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1、Contents lists available at ScienceDirectEcotoxicology and Environmental Safetyjournal homepage: of ambient PM2.5on adverse birth outcome and potential molecularmechanismZhou Li,Yuqing Tang,Xin Song,Lissy Lazar,Zhen Li,Jinshun ZhaoDepartment of Preventative Medicine,Zhejiang Key Laboratory of Pathop
2、hysiology,Medicine School of Ningbo University,818 Fenghua Road,Ningbo,Zhejiang Province315211,Peoples Republic of ChinaA R T I C L E I N F OKeywords:PM2.5(particulate matter 2.5m inaerodynamic diameter)Prenatal exposureAdverse birth outcomeOxidative stressMitochondrial DNAEndocrine disruptionA B S
3、T R A C TPM2.5(particulate matter 2.5 m in aerodynamic diameter)refers to atmospheric particulate matter(PM)withan aerodynamic diameter of equal and less than 2.5 m that tends to be suspended for long periods of time andtravel over long distances in both outdoor and indoor atmospheres.PM2.5,along wi
4、th the toxic compoundsattached on it,may cause a wide range of disorders.The fetus is considered to be highly susceptible to a varietyof toxicants including atmospheric pollutants such as PM2.5through prenatal exposure.To better understand therelationship between maternal exposure to PM2.5and advers
5、e birth outcomes for reproduction and fetus de-velopment,we studied the published data on this issue including case-control studies,cohort studies and meta-analyses studies,and summarized the basic impact of ambient particulate matter on adverse birth outcomes.Research evidence indicates that PM2.5h
6、as a potential to induce low birth weight(LBW),preterm birth(PTB),and stillbirth.A further in-depth analysis shows that oxidative stress,DNA methylation,mitochondrial DNA(mtDNA)content alteration,and endocrine disruptions may all play an important role in PM2.5induced adverseeffects to pregnant wome
7、n and fetuses.In addition,PM2.5exposure can cause male reproductive toxicity,leadingto associated adverse pregnancy outcomes.1.IntroductionPM2.5refers to a heterogeneous mixture of substances,anthro-pogenic and naturally derived,that can include accumulated heavymetals and toxic organic pollutants,s
8、uch as polycyclic aromatic hy-drocarbons(PAHs)(Pandey et al.,2013).The health effects of PM2.5vary greatly based on its source and components.Many studies havefound that the percentages of the PM2.5constituents such as EC,Ni,andPb may vary across regions.Additionally,indoor air pollution andsmoking
9、have been identified as the main sources of overall personalPM2.5exposure for those mothers living in affected households.TheWorld Health Organization(WHO)estimated that in 2013,87%of theglobal population lived in communities that exceeded WHOs air qualityguideline of a maximum mean ambient PM2.5of
10、10g/m3(Braueret al.,2015).A fraction of the particles inhaled can not only penetrateinto the lungs gas-exchange region but also further travel through therespiratory barrier and enter the circulatory system,thereby spreadingthroughout the entire body(Wang et al.,2013).Some PM2.5metalconstituents suc
11、h as Ni and Pb have been confirmed to be embry-onically toxic and teratogenic in various animal species,and they mightalso impact human intrauterine growth(Manzo et al.,2010).Currently,household PM2.5concentrations(specifically in the kitchen area)arethe parameters most often used for evaluating emi
12、ssions to indoor ex-posure,specifically the contributions from solid cook-fuels(Smith et al.,2014).The prenatal stage of life is a very sensitive period when anyhttps:/doi.org/10.1016/j.ecoenv.2018.10.109Received 30 August 2018;Received in revised form 26 October 2018;Accepted 30 October 2018Abbrevi
