Elevated Plasma Endothelin-1 and Pulmonary Arterial Pressure in Children Exposed to Air Pollution

Elevated Plasma Endothelin-1 and Pulmonary Arterial Pressure in Children Exposed to Air Pollution
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  1248 VOLUME 115 | NUMBER 7 | July 2007  • Environmental Health Perspectives Research  | Children’s Health  Activation of the endothelin system and vaso-constriction has been reported in animal mod-els (Bouthillier etal. 1998; Kang etal. 2002;Thomson etal. 2004, 2005; Vincent etal.2001a) and humans (Brook etal. 2002;Calderón-Garcidueñas etal. 2005; Vincentetal. 2001b) after exposure to air pollutants.Endothelin-1 (ET-1) is implicated directly inthe progression of cardiovascular diseases(Luscher and Barton 2000), and a number of polymorphisms for ET-1 and endothelin recep-tor genes have been identified that are associ-ated with increased risk for pulmonary andcardiovascular conditions (Charron etal. 1999;Dong etal. 2004; Immervoll etal. 2001; Jinetal. 2003). ET-1 is atherogenic (Ihling etal.2001; Lerman etal. 1995), and exposure to airpollutants has been shown to accelerate athero-sclerosis in animals (Sun etal. 2005; Suwa etal.2002) and humans (Künzli etal. 2005).Therefore, recurrent or sustained elevation of circulating ET-1 constitutes a plausible cause of some acute and chronic adverse health effects of air pollutants (Thomson etal. 2005).The ambient atmosphere in Mexico City is characterized by elevated concentrations of ozone (especially in the southwest), and par-ticulate matter (in the northeast), that fre-quently exceed United States air quality standards. Particulate matter (PM) is catego-rized by aerodynamic diameter into threeclasses: coarse PM 2.5–10 µm in aerodynamicdiameter (PM 10 ), fine PM 0.1–2.5 µm inaerodynamic diameter (PM 2.5 ), and ultrafinePM < 0.1 µm in aerodynamic diameter. Inaddition to particulate matter and O 3 , alde-hydes, volatile and nonmethane organiccompounds, alkane hydrocarbons, andlipopolysaccharide (LPS) (15.3–20.6 ng/mg)are other typical contaminants of ambientMexico City air (Bonner etal. 1998). Becauseof moderate climatic conditions, children inMexico City engage in play and outdoorphysical activities throughout the year in thelate morning and afternoon when the diurnalpollutant levels are at their maximum(Villarreal-Calderón etal. 2002). Exposure tosuch contaminated air may pose a significanthealth risk for children.Clinically healthy children residing inMexico City exhibit pulmonary hyperinfla-tion and interstitial markings on chest X rays(Calderón-Garcidueñas etal. 2006), and animbalance of serum cytokines with signifi-cantly increased concentrations of interleukin(IL)-6 and IL-10 compared with childrenresiding in areas with low levels of pollution(Calderón-Garcidueñas etal. 2003). In thestudy reported here, we investigated theplasma concentrations of ET-1 in MexicoCity children and children from a control city  with low levels of air pollutants. Becausepediatric radiologists have noticed prominentpulmonary arteries in anterior–posterior chest X rays of Mexico City children, and giventhat ET-1 regulates pulmonary arterial pres-sure (PAP), our secondary objective was todetermine whether these children haveincreased PAP. Our third objective was to  Address correspondence to W. Reed, CB# 7310,104 Mason Farm Rd., Chapel Hill, NC 27599-7310USA. Telephone: (919) 966-0669. Fax: (919) 966-9863. E-mail: william_reed@med.unc.edu We acknowledge the technical support of R.García, N. Osnaya, and S. Monroy. We expressour gratitude to the Hematology personnel at theNational Institute of Pediatrics, particularly E.Hernandez García and B. Santiago Chávez fortheir continuous support. We thank P. Gutiérrez-Castrellón of the National Institute of Pediatrics forreviewing the manuscript. This work was supported by grants from theNational Institutes of Health (NIH)–NationalInstitute of Neurological Disorders and Stroke (1KO1NS046410-01A1), NIH–National Institute of Environmental Health Sciences (1R21-ES013293-01A1), NIH–National Center for Research Resources(P20 RR15583), U.S. Environmental Protection Agency (EPA; CR829522), National ScienceFoundation (0346458), and the Montana Board of Research and Commercialization Technology (04-06). Although the research described in this article hasbeen funded wholly or in part by the U.S. EPA through cooperative agreement CR829522 