Molecular mechanisms of zinc oxide nanoparticles neurotoxicity

Abstract

Zinc oxide nanoparticles (ZnONPs) are widely used in industry and biomedicine. A growing body of evidence demonstrates that ZnONPs exposure may possess toxic effects to a variety of tissues, including brain. Therefore, the objective of the present review was to summarize existing evidence on neurotoxic effects of ZnONPs and discuss the underlying molecular mechanisms. The existing laboratory data demonstrate that both in laboratory rodents and other animals ZnONPs exposure results in a significant accumulation of Zn in brain and nervous tissues, especially following long-term exposure. As a result, overexposure to ZnONPs causes oxidative stress and cell death, both in neurons and glial cells, by induction of apoptosis, necrosis and ferroptosis. In addition, ZnONPs may induce neuroinflammation through the activation of nuclear factor kappa B (NF-κB), extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (MAPK), and lipoxygenase (LOX) signaling pathways. ZnONPs exposure is associated with altered cholinergic, dopaminergic, serotoninergic, as well as glutamatergic and γ-aminobutyric acid (GABA)-ergic neurotransmission, thus contributing to impaired neuronal signal transduction. Cytoskeletal alterations, as well as impaired autophagy and mitophagy also contribute to ZnONPs-induced brain damage. It has been posited that some of the adverse effects of ZnONPs in brain are mediated by altered microRNA expression and dysregulation of gut-brain axis. Furthermore, in vivo studies have demonstrated that ZnONPs exposure induced anxiety, motor and cognitive deficits, as well as adverse neurodevelopmental outcome. At the same time, the relevance of ZnONPs-induced neurotoxicity and its contribution to pathogenesis of neurological diseases in humans are still unclear. Further studies aimed at estimation of hazards of ZnONPs to human brain health and the underlying molecular mechanisms are warranted.