13、ations:PM2.5,particulate matter 2.5 m in aerodynamic diameter;PM,particulate matter;LBW,low birth weight;PTB,preterm birth;mtDNA,mi-tochondrial DNA;PAHs,polycyclic aromatic hydrocarbons;SGA,small for gestational age;DEP,diesel exhaust particles;GD,gestational day;OR,odds ratio;TLBW,term low birth we
14、ight;BMI,body mass index;IQR,interquartile range;LCC,low concentration cut-off;RRs,relative risk;ROS,reactive oxygen species;EPFRs,environmentally persistent free radicals;8-OHdG,8-hydroxy-2deoxyguanosine;OGG1,oxoguanine glycosylase 1;PROGRESS,Programming Research in Obesity,Growth,Environment and S
15、ocial Stressors;D-loop,displacement loop;MT-RNR1,mitochondrial RNR1;BER,base excision repair;NER,nucleotide excision repair;APEX1,AP endonuclease 1;ERCC14,Excision repair complementing factors 1 and 4;CLOCK,circadian locomotor output cycles kaput;NPAS2,neuronal PASdomain-containing protein 2;CRY12,c
16、rypto chrome circadian clock 1 or 2;PER13,period circadian clock 1,2 or 3;ENVIRONAGE,environmental influence onearly aging;EDCs,Endocrine-disrupting chemicals;POPs,Persistent organic pollutants;hCG,Human chorionic gonadotropin;3-HSD1,3-Hhydroxysteroid de-hydrogenase;SD,Sprague Dawley;LDH,lactate deh
17、ydrogenase;TUNEL,terminal dUTP nick-end labellingCorresponding authors.E-mail addresses:(Z.Li),(J.Zhao).Ecotoxicology and Environmental Safety 169(2019)2482540147-6513/2018 Published by Elsevier Inc.Texposure to harmful substances can adversely affect the developingfetus.Numerous studies have docume
18、nted associations between PM2.5exposure and harmful health effects including the exacerbation ofasthma(Evans et al.,2014),chronic obstructive pulmonary disease,lung cancer(Hamra et al.,2014)and cardiovascular diseases(Huttunenet al.,2012).Recent epidemiological investigations(Clemente et al.,2016a;S
19、aenen et al.,2016),covering large populations and includingboth case-control and cohort studies,have shown that PM2.5exposurecan also contribute to the incidence and development of adverse birthoutcomes,such as LBW,PTB,small for gestational age(SGA)births(Scheers and Nawrot,2011),low birth length(Ba
20、llester et al.,2010a)and head circumference(Ballester et al.,2010b),still birth(Yang et al.,2018),as well as diseases arising later in life such as pulmonary andcardiovascular disorders and even mortality(Bourdrel et al.,2017).Moreover,in animal studies,harmful effects were observed on fetalweight,e
21、arly embryonic development and the hatching process afterexposure to PM2.5and diesel exhaust particles(DEP)(Janurio et al.,2010).Another animal study demonstrated that a 24h/d exposure ofpregnant Balb/c mice to 27.5 g/m3PM2.5from the start of pregnancythrough gestational day(GD)resulted in decreased
22、 placental weight(Zhao et al.,2016).Additionally,one study(Dadvand et al.,2014)showed a strong association between exposure to particulate air pol-lutants and adverse birth outcomes during the third-trimester,but nosignificant correlation was found during the first and second trimesters.Another stud
23、y(Ballester et al.,2010b)found that exposure during thefirst trimester was most closely related to a decrease in birth weight andlength.A further study(Lee et al.,2013)found that exposure to par-ticulate matter(mainly PM2.5)and ozone air pollutants during the firsttrimester were associated with an i
24、ncreased risk of developing pre-eclampsia,gestational hypertension,and preterm delivery.These re-sults indicate that particulate matter exposure during any stage ofpregnancy may lead to adverse birth outcomes.Entry of PM2.5into pregnant womens bodies may lead to oxidativeinflammation,mitochondrial a
25、nd nuclear DNA methylation and endo-crine disruption in the placenta,thereby increasing the potential foradverse reproductive outcomes.The placenta plays a unique role in thetransfer of gases,nutrients,and waste between the mother and devel-oping child.However,the placenta has a limited capability t