with theCenter for Environmental Medicine, Asthma, andLung Biology at the University of North Carolina atChapel Hill, it has not been subjected to theagency’s required peer and policy review, and there-fore does not necessarily reflect the views of theagency, and no official endorsement should beinferred. Mention of trade names or commercialproducts does not constitute endorsement or recom-mendation for use. The authors declare they have no competing financial interests.Received 22 August 2006; accepted 27 April 2007. Elevated Plasma Endothelin-1 and Pulmonary Arterial Pressure in ChildrenExposed to Air Pollution Lilian Calderón-Garcidueñas, 1,2  Renaud Vincent, 3  Antonieta Mora-Tiscareño, 1 Maricela Franco-Lira, 4  Carlos Henríquez-Roldán, 5  Gerardo Barragán-Mejía, 1 Luis Garrido-García, 1 Laura Camacho-Reyes, 1 Gildardo Valencia-Salazar, 1 Rogelio Paredes, 1 Lina Romero, 1 Hector Osnaya, 1 Rafael Villarreal-Calderón, 2  Ricardo Torres-Jardón, 6  Milan J. Hazucha, 7,8  and William Reed  8,9  1 Instituto Nacional de Pediatría, Mexico City, Mexico; 2 The Center for Structural and Functional Neurosciences, University of Montana,Missoula, Montanta, USA; 3 Inhalation Toxicology and Aerobiology Section, Safe Environments Programme, Health Canada, Ottawa,Ontario, Canada; 4 Escuela Médico Militar, Universidad del Ejército y Fuerza Aérea, México; 5 Departamento de Estadística, Universidadde Valparaíso, Valparaíso, Chile; 6 Centro de Ciencias de la Atmósfera, Universidad Nacional Autónoma de México, Mexico City, Mexico; 7 Department of Medicine, 8 Center for Environmental Medicine, Asthma and Lung Biology, and 9 Department of Pediatrics, University of North Carolina, Chapel Hill, North Carolina, USA B  ACKGROUND : Controlled exposures of animals and humans to particulate matter (PM) or ozoneair pollution cause an increase in plasma levels of endothelin-1, a potent vasoconstrictor that regu-lates pulmonary arterial pressure. O BJECTIVES : The primary objective of this field study was to determine whether Mexico City chil-dren, who are chronically exposed to levels of PM and O 3 that exceed the United States air quality standards, have elevated plasma endothelin-1 levels and pulmonary arterial pressures. M ETHODS :  We conducted a study of 81 children, 7.9 ±1.3 years of age, lifelong residents of either northeast ( n  = 19) or southwest ( n  = 40) Mexico City or Polotitlán ( n  = 22), a control city with PMand O 3 levels below the U.S. air quality standards. Clinical histories, physical examinations, and complete blood counts were done. Plasma endothelin-1 concentrations were determined by immunoassay, and pulmonary arterial pressures were measured by Doppler echocardiography. R  ESULTS : Mexico City children had higher plasma endothelin-1 concentrations compared with con-trols (  p  < 0.001). Mean pulmonary arterial pressure was elevated in children from both northeast (  p  < 0.001) and southwest (  p  < 0.05) Mexico City compared with controls. Endothelin-1 levels inMexico City children were positively correlated with daily outdoor hours (  p  = 0.012), and 7-day cumulative levels of PM air pollution < 2.5 µm in aerodynamic diameter (PM 2.5 ) before endothe-lin-1 measurement (  p  = 0.03). C ONCLUSIONS : Chronic exposure of children to PM 2.5 is associated with increased levels of circulat-ing endothelin-1 and elevated mean pulmonary arterial pressure. K  EYWORDS : air pollution, endothelial dysfunction, endothelin-1, children, particulate matter, pul-monary arterial pressure. Environ Health Perspect 115:1248–1253 (2007).doi:10.1289/ehp.9641available via http://dx.doi.org/  [Online 27 April 2007]  determine whether plasma ET-1 levels inMexico City children were correlated withpollutant exposure levels. Materials and Methods Study areas and pollutant exposure estimates.  