Abstract
Fine particulate matter (PM2.5) has been implicated as a risk factor for neurodevelopmental disorders including autism in children. However, the underlying biological mechanism remains unclear. DNA methylation is suggested to be a fundamental mechanism for the neuronal responses to environmental cues. We prepared whole particle of PM2.5 (PM2.5), water-soluble extracts (Pw), organic extracts (Po) and carbon core component (Pc) and characterized their chemical constitutes. We found that PM2.5 induced significant redox imbalance, decreased the levels of intercellular methyl donor S-adenosylmethionine and caused global DNA hypomethylation. Furthermore, PM2.5 exposure triggered gene-specific promoter DNA hypo- or hypermethylation and abnormal mRNA expression of autism candidate genes. PM2.5-induced DNA hypermethylation in promoter regions of synapse related genes were associated with the decreases in their mRNA and protein expression. The inhibiting effects of antioxidative reagents, a methylation-supporting agent and a DNA methyltransferase inhibitor demonstrated the involvement of redox/methylation mechanism in PM2.5-induced abnormal DNA methylation patterns and synaptic protein expression. The biological effects above generally followed a sequence of PM2.5 ≥ Pwo > Po > Pw > Pc. Our results implicated a novel epigenetic mechanism for the neurodevelopmental toxicity of particulate air pollution, and that eliminating the chemical components could mitigate the neurotoxicity of PM2.5.
Highlights
Activities have been correlated with increased methylation in the promoter region of the inducible nitric oxide synthase gene[10]
We aimed to investigate whether exposure of human neuronal cells to PM2.5 could induce abnormal DNA methylation patterns through redox/methylation mechanism
The contents of the metals and polycyclic aromatic hydrocarbons (PAHs) generally showed similar results between PM2.5 and the sum of the three extracts (Pw, Po and Pc), which indicates the good quality of sample preparation and chemical analysis (Fig. 1a,b)
Summary
Activities have been correlated with increased methylation in the promoter region of the inducible nitric oxide synthase gene[10]. The association between developmental PM2.5-induced neurotoxicity and DNA methylation as well as correlative gene expression remains to be identified, and the underlying molecular mechanisms are largely unknown. A large number of studies have shown that oxidative stress is one of the most important mechanisms for the adverse health effects of ambient particulate matter[14]. Oxidative stress status, an imbalance in glutathione redox metabolism and impairments in genomewide DNA methylation as well as gene-specific DNA methylation have been reported in children with ASD15,16. Based on the metabolic relationship between oxidative stress and the methylation groups, we further proposed that the oxidative stress-induced methylation abnormality (redox/ methylation mechanism) might be involved in PM2.5-induced neurodevelopmental disorders. We aimed to investigate whether exposure of human neuronal cells to PM2.5 could induce abnormal DNA methylation patterns through redox/methylation mechanism. We analyzed the effects of different types of PM2.5 extracts to evaluate the contribution of different chemical compositions to the toxicity of PM2.5
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