26、o meta-bolize a large number of foreign compounds;therefore,environmentalchemicals and fine particles have a chance to pass through the ma-ternal-fetal barrier to reach fetus.Study of disease burdens resulting from ambient air pollution canprovide scientific evidence for determining steps to protect
27、 pregnantwomen from hazardous PM2.5exposure.In this paper,we system-atically reviewed and summarized the risks of LBW,PTB,and stillbirthamong pregnant women exposed to PM2.5.We also discuss the potentialmechanisms for the adverse birth outcomes resulting from PM2.5.2.Impact of ambient particulate ma
28、tter on adverse birth outcome2.1.Low birth weightWHO defines LBW as an infant weighing 2499 g or less,regardlessof gestational age(Gai et al.,2017).LBW is a risk factor for greaterinfant mortality and morbidity throughout adulthood(Wu et al.,2017).While not necessarily the outcome of a disease,LBW h
29、as been linked toa wide range of adverse health endpoints ranging from coronary heartdisease to premature mortality.It is estimated that 1520%of all birthsare LBW globally,representing more than 20 million births a year(2016).Infants who are born LBW show a higher incidence of death anddisabilities
30、that continue into adulthood(Valsamakis et al.,2006).Asone of the common adverse outcomes of pregnancy,LBW has variousetiologies and pathogeneses and,among all potential risk factors,airpollution exposure is usually neglected as a risk factor because its es-timated to have a relatively minor effect.
31、For example,a recent meta-analysis reported that the pooled odds ratio(OR)between PM2.5exposure(per 10g/m3increment)during the entire pregnancy andLBW risk were 1.09(95%CI:1.03,1.15)(Li et al.,2017).However,incontext of the numerous annual new births,minor risk effect estimatesmight still represent
32、a substantial public health problem,especiallyconsidering the severe air pollution in many areas.To date,many studies have been conducted on the relationshipbetween PM2.5exposure and LBW(Basu et al.,2014;Coker et al.,2015).The majority of these studies used a relatively wide range oftime periods as
33、the exposure windows(i.e.,trimesters or entire preg-nancy)to evaluate the associations between maternal PM2.5exposureand LBW.A recent meta-analyses study(Sun et al.,2015)reported a15.9 g(95%CI:5.0,26.8)decrease in birth weight and a 9%increase inrisk for LBW(OR 1.090,95%CI:1.032,1.150)per 10g/m3incr
34、ease inPM2.5exposure during pregnancy.Data on a group of 1,374,875 sin-gletons born between 2001 and 2004 obtained from the National Centerfor Health Statistics vital statistics Public Use Micro Data found that theeffect size per 10g/m3increase in PM2.5,as measured by the OR is1.030(95%CI:1.022,1.03
35、7)for exposure during the full gestationperiod,1.018(95%CI:1.013,1.022)for exposure during the first tri-mester,1.012(95%CI:1.007,1.017)and 1.009(95%CI:1.005,1.014)for exposure during the second and third trimesters,respectively(Harris et al.,2014).A cohort study(Dadvand et al.,2014)based on6438 sin
36、gleton term births in Barcelona,Spain,(20012005)reportedthat living within 200 m of major roads was associated with a 46%increase in TLBW risk,and third-trimester exposure to PM2.5andPM2.510with 24%and 25%increases,respectively.In a multi-countrystudy,Sapkota et al.(2012)found that exposure to PM2.5
37、was sig-nificantly associated with LBW(OR 1.10,95%CI:1.03,1.18)per 10g/m3increase in PM2.5.Another cohort study(Balakrishnan et al.,2018)investigated the relationship between birth weight and pregnancyperiod PM2.5exposures(using serial measurements of 24h kitchen areaconcentrations across trimesters