We selected two urban areas, Mexico City and Polotitlán, for this field study. MexicoCity is located in a high mountain basin2,250 m above sea level. The control city,Polotitlán, is located in the Mexico State114km northwest of Mexico City at 2,380 mabove sea level. Mexico City residents arechronically exposed to concentrations of crite-ria air pollutants that exceed the United Statesstandards, whereas air pollutant levels rarely exceed the standards in Polotitlán. Criteria airpollutants were monitored in Mexico City by the government atmospheric monitoring sys-tem at four stations: two in the southwest(Pedregal and Coyoacán) and two in thenortheast (Xalostoc and San Agustín). Eachchild’s residence and school was within5miles of one of these monitoring stations.The pollutants that consistently exceededtheir respective standard in the preceding 5years were O 3, PM 10, andPM 2.5 . Thus, forthese pollutants we estimated the cumulativeexposure levels for each child for 1, 2, and7days before the measurement of plasma ET-1 levels. Pollutant concentrations between0700 and 1900 hr, when the children weremost active, were used for these estimates. Study population.  We studied twocohorts of clinically healthy children, 6–13years of age: The control cohort fromPolotitlán ( n  = 22), and the exposed cohortfrom Mexico City ( n  = 59). Mexico City chil-dren came from two areas, the southwest ( n  =40) and the northeast ( n  = 19), which havedifferent air pollutant profiles (Raga etal.2001). All included children were physically active and regular participants in a variety of outdoor physical activities. The informationobtained from each child and/or parent (usu-ally the mother) included age, place andlength of residency, daily outdoor time,household cooking methods, parents’ occupa-tional history, family history of atopic ill-nesses and respiratory disease, and personalhistory of otolaryngologic and respiratory symptoms. The study protocol was approvedby the Human Studies Committee of theInstitutional Review Board of the NationalInstitute of Pediatrics, Mexico City. Study protocol. Recruitment (by word of mouth) was done between July 2003 andDecember 2004. The children of parents whovolunteered their participation made at leastfour visits to the facility. The first visit was a screening visit. The study inclusion criteria  were nonsmoking household and negativepersonal smoking history and environmentaltobacco smoke exposure; lifelong residency inMexico City or Polotitlán; residency within5miles of air pollutant monitoring stations;age 6–13 years; full-term birth; no knownexposures to local sources of air pollutants(e.g., proximity to car-painting shops, gas sta-tions, factories, solvents, carpenter’ shops,printing business); unremarkable clinical his-tories, including negative history of hospital-izations for respiratory illnesses, negativepersonal and family histories of atopic diseases,no lower respiratory illnesses, febrile episodes,or vaccinations in the previous 3 months; noindoor pets; and negative history of frequenttravels outside Mexico City, or to a large city in the case of control children. Those whoqualified for the study came for a second visitto give written consent from the children’sparents and oral consent from the childrenthemselves. Once qualified, they were sched-uled for subsequent visits, which included a physical by a pediatrician, fasting blood draw,and the Doppler echocardiogram exam. Plasma ET-1 levels and blood tests. Fasting peripheral blood samples were takenbetween 0700 and 0900 hr for completeblood count with differential and the prepara-tion of plasma for determination of ET-1 lev-els. A QuantiGlo ELISA was used for thedetermination of ET-1 concentrations inaccordance with the manufacturer’s instruc-tions (R&D Systems, Inc., Minneapolis, MN,USA). The mean minimum detectable ET-1concentration was 0.064 pg/mL. Doppler echocardiography. Cardiovascularfunction was assessed by two-dimensional(2D), M-mode, and Doppler echocardiogra-phy. Standard 2D echocardiographic examina-tions were performed with each child in thesupine left position in accordance with recom-mendations of the American Society of Echocardiography (Schiller etal. 1989). Theparents were instructed to avoid caffeine-con-taining beverages 24 hr before the children’sexaminations. The echocardiographic analysis was performed with commercially availableultrasound systems (Sonos 2500; Hewlett–Packard Co./Agilent Technologies, Andover,MA, USA) equipped with 2.5- and 3.5-mHztransducers. Parasternal long- and short-axisviews, as well as apical four- and two-chamberviews, were used for evaluation of the functionsof the ventricles and the heart valves. The pro-tocol placed highest priority on systolic PAP,tricuspide, and right ventricle measurements.Systolic PAP encompasses the pulsatile compo-nent of arterial load, which includes the charac-teristics of right ventricular ejection and theproximal pulmonary arteries and wave reflec-tions (Chemla