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Manganese oxidation state mediates toxicity in PC12 cells
1Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA 95064, USA. stevereaney@hotmail.com
Abstract:
The role of the manganese (Mn) oxidation state on cellular Mn uptake and toxicity is not well understood. Therefore, undifferentiated PC12 cells were exposed to 0-200 microM Mn(II)-chloride or Mn(III)-pyrophosphate for 24 h, after which cellular manganese levels were measured along with measures of cell viability, function, and cytotoxicity (trypan blue exclusion, medium lactate dehydrogenase (LDH), 8-isoprostanes, cellular ATP, dopamine, serotonin, H-ferritin, transferrin receptor (TfR), Mn-superoxide dismutase (MnSOD), and copper-zinc superoxide dismutase (CuZnSOD) protein levels). Exposures to Mn(III) >10 microM produced 2- to 5-fold higher cellular manganese levels than equimolar exposures to Mn(II). Cell viability and ATP levels both decreased at the highest Mn(II) and Mn(III) exposures (150-200 microM), while Mn(III) exposures produced increases in LDH activity at lower exposures (> or =50 microM) than did Mn(II) (200 microM only). Mn(II) reduced cellular dopamine levels more than Mn(III), especially at the highest exposures (50% reduced at 200 microM Mn(II)). In contrast, Mn(III) produced a >70% reduction in cellular serotonin at all exposures compared to Mn(II). Different cellular responses to Mn(II) exposures compared to Mn(III) were also observed for H-ferritin, TfR, and MnSOD protein levels. Notably, these differential effects of Mn(II) versus Mn(III) exposures on cellular toxicity could not simply be accounted for by the different cellular levels of manganese. These results suggest that the oxidation state of manganese exposures plays an important role in mediating manganese cytotoxicity.
Insights
Manganese oxidation state significantly impacts cellular uptake and toxicity. Mn(III) increased cellular manganese more than Mn(II), causing distinct toxic effects and neurotransmitter level changes.
Area of Science:
- Neuroscience
- Toxicology
- Cell Biology
Background:
- The impact of manganese (Mn) oxidation state on cellular manganese uptake and toxicity remains unclear.
- Understanding these differences is crucial for assessing Mn-related health risks.
Purpose of the Study:
- To investigate the differential effects of manganese(II) and manganese(III) on cellular manganese levels, viability, and specific cellular functions.
- To elucidate the role of manganese oxidation state in mediating manganese-induced cytotoxicity.
Main Methods:
- PC12 cells were exposed to varying concentrations of Mn(II)-chloride and Mn(III)-pyrophosphate.
- Cellular manganese levels, viability (trypan blue exclusion, ATP), cytotoxicity (LDH), and protein levels (H-ferritin, TfR, MnSOD, CuZnSOD) were measured.
- Neurotransmitter levels (dopamine, serotonin) were also assessed.
Main Results:
- Mn(III) exposures resulted in 2- to 5-fold higher cellular manganese levels than equimolar Mn(II) exposures.
- Both Mn(II) and Mn(III) decreased cell viability and ATP at high concentrations (150-200 microM).
- Mn(III) increased LDH activity at lower concentrations than Mn(II), and differential effects on dopamine, serotonin, H-ferritin, TfR, and MnSOD were observed.
Conclusions:
- The oxidation state of manganese exposure plays a critical role in mediating manganese cytotoxicity.
- Differential cellular responses to Mn(II) versus Mn(III) suggest oxidation state-specific mechanisms of toxicity beyond simple cellular manganese levels.
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