Genetics and Epigenetics of Manganese Toxicity

At elevated levels, the essential element manganese (Mn) is neurotoxic and increasing evidence indicates that environmental Mn exposure early in life negatively affects neurodevelopment. In this review, we describe how underlying genetics may confer susceptibility to elevated Mn concentrations and how the epigenetic effects of Mn may explain the association between Mn exposure early in life and its toxic effects later in life.

Common polymorphisms in the Mn transporter genes SLC30A10 and SLC39A8 seem to have a large impact on intracellular Mn levels and, in turn, neurotoxicity. Genetic variation in iron regulatory genes may to lesser extent also influence Mn levels and toxicity. Recent studies on Mn and epigenetic mechanisms indicate that Mn-related changes in DNA methylation occur early in life. One human and two animal studies found persistent changes from in utero exposure to Mn but whether these changes have functional effects remains unknown. Genetics seems to play a major role in susceptibility to Mn toxicity and should therefore be considered in risk assessment. Mn appears to interfere with epigenetic processes, potentially leading to persistent changes in developmental programming, which warrants further study.