etal. 2004). We calculated meanpulmonary arterial pressure (MPAP) from thesystolic pressure using the formula fromChemla etal. (2004). The MPAP reflects thesteady component of flow and the functionalstatus of the distal pulmonary vasculature(Chemla etal. 2004). The complete protocolimaged the morphology of all four cardiacchambers and valves, and evaluated valve func-tion and right ventricular outflow. Statistical analyses. The primary variablesof interest were ET-1 concentrations andMPAP. We performed analysis of variance by a parametric one-way analysis of variance andthe Newman-Keuls multiple comparison posttest. We calculated correlations between vari-ables using Pearson’s correlation. We consid-ered a two-sided type I error rate of 0.05 to besignificant when comparing differencesbetween group means. Data are expressed asmean ±SE. All the statistical computations were performed with the use of Stata 8.3 soft- ware (StataCorp., College Station, TX, USA)or GraphPad Prism version 3.3 (GraphPadSoftware Inc., San Diego, CA, USA). Results Demographics and physical exams.  All partici-pant children were from middle-class families who lived in single-family houses. No occupa-tional toxic exposures were reported by par-ents or close relatives. Children slept inbedrooms with no carpeting and had open windows for ventilation. All households hadkitchens separated from the living and sleep-ing areas and used gas for cooking. A physicalexamination performed by the pediatricianshowed that vital signs were unremarkable inall participant children. Children in this study had anthropometric values (weight andheight) within normal limits for their age andsex. The demographic, clinical, and labora-tory data for the three cohorts are summa-rized in Table 1. Plasma ET-1 levels and pulmonary arter- ial pressures. Compared with those from con-trols, mean plasma ET-1 concentrations weresignificantly higher in children from bothnortheast (  p  < 0.001; Figure 1, Table 1) andsouthwest (  p  < 0.001; Figure 1, Table 1)Mexico City as well as for all Mexico City chil-dren combined (2.24 ±0.12 pg/mL;  p < 0.001,Figure 1, Table 1). ET-1 levels tended to behigher in northeastern children than in south- western children (Figure 1, Table 1), althoughthe difference was not statistically significant.None of the children had cardiac ana-tomic abnormalities as assessed by echo-cardiography. Compared with the controlcohort, the average MPAP, computed fromsystolic PAP determined by Doppler echocar-diography, was significantly elevated in chil-dren from both northeast (  p  < 0.01; Figure 2,Table 1) and southwest (  p  < 0.05; Figure 2,Table 1) Mexico City, as well as for allMexico City children combined (17.3 ±0.5mmHg,  p  < 0.01; Figure 2, Table 1). As wasthe case for ET-1 levels, MPAP tended to behigher in northeastern children than in south- western children (Figure 2, Table 1). When Air pollution and endothelin-1 Environmental Health Perspectives  • VOLUME 115 | NUMBER 8 | August 2007  1249  children from all sites were considered, there was a significant positive correlation betweenMPAP and plasma ET-1 levels ( r  = 0.43,  p  <0.0001, Figure 3).Three children in the Mexico City cohorthad MPAPs > 25 mmHg at rest and/or sys-tolic pressure > 40 mmHg at rest, levels thatare characteristic of pulmonary arterial hyper-tension (Simonneau etal. 2004). The threeMexico City children included two 8-year-oldgirls, one from the southwest and one fromthe northeast, and one 8-year-old boy fromthe southwest. All three had elevated plasma ET-1 (1.8, 1.9, and 2.9 pg/mL, respectively).Their systolic pressures ranged from 40 to 45mmHg and their mean pressures ranged from26 to 29 mmHg. White blood cell counts. Children fromnortheast Mexico City exhibited significantdecreases in both neutrophil absolute counts(  p < 0.05) and neutrophils as a percentage of  white blood cells (  p  < 0.01) when compared with controls (Figure 4A, Table 1). Childrenfrom southwest Mexico City had depressedneutrophil levels as well (Figure 4A, Table 1),but the differences between southwest MexicoCity children and control children were notstatistically significant. Even so, all MexicoCity children taken together had statistically significant decreases in circulating neutrophilconcentrations compared with controls (3.0 ±0.2 × 10 3 /µL,  p  < 0.05; Figure 4A). The low-est absolute neutrophil counts recorded were1.4 × 10 9 /L. No children had neutropenia defined as < 1 × 10 9 neutrophils/L.There was an increase in average lympho-cyte concentrations in children from north-eastern Mexico City (  p  < 0.05) and a smallernonsignificant increase in lymphocyte con-centrations in children from southwesternMexico City (Figure 4B, Table 1) compared with control children. Average monocyte con-centrations were essentially the same inMexico City children (Figure 4C, Table 1)compared with controls. Average total whiteblood cell counts were lower in both north-eastern and southwestern (Figure 4D, Table1) Mexico City children, but the differences were not statistically significant. Correlation of ET-1 levels with outdoor hours and pollutant exposure. For MexicoCity children, there was a significant, positivecorrelation between the number of hoursspent outdoors every day (outdoor hours) andET-1 levels ( r  = 0.31,  p  = 0.012). Likewise,there was a significant, positive correlationbetween outdoor hours and mean PAP ( r  =0.42,  p  = 0.0008). This supported the notionthat these effects are associated with exposureto air pollutants. To determine which air pol-lutants might be involved, we examined theacute cumulative exposure levels of PM 2.5 ,PM 10 , and O 3 for each Mexico City subjectover 1, 2, and 7 days preceding the measure-ment of ET-1 levels. The average PM 2.5 expo-sures for northeast Mexico City children overthe 2- and 7-day cumulative periods preceding the measurement of ET-1 levels were signifi-cantly greater than for southwestern children(Figure 5A). In contrast, the average PM 10 exposures were not significantly different fornortheastern and southwestern children(Figure 5B). O 3 exposures had a pattern that was the opposite of PM 2.5 exposures. South- western children were exposed to significantly higher O 3 levels than northeastern childrenover the 2-day and 7-day periods before ET-1measurement (Figure 5C). Thus only PM 2.5 exposures were greater in northeastern chil-dren than in southwestern children. This pat-tern was similar to the pattern of ET-1 levels, which tended to be higher in the northeastthan in the southwest (Figure 1). When allMexico City children were considered, there was a significant, positive correlation betweenET-1 levels and the 7-day cumulative PM 2.5 exposure ( r  = 0.28,  p  = 0.03). Discussion Mexico City is located in a high mountainbasin 2,250 m above sea level. Sunshine, light winds, temperature inversions, a basin setting,overcrowded population, heavy traffic, fre-quent urban leakage of liquefied petroleumgas, and intense industrial activity promotecomplex photochemical reactions producing a variety of oxidant chemicals and particulatematter. Because of the subtropical latitude andhigh altitude, the high concentrations of pol-lutants in Mexico City are seen throughoutthe year, with only small seasonal variation. Calderón-Garcidueñas et al. 1250 VOLUME 115 | NUMBER 8 | August 2007  • Environmental Health Perspectives Table 1. Demographic, clinical, and laboratory data (mean ±SE) in the control (Polotitlán) and the north-east (NEMC) and southwest (SWMC) Mexico City cohorts. CharacteristicControlSWMCNEMCNo.224019Age (years)7.4 ±0.29.0 ±0.37.2 ±0.3Sex (male/female)9/1320/219/10Plasma ET-1 (pg/mL)1.23 ±0.062.40 ±0.142.09 ±0.10Systolic pulmonary pressure (mmHg)20.7 ±0.724 ±0.927.2 ±1.4Mean pulmonary pressure (mmHg)14.6 ±0.416.7 ±0.618.6 ±0.9Fraction of children with pulmonary arterial pressure > 25 mmHg at rest 0/22 2/40 1/19 Sex (male/female) 0/01/10/1Outdoor exposure time per day (hr)4.3 ±0.23.9 ±0.24.0 ±0.2White blood cells (10 9  /L)6.9 ±0.36.4 ±0.35.9 ±0.3Neutrophils (%)54.1 ±1.948.8 ±1.844.4 ±2.2Neutrophils (10 9  /L)3.8 ±0.33.2 ±0.22.6 ±0.2Lymphocytes (%)36.4 ±1.840.4 ±1.745.8 ±2.0Monocytes (%)6.9 ±0.46.8 ±0.36.6 ±0.3Platelets (10 9  /L)312 ±16304 ±11299 ±20Hemoglobin (g/dL)14.0 ±0.114.2 ±0.114.0 ±0.1Hematocrit (%)41.1 ±0.442.7 ±0.341.5 ±0.6 Figure 1. A scatterplot of plasma ET-1 levels by region.Mean plasma ET-1 levels for Mexico City childrenasa whole ( n  = 59), as well as for northeast (NEMC, n  = 19) and southwest (SWMC, n  = 40) Mexico Citychildren analyzed separately were significantlygreater than the mean for control (Polotitlán) chil-dren ( n  = 22). Horizontal bar indicates group means. * p  < 0.001. 