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化学进展 2021, Vol. 33 Issue (5): 713-725 DOI: 10.7536/PC210102   后一篇

• 研究论文 •

大气细颗粒物引发的神经毒性和分子机理

张雨竹1,2, 詹菁1, 刘倩1,*(), 周群芳1,2,3, 江桂斌1   

  1. 1 中国科学院生态环境研究中心 环境化学与生态毒理学国家重点实验室 北京 100085
    2 中国科学院大学资源与环境学院 北京 100049
    3 中国科学院大学杭州高等研究院环境学院 杭州 310000
  • 收稿日期:2021-01-07 修回日期:2021-01-31 出版日期:2021-05-20 发布日期:2021-03-04
  • 通讯作者: 刘倩
  • 作者简介:
    * Corresponding author E-mail:
  • 基金资助:
    国家自然科学基金项目(91943301); 国家自然科学基金项目(21806178); 国家自然科学基金项目(21527901)
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Neurotoxicity Induced by Atmospheric Fine Particulate Matters and the Underlying Molecular Mechanism

Yuzhu Zhang1,2, Jing Zhan1, Qian S. Liu1,*(), Qunfang Zhou1,2,3, Guibin Jiang1   

  1. 1 State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
    2 College of Resources and Environment, University of Chinese Academy of Sciences, Beijing 100049, China
    3 School of Environment, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310000, China
  • Received:2021-01-07 Revised:2021-01-31 Online:2021-05-20 Published:2021-03-04
  • Contact: Qian Liu
  • Supported by:
    National Natural Science Foundation of China(91943301); National Natural Science Foundation of China(21806178); National Natural Science Foundation of China(21527901)

大气细颗粒物(Atmospheric fine particulate matters,PMs)对人体健康产生的潜在危害已得到广泛关注。越来越多的研究表明,PMs暴露可产生呼吸、心血管系统等损伤影响,然而PMs是否可以进入大脑并产生神经毒性,一直是近年来大气雾霾健康效应的重要研究方向。本文通过梳理现有流行病学研究证据以及体内外实验相关结果,讨论了PMs调控脑神经毒理学效应的潜在途径、不同生理阶段脑神经组织的损伤效应及其内在分子机理。据报道,大气PMs可通过血脑屏障途径和嗅觉神经途径和微生物群肠脑轴等影响神经系统。氧化应激、线粒体损伤、炎症、DNA损伤、表观遗传调节、血液稳态以及几个关键的信号通路被发现与大气PMs暴露引起的神经毒性有关。本文提出了进一步研究PMs神经毒理学效应,特别是针对特殊人群如儿童等神经发育的影响等方面研究的需求。在此基础上,本文指出了今后该领域的研究方向,为大气PMs的神经毒性和公共卫生危害的评价提供了理论依据。

关键词： 大气细颗粒物, 神经毒性, 流行病学, 分子机理

The health effect of atmospheric fine particulate matters(PMs) is now being increasingly concerned, and a growing number of epidemiological studies have reported the adverse impacts of PMs on the respiratory system, cardiovascular system, etc. However, whether PMs can enter the brain and cause neurotoxicities or not remains unknown, which has been an important research direction for the health risk evaluation of atmospheric smog in recent years. Based on the relevant epidemiological studies and experimental evidences in vitro and in vivo, this paper summarizes the potential pathways regulating the neurotoxicity of atmospheric PMs, their detrimental effects on the adult, elderly, and developmental nervous systems, as well as the underlying molecular mechanisms. Atmospheric PMs were reported to affect the nervous system through the blood-brain barrier pathway, the olfactory nerve pathway, the microbiota-gut-brain axis, etc. Herein, oxidative stress, mitochondrial damage, inflammation, DNA damage, epigenetic regulation, hematological homeostasis, and several key signaling pathways were found to be involved in the observed neurotoxicities caused by atmospheric PM exposure. This review aims to reveal the neurotoxicities of atmospheric PMs, especially their neurodevelopmental effects on special populations such as children. On this basis, this article points out the future research directions in this field, providing a theoretical basis for the evaluation of neurotoxicities and public health hazards of atmospheric PMs.

