Role of oxidative stress and DNA hydroxymethylation in the neurotoxicity of fine particulate matter.
Epidemiological studies have implicated fine particulate matter (PM2.5) as a risk factor for neurodegenerative diseases and neurodevelopmental disorders. However, the underlying molecular mechanisms and the influences of different components remain largely elusive. Here, we extended our previous work to investigate the role of oxidative stress and DNA hydroxymethylation in neuronal pathology of PM2.5. We found PM2.5and its extracts (water-soluble extracts, organic extracts and carbon core component) differentially caused cell cycle arrest, cell apoptosis and the cell proliferation inhibition in neuronal cells. These effects were mechanistically related to each other and oxidative stress, suggesting PM2.5and toxic compounds adsorbed on the particles may cause different types of brain damages. In addition, PM2.5and its organic extracts increased global DNA hydroxymethylation and gene-specific DNA hydroxymethylation of neuronal genes, and subsequently interfered with their mRNA expression. The impairments in neuronal progression characterized with decreased length of neurite and reduced mRNA expression of neuronal markers and synaptic markers. The blocking effects of antioxidants demonstrated the involvement of oxidative stress-mediated hydroxymethylation abnormalities in PM2.5-induced defects in neurite outgrowth and synapse formation. Our results first revealed the role of oxidative stress-mediated abnormal DNA hydroxymethylation in neuronal impairments of PM2.5, and thoroughly evaluated the neurocytotoxicity of different components.
The Ninth People Hospital of Shanghai Jiao Tong University School of Medicine, No. 639 Zhizaoju Road, Shanghai 200011, China.
Hongying
H
Wei
School of Public Health, Shanghai Jiao Tong University School of Medicine, No. 227 Chongqing South Road, Shanghai 200025, China.
Yan
Y
Feng
School of Public Health, Shanghai Jiao Tong University School of Medicine, No. 227 Chongqing South Road, Shanghai 200025, China.
Fan
F
Liang
School of Public Health, Shanghai Jiao Tong University School of Medicine, No. 227 Chongqing South Road, Shanghai 200025, China.
Wei
W
Cheng
School of Public Health, Shanghai Jiao Tong University School of Medicine, No. 227 Chongqing South Road, Shanghai 200025, China.
Xiaomeng
X
Wu
School of Public Health, Shanghai Jiao Tong University School of Medicine, No. 227 Chongqing South Road, Shanghai 200025, China.
Ren
R
Zhou
The Ninth People Hospital of Shanghai Jiao Tong University School of Medicine, No. 639 Zhizaoju Road, Shanghai 200011, China; School of Public Health, Shanghai Jiao Tong University School of Medicine, No. 227 Chongqing South Road, Shanghai 200025, China; MOE-Shanghai Key Laboratory of Children's Environmental Health, No. 1665 Kongjiang Road, Shanghai, 200092, China. Electronic address: wangyan@shsmu.edu.cn.
Yan
Y
Wang
D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019175:DNA Methylation / Q000187:drug effects*; D006801:Humans; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D009498:Neurotoxins / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects*; D052638:Particulate Matter / Q000633:toxicity*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
D009498:Neurotoxins; D052638:Particulate Matter; D012333:RNA, Messenger; D017382:Reactive Oxygen Species
DNA hydroxymethylation; Fine particulate matter; Neurite outgrowth; Neurocytotoxicity; Oxidative stress; Synapse formation