Molecular Mechanisms of Manganese Oxide Nanoparticles Toxicity in Brain and Other Tissues: An Overview.

The use of manganese oxide nanoparticles (MnOxNPs) in biomedicine increases the risk of their accumulation in the body, potentially leading to toxicity in various organs and tissues. In addition, occupational exposure to MnOxNPs-containing aerosols may also occur. MnOxNPs have been shown to accumulate in the brain and induce neurobehavioral alterations. However, the specific mechanisms of MnOxNPs toxicity in the brain and other tissues remain incompletely understood. Therefore, the objective of this review is to summarize existing data on the toxicity of MnOxNPs in the brain and other tissues, and to discuss the molecular mechanisms underlying their neurotoxic effects. It has been shown that MnOxNPs induce neuronal death through induction of mitochondrial dysfunction and subsequent apoptosis, and overaccumulation of tau protein and amyloid-β. Neurotoxic effects of MnOxNPs may also be mediated by blood-brain barrier disruption, and dysregulation of dopaminergic and glutaminergic signaling. Exposure to MnOxNPs induces neuroinflammation through activation of nuclear factor kappa B (NF-κB) and p38 mitogen-activated protein kinase (p38 MAPK) pathways in a reactive oxygen species-dependent manner. In vitro studies further demonstrate that MnOxNPs exhibit a dose-dependent cytotoxic effects in alveolar macrophages, as well as in respiratory, colonic, and other epithelial cells, through the promotion of oxidative stress and an inflammatory response. Overexposure to MnOxNPs has significant nephrotoxic, hepatotoxic, and immunotoxic effects, as well as affecting the reproductive system. Smaller particles exhibit more pronounced toxic effects in the brain and other tissues than larger nanoparticles or microparticles. However, the mechanisms underlying the different toxicities of MnOxNPs of different sizes, shapes, and surface modifications remain unclear. These observations highlight the potential of MnOxNP exposure to contribute to neurological disorders and dysfunction of other systems, underscoring the need for further mechanistic studies to ensure their safe application in biomedicine.