Contents

1 Introduction

2 Epidemiological studies on neurological diseases induced by PM exposure

2.1 Developmental nervous system

2.2 Adult nervous system

2.3 Elderly nervous system

3 Pathways by which PMs affect the nervous system

3.1 The blood-brain barrier pathway

3.2 The olfactory nerve pathway

3.3 Other pathways

4 Experimental findings on neurotoxic effects of PMs

4.1 In vitro experiments

4.2 In vivo experiments

5 Molecular mechanisms underlying the neurotoxicities of PMs

5.1 Oxidative stress and mitochondrial damage

5.2 Inflammation

5.3 Key signaling pathways regulating the neurotoxicities of PMs

5.4 DNA damage and epigenetic regulation

5.5 Effects on hematological homeostasis

6 Prospects and research points

Key words: atmospheric fine particulate matters, neurotoxicity, epidemiological study, molecular mechanism
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表1 大气颗粒物神经生物学效应的流行病学调查结果
Table 1 The epidemiological findings on neurological effects of atmospheric particulate matters
Population Scale Research design Exposure method Exposure estimate Main findings ref
Pregnant women
living in four
residential areas of
Beijing(1988~1991) 		74 671 Multiple linear
regression, logistic
regression 		Total suspended particles(TSP), SO2 Low birth weight Wang
et al.[46]
Preterm birth records in Pennsylvania(1997~2001) Time-series analysis PM10, SO2 Increase in preterm birth risk Sagiv
et al.[48]
Birth records in Atlanta(1994-2004) 476 489 Time-series analysis, Poisson
generalized linear
models 		PM10, PM2.5,
NO, NO2,
SO2, O3 		Data collected from air quality monitors Increase in preterm birth risk Darrow
et al.[47]
Urban children 267 Distributed lag
models, intelligence assessment 		PM2.5 Spatio-temporally resolved prediction
model 		Exposure in specific prenatal windows was associated with poor intellectual functions Chiu
et al.[51]
Representative children in Japan since 2001 33 911 Multilevel logistic
regression analysis 		PMs, NO2,
SO2 		Stunting Yorifuji
et al.[52]
Newborns of Rome
GASPII project 		719 Wechsler Intelligence Scale for Children-Ⅲ, linear
regression model 		PM2.5, NO2 Land use regression
models 		Cognitive impairment Porta
et al.[53]
Mother-child pairs in
Massachusetts(USA) 		1109 Linear regression
models 		PM2.5, black
carbon(BC) 		Space-time LUR model Partial cognitive
decline 		Harris
et al.[54]
NHS II autism spectrum disorder children(USA) 245 Linear regression
models 		PM2.5, PM2.5-10 Spatio-temporal prediction model PM2.5 is associated with an increased risk of autism Raanan
et al.[60]
Autism children born in Carolina 979 Multiple regression
analysis 		PM10 Statistical interpolation method Third-trimester exposure is associated with an increased risk of autism Kalkbrenner
et al.[58]
Children from 39 schools in Barcelona exposed to traffic-related air
pollution(7~10 y) 		2715 Stratified analyses Traffic source
UFP 		Linear mixed effects models Higher traffic-related air pollution made children a smaller improvement in cognitive development Sunyer
et al.[63]
Patients with acute
ischemic stroke in
Ontario, Canada 		9202 Time-stratified case-crossover design, random-effects meta-analysis techniques Increased risk of
particulate-related ischemic strokes 		O’Donnell
et al.[30]
City populations with high-level exposure to air pollution Cognitive and
neurological integrity testing, genome
analysis 		Accumulation of COX2 and Aβ42 in nerve cells Lilian
et al.[64]
Healthy adults 27 Serum and plasma were collected and analyzed for inflammatory cytokines Filtered air
(FA) and diesel exhaust(DE) 		Cortical stress response Cliff
et al.[74]
Populations in northern Sweden 1806 Cohort analysis PM2.5-10, PM2.5 Spatiotemporal smoothing model Cognitive decline was speed up Oudin
et al.[66]
MS-related hospitalization in
Lombardy region, Italy,(2001~2009) 		8287 Poisson regression analysis PM10 Daily concentrations
from 53 monitoring sites 		Determining MS
occurrence and relapses 		Laura
et al.[65]
Populations(> 65 y) 95 690 Cohort study, Cox proportional hazards model O3, PM2.5 Air data from Taiwan Environmental Protection Agency Long-term exposure
increased the risk of AD 		Zhong
et al.[73]
US women(70~81y) 19 409 Cognitive test Exposure to
PM2.5-10 and
PM2.5 in the last month or for a long term of 7~14 years 		Geographic information system-based spatiotemporal smoothing models Cognitive decline of old women Weuve
et al.[13]
表2 大气颗粒物神经毒理学效应的实验研究结果
Table 2 Experimental findings on neurotoxic effects of PMs
Experimental model Exposure method Exposure time Main findings ref
In vivo In vitro
/ Primary mouse
hippocampal neurons 		PM2.5 24 h PM2.5 elevated COX-2 expression,increased the amplitude of excitatory postsynaptic potentials by ROS-NF-κB pathway Li et al.[38]
/ Rat microglia SiO2NPs, TiO2NPs, HAPNPs, Fe3O4NPs 24 h Microglial activation and the release of proinflammatory factors Xue et al.[89]
/ Human neuroblastoma SH-SY5Y cells Diesel exhaust particle 3, 24 h Gluconeogenesis Ji et al.[90]
/ Human neuroblastoma SH-SY5Y cells PM2.5 and its extracts 72 h Oxidative stress-mediated abnormal DNA hydroxymethylation Wei et al.[91]
/ Mixed glia derived from neonatal rat cerebral cortex. traffic ultrafine
particulate matter 		24 h Microglia-derived TNF-α increased Cheng
et al.[33]
/ Primary culture of mouse olfactory bulb and olfactory
epithelial cells 		Urban traffic ultrafine particulate matter
(< 200 nm) 		5, 20, 45 h inflammation during different time courses Cheng
et al.[79]
/ BV-2 microglia am-PM2.5, pm-PM2.5 24 h Am-PM2.5 had a higher pro-
inflammatory activity than pm-PM2.5 		Lovett
et al.[92]
C57BL/6J mice / PM2.5, SO2 and NO2 co-exposure 28 days Impaired spatial learning and memory, mitochondrial dysfunction Ku et al.[40]
Male SD rat / PM2.5 12 weeks Morphological abnormalities of the hippocampus, abnormal expression of neurotransmitters and receptors. Li et al.[93]
Nrf2-/- mice Astrocyte PM2.5 24 weeks NF-κB induced metabolic disorders and neuroinflammation Xu et al.[96]
ApoE-/-mice,
C57BL/6 mice 		/ PMs 6 h/day
(30 days) 		Disruption of blood-brain barrier and increased inflammatory marker expression Oppenheim et al.[100]
ApoE-/- mice / Low concentrations of PM2.5 6 h/day
(30 days) 		PM2.5 altered vasomotor tone, induced vascular inflammation, and potentiated atherosclerosis Sun et al.[99]
ApoE-/- mice / Mixture of gasoline and diesel engine exhaust 6 h/day
(30 days) 		Increased levels of oxidative stress in microvascular Lucero et al.[101]
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