38、 as a surrogate)and found that a 10 g/m3increase in PM2.5exposure during the pregnancy period was asso-ciated with a 4g(95%CI:1.08g,6.76 g)decrease in birth weight and2%increase in prevalence of LBW(OR 1.02,95%CI:1.005,1.041)afteradjusting for gestational age,infant sex,maternal body mass index(BMI)
39、,maternal age,history of a previous LBW child,birth order andseason of conception.The differences in effects on birth outcome may relate to differencesin the particles chemical compositions.The extreme discrepancy inPM2.5constituents is a noticeable factor contributing to the hetero-geneousresultsan
40、drequiresfurtherexploration.TheU.S.Environmental Protection Agency identified a better understanding ofthe harmful characteristics of particles as a critical research need.Associations between specific components of PM2.5and LBW havebeen reported in several studies;for example,Ebisu and Bell(2012)fo
41、und associations of LBW with Al,Ca,Cd,elemental C,Ni,Si,Ti,andZn.Darrow et al.(2011)found associations of LBW with elementalcarbon and PM2.5water soluble metals in the Atlanta,Georgia,region.A recent study conducted in Los Angeles,California,found PM2.5and itsconstituent PAHs to be associated with T
42、LBW(Coker et al.,2015).Bellet al.(2012)investigated mothers exposure to K and Ti fine particu-lates.In this study,researchers observed an interquartile range(IQR)increase in K associated with an 8.75%(95%CI:1.24,16.8%)increasein the risk of LBW,and an IQR increase in Ti associated with a 12.1%(95%CI
43、:3.55,21.4%)increase in the risk of LBW.Another study alsofound that higher exposures to PM2.5from oil combustion and PM2.5components of elemental C,Zn,V,and Ni were associated with in-creased risk of LBW.2.2.Preterm birthIn almost all studies,PTB was defined as birth at 0.95(P 8.8g/m3)in the U.S.in
44、 2010.InChina,3040%of total PTBs were estimated to be associated withPM2.5exposure for a LCC of 10g/m3in 2010(Malley et al.,2017).Guoet al.(2018)described the risk of PTB for participants exposed to dif-ferent PM2.5exposure categories during different periods of pregnancy.A total of 426,246 singleto
45、n births were included,among which 35,261(8.3%)were PTB.The effect of each 10g/m3increase of PM2.5on PTBwas most significant during the third trimester(OR 1.06,95%CI:1.06,1.07),but was also significant during the first trimester(OR 1.04,95%CI:1.03,1.04),the second trimester(OR 1.02,95%CI:1.02,1.02)a
46、nd the entire pregnancy(OR 1.06,95%CI:1.05,1.06).Research has also shown evidence that individual PM2.5constituentsmay play a larger role in PTB specifically.Potential effects of PM onPTB might be mediated by core chemical components(e.g.,elementalcarbon,nitrates)or by organic compounds(e.g.,PAHs)or
47、 metals at-tached to the particle surface(Schlesinger et al.,2008).Recently,a fewstudies throughout the U.S.have examined the associations betweenPM2.5constituents and PTB in Georgia on the East Coast(Rappazzoet al.,2015)and California on the West Coast(Laurent et al.,2016).Laurent et al.(2016)found
48、 that ORs for PTB in association with IQRincreases in average exposure during pregnancy were positive andstatistically significant:1.096(95%CI:1.085,1.108)for a 11.53ppbincrease in O3,and 1.079(95%CI:1.065,1.093)for a 9.99 ppb increasein NO2.Basu et al.(2017)designed a retrospective cohort study usi
49、ngmonitored air pollution data to examine the relationship between PTBand PM2.5and its constituents in California.They found that per IQRincrease,NH4+(21.2%),NO3(18.1%)and Br(16.7%)demonstratedthe largest risk increase for preterm delivery.NH4+,NO3,Br,EC andZn had positive associations with PTB for
50、full pregnancy exposure.2.3.StillbirthStillbirth is estimated to occur in approximately 28%of pregnanciesin prospective cohorts with preconception enrollment and longitudinalfollow up(Buck Louis et al.,2011).Stillbirth is currently one of themost unheeded tragedies worldwide.Pregnancy loss can be a