the dynamics of EPR measurable Mn(II) in fresh human plasma and cultured PC12 cell lysates as a function of exposure to either manganese(II) chloride or manganese(III) pyrophosphate, and the effects of exposure to Mn(II) versus Mn(III) on total cellular aconitase activity and cellular Mn uptake. The results indicate that Mn(II) or Mn(III) added in vitro to fresh human plasma or cell lysates yielded similar amounts of EPR measurable Mn(II). In contrast, Mn added as Mn(III) was significantly more effective in inhibiting total cellular aconitase activity, and intact PC12 cells accumulated significantly more Mn when exposures occurred as Mn(III). Collectively, these data reflect the dynamic nature of Mn speciation in simple biological systems, and the importance of Mn oxidation/speciation state in mediating potential cellular toxicity. This study supports concern over increased environmental exposures to Mn in different oxidation states [Mn(II), Mn(III), and Mn(IV)] that may arise from combustion products of the gasoline antiknock additive methycyclopentadienyl manganese tricarbonyl (MMT).