The Role of Epigenetics in Manganese Neurotoxicity: An Update with a Focus on Non-Coding RNAs and Histone Modifications.

The objective of this review is to examine the direct evidence implicating epigenetic mechanisms in manganese (Mn)-induced neurotoxicity, with particular emphasis on the modulation of non-coding RNA (ncRNA) expression and histone modifications. Existing data demonstrate that Mn exposure modulates expression of various types of ncRNAs, especially micro RNAs (miRNAs or miRs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs). Through regulation of target gene expression, these differentially expressed ncRNAs likely mediate Mn-induced neuronal oxidative stress, ferroptosis, apoptosis, autophagy, inflammation, as well as α-synuclein expression. Additionally, Mn exposure affects histone acetylation in neurons by modulating enzymes such as histone deacetylases (HDACs) and histone acetyltransferases (HATs). These Mn-induced changes in histone acetylation enhance neuronal oxidative stress by down-regulating antioxidant gene expression and promoting neuroinflammation. Alterations in HDACs activity and the ensuing histone acetylation modifications play a role in Mn-induced down-regulation of glutamate transporter 1 (GLT-1) and glutamate-aspartate transporter (GLAST) expression which results in reduced glutamate uptake and ensuing excitotoxicity. Additionally, Mn exposure impacts the methylation of genes involved in neuroinflammation, neurogenesis, neuronal migration, signal transduction, mitochondrial functioning, cell cycle, and DNA damage response, as well as apoptosis. Detailed analysis reveals that Mn-induced DNA methylation leads to the down-regulation of brain-derived neurotrophic factor (BDNF) expression and the up-regulation of p53. Collectively, current evidence indicates that epigenetic mechanisms are key mediators of manganese (Mn)-induced neurotoxicity in both in vivo and in vitro models. However, the specific target genes and downstream signaling pathways involved in Mn-associated epigenetic regulation have yet to be fully characterized.