Investigating the Role of Zinc in Manganese-induced Hepatotoxicity

Abstract

The objective of this study was to investigate the role of zinc (Zn) status in manganese (Mn) -induced hepatotoxicity using epidemiological data and vitro experiments. First, we conducting epidemiological study using the National Health and Nutrition Examination Survey (NHANES) to determine the relationship between Zn status and blood Mn levels on enzymatic markers of liver damage. The findings indicated that without the regression interaction of Zn intake or serum Zn, blood Mn exhibits a direct (positive) association with Alkaline Phosphatase (ALP) and Aspartate Amino transferase (AST). The results however showed that with the interaction of blood Mn and Zn intake at the second quartile (Q2) (marginal low Zn intake), a negative association was found with ALP in model 1,model 2 (corrected by age and gender), and model 3 (corrected by age, gender, race, education, BMI, alcohol, smoking and diabetes ). A similar association was found between Q4 (adequate/high Zn intake) and Lactate Dehydrogenase (LDH) activity in all three models of the study. Second, the effect of Zn deficiency and adequacy on Mn toxicity and the expression level of the cellular Mn efflux transporter SCL30A10 in human hepatocytes was evaluated. Mitochondria oxidative stress, apoptosis, and cell death and proliferation studies showed that exposure to elevated levels of Mn increased oxidative stress, apoptosis, and cell death. Mn exposure also decreased cell proliferation. Noteworthy, Zn depletion was found to enhance Mn induced apoptosis and cell death. Lastly, the mRNA expression of SLC30A10 was significantly decreased by Mn exposure (p < 0.05). However, no significant difference in the protein expression level of SCL30A10 was found. This suggests that there was no compensatory regulatory response of this transporter expression to either Zn deficiency or Mn exposure for the time point analyzed. Overall, the results from the epidemiological data and in vitro studies indicate that Zn deficiency could enhance the toxic effects of Mn. The results underscore the importance of having an adequate Zn intake in mitigating Mn induced cytotoxicity.