543210     E    T  -    1    (   p   g    /   m    L    ) Mexico CityNEMCSWMCPolotitlán Figure 2. A scatterplot of MPAP by region. Theaverage MPAP for Mexico City children as a whole( n  = 59), as well as for northeast (NEMC, n  = 19) andsouthwest (SWMC, n  = 40) Mexico City childrenanalyzed separately were significantly greater than the mean for control (Polotitlán) children ( n  = 22).Horizontal bar indicates group means. * p < 0.01;  #  p  < 0.05. 3020100     M    P    A    P    (   m   m    H   g    ) Mexico CityNEMCSWMCPolotitlán Figure 3. A plot of MPAP versus ET-1 levels forPolotitlán, northeast (NEMC), and southwest (SWMC)Mexico City children. MPAPs were significantlycorrelated with ET-1 levels ( r  = 0.43, p  = 0.0001). Alinear regression fit to the data is shown. 403020100     M    P    A    P    (   m   m    H   g    ) 012345 ET-1 (pg/mL) PolotitlánNEMCSWMC  Under these environmental conditions, chil-dren living in the city are most likely to beexposed to high doses of air pollutants. Onschool days, they spend significant amounts of time outdoors (3.94 ±1 hr/day in this study),both during school exercise periods and afterschool (Villarreal-Calderón et al. 2002). On weekends the outdoor play time is evenlonger. This outdoor activity usually occursduring hours when air pollutant levels are nearor exceed the standards. Healthy adulthumans exposed to concentrated ambientPM 2.5 and O 3 experienced a significantbrachial artery vasoconstriction (Brook etal.2002), whereas exposure to PM 2.5 alone ele-vated circulating ET-1 and ET-3 levels(Vincent etal. 2001b). Compared with adults,infants and children have much higher levelsof plasma ET-1. Moreover, the number of ET-1 specific binding sites in infant’s and chil-dren’s hearts (both atria and ventricles) hasbeen found to be significantly higher than inadults implying an enhanced physiologic func-tion (Giannessi etal. 1999). Our data show that clinically healthy children living inMexico City had increased concentrations of circulating ET-1 and MPAP and that ET-1levels were positively correlated with daily out-door hours (  p  = 0.012), and 7-day cumulativelevels of PM 2.5 (  p  = 0.03) before ET-1 mea-surement. These findings are consistent withcontrolled laboratory exposures of humans toair pollutants. Several animal studies have reportedincreased levels of ET-1 after exposure to airpollutants (Bouthillier etal. 1998; Kang etal.2002; Thomson etal. 2004, 2005; Vincentetal. 2001a). Inhaled O 3 and urban particleshave distinct toxicodynamics in rats withrespect to regulation of lung preproET-1 andalteration of circulating ET-1 peptide levels. Whereas O 3 causes a rapid response, detectedimmediately after exposure and subsiding  within 24 hr, urban particles cause a moreprogressive and sustained response, with peak increase of plasma ET-1 24–36 hr after expo-sure (Thomson etal. 2005; Vincent etal.2001a). The apparent predominant effect of PM 2.5 on ET-1 in the present study is inkeeping with these observations. The lungs are the primary source of circu-lating endothelins, including ET-1. Matureendothelins have a half-life on the order of minutes due to rapid clearance from the blood-stream through binding to G-protein-coupledendothelin B (ET B ) receptors in caveolae onthe surface of lung capillary endothelial cells(Yamaguchi etal. 2003). Previous studies sug-gest that there are at least three mechanismsby which air pollutants could cause anincrease in ET-1 levels. First, both O 3 andPM can generate reactive oxygen species intissues, a condition that has been linked toenhanced ET-1 expression (Kaehler etal.2002). Second, ultrafine PM taken up by endothelial cell caveolae, as described in north-east Mexico City dogs (Calderón-Garcidueñasetal. 2001b), may directly interfere with bind-ing of ET-1 to ET B receptors, resulting in anincrease in the half-life of circulating ET-1.Third, PM-associated LPS may increasepreproET-1 mRNA transcription and stability.Douthwaite etal. (2003) exposed bovine aorticendothelial cells to LPS and found a concentra-tion-dependent ET-1 release that was associated with increased transcription of preproET-1mRNA and a 2-fold increase in preproET-1mRNA half-life. This link between inductionof ET-1 synthesis and LPS exposure ought tobe considered in populations exposed to LPS,both in environmental and occupational set-tings. Environmental LPS is ubiquitous, soeveryone is exposed to this biological pollutant.Mexico City has a variety of sources of environ-mental LPS (e.g., open field waste, waste dis-posal dust, wastewater treatment plants, opensewer channels, and daily outdoor deposits of thousands of pounds of animal and humanfecal material) that contribute to measurablelevels of LPS in Mexico City PM 10 (Osornio-Vargas etal. 2003) and chronic exposure of Mexico City residents to LPS. Although thestudies cited above present several plausiblemechanisms by which chronic exposure to thecomplex mixture of air pollutants could inducesustained increases in plasma ET-1 concentra-tions, the extent of involvement of these mech-anisms in humans remains to be determined. The consequences of sustained elevationsof ET-1 levels have been explored in animal Air pollution and endothelin-1 Environmental Health Perspectives  • VOLUME 115 | NUMBER 8 | August 2007  1251 Figure 4. Scatterplots of complete blood count data by region. WBC, white blood cell. ( A ) Mean absoluteneutrophil counts were significantly lower in Mexico City children ( n  = 56) than in control children(Polotitlán, n  = 22). Northeast Mexico City children (NEMC, n  = 17) had significantly lower neutrophil counts than control children (Polotitlán, n = 22). ( B  ) The mean concentration of lymphocytes as a percentage ofwhite blood cells was significantly higher in northeast Mexico City children (NEMC, n  = 17) than in controls.( C  ) Monocyte concentrations were similar in northeast (NEMC, n  = 17) and southwest (SWMC, n  = 39)Mexico City and control (Polotitlán, n  = 22) children. ( D  ) White blood cell concentrations were not signifi-cantly different among Mexico City children ( n  = 59), Polotitlán children ( n  = 22), northeast (NEMC, n  = 19)and southwest (SWMC, n  = 40) Mexico City children. Horizontal bar indicates group means. * p  < 0.05. 86420     N   e   u   t   r   o   p    h    i    l   s    (      ×     1    0     9     /    L    )    W    B    C   s    (      ×     1    0     9     /    L    )    L   y   m   p    h   o   c   y   t   e   s    (   p   e   r   c   e   n   t   o    f    W    B    C   s    )    M   o   n   o   c   y   t   e   s    (   p   e   r   c   e   n   t   o    f    W    B    C   s    ) 7560453015119753151050 ABCD Mexico CityNEMCSWMCPolotitlánMexico CityNEMCSWMCPolotitlánMexico CityNEMCSWMCPolotitlánMexico CityNEMCSWMCPolotitlán Figure 5. Estimated cumulative dose of PM 2.5 ( A ), PM 10 ( B  ), and O 3 ( C  ) for northeast (NEMC) and southwest(SWMC) Mexico City averaged (±SE) over the 1-, 2-, and 7-day periods before measurement of ET-1 lev-els. The average dose calculations were based on estimates for each participating child. There were sig-nificant differences between the regions in the 1-, 2-, and 7-day cumulative PM 2.5 dose and in the 2-dayand 7-day cumulative O 3 dose. * p  < 0.05;  #  p  < 0.001. 5,0004,0003,0002,0001,0000     P    M     1    0    c   u   m   u    l   a   t    i   v   e    d   o   s   e    (      µ    g    /   m     3     /    h   r    ) BC 543210     O     3    c   u   m   u    l   a   t    i   v   e    d   o   s   e    (   p   p   m    /    h   r    )  #  # 5,0004,0003,0002,0001,0000     P    M     2 .    5    c   u   m   u    l   a   t    i   v   e    d   o   s   e    (      µ    g    /   m     3     /    h   r    ) A 127 Cumulative time (days)  #  # *NEMCSWMC127 Cumulative time (days) 127 Cumulative time (days)  models. Chronic expression of ET-1 in thelungs of ET-1 transgenic mice causes progres-sive pulmonary fibrosis and recruitment of inflammatory cells, predominantly CD4-posi-tive cells (Hocher etal. 2000). Chronic perfu-sion of ET-1 in rats after 7 days increasespulmonary vascular resistance, an effect thatdisappears after 28 days of infusion possibly because of compensatory mechanisms(Migneault etal. 2005). In the same work,Migneault etal. (2005) demonstrated thatchronic perfusion of ET-1 reduces the pul-monary vasodilator reserve in response tonitric oxide. The authors hypothesized thatan ET-1–induced increase of reactive oxygenspecies production in both endothelial andsmooth muscle cells contributes to a reduc-tion in the bioavailability of nitric oxide(Migneault etal. 2005).  Acute exposure to air pollutants such asO 3 and PM (especially fine and ultrafine PM)produces significant lung inflammation andinjury that involves both epithelial andendothelial cells. Exposure to PM is also asso-ciated with a systemic inflammatory responsethat involves increased circulating levels of inflammatory mediators that can activateendothelium. Mexico City dogs exhibit focalperibronchiolar inflammatory infiltrates thatsurround the adjacent blood vessels, some of  which contain platelet thrombi and mar-ginated neutrophils (Calderón-Garcidueñasetal. 2001b). Moreover, pulmonary endothe-lial cells in these dogs contain free ultrafinePM in their cytoplasm, a situation that likely promotes the production of free radicals andendothelial damage (Calderón-Garcidueñasetal. 2001a). Children in Mexico City havefragmented red blood cells in peripheralblood smears, also suggestive of endothelialinjury, most likely in the lung, becausemicrothrombi are numerous in small vesselsin the lungs of Mexico City dogs (Calderón-Garcidueñas etal. 2001a, 2001b). Moreover,ET-1 stimulates integrin-dependent adhesionof neutrophil granulocytes to endothelial cells(López etal. 1993), which could explain thedecreases in the concentration and total num-ber of circulating neutrophils in Mexico City children seen in this study. This notion issupported by analysis of lung tissue fromhealthy accidental-death victims from MexicoCity showing neutrophils attached to dam-aged capillary endothelial cells (Calderón-Garcidueñas etal. 2007). Taken together, thisevidence supports the notion that the sys-temic increase in ET-1 in Mexico City chil-dren could be a consequence of endothelialdamage and dysfunction. Endothelial dys-function is characterized by a shift in theactions of the endothelium toward reducedvasodilatation, a proinflammatory state, andprothrombic activities (Endemann andSchiffrin 2004). Endothelial dysfunctionleads to chronic overproduction of vasocon-strictors such as ET-1 (Humbert etal. 2004).It is noteworthy that all the children fromnortheast Mexico City in our study hadplasma ET-1 levels that were above the con-trol mean. Of 19 subjects from the northeast,14 had ET-1 values higher than all controls.These data indicate that endothelial dysfunc-tion and activation of the endothelin systemin response to air pollutant exposure, given a sufficient PM dose, is a generalized effectrather than being restricted to a subset of sen-sitive individuals. This generalized effect foran environmental exposure to pollutants is inline with preliminary data from human sub- jects exposed to concentrated urban fine par-ticles (Vincent etal. 2001b).Mean pulmonary arterial pressures wereelevated on average in Mexico City children,and the pressures correlated with ET-1 levels,as might be expected given the pulmonary vasoconstrictor effects of ET-1 and therepeated observations of increased circulating ET-1 in patients with elevated pulmonary arterial pressure (Fratz etal. 2003; Galie etal.2004; Mathew etal. 2004). Three of theMexico City children had MPAP levels at rest>25 mmHg, a characteristic of pulmonary arterial hypertension (PAH). All children hada negative family history of PAH, no knownrisk factors for any disease that can causePAH (Simonneau etal. 2004), and no otherclinical symptoms of PAH. It is unclear atthis point whether these and perhaps otherMexico City children will go on to developPAH. Both adults and children living at highaltitude, as all of our study subjects do, have a higher prevalence of elevated MPAP and aremore prone to developing PAH. ET-1 over-production is a plausible contributor to thepathogenesis of PAH (Galie etal. 2004), andpulmonary vasoconstriction is a likely early component of PAH pathogenesis that can berelated to endothelial dysfunction (Humbertetal. 2004). Taken together, these observa-tions warrant additional studies that follow Mexico City children for the development of clinical symptoms of PAH as they grow older. A prooxidative, dysfunctional endothe-lium may contribute to a proatherogenicenvironment through an inappropriate regu-lation of vascular tone, permeability, coagula-tion, fibrinolysis, and cell adhesion andproliferation (Laight etal. 2000). Thus,endothelial dysfunction is recognised as anaccessory in the pathogenesis of diabeticmacroangiopathy, obesity, hypertension, dys-lipidemia, and invivo  insulin resistance(Avogaro and De Kreutzenberg 2005; Laightetal. 2000). Dong etal. (2004) have identi-fied at least one allele of the ET-1 gene(T1370G single nucleotide polymorphism)that confers an increased risk of left ventricu-lar hypertrophy in response to environmentalstress. Finally, ET-1 evokes cardiac mast celldegranulation (Murray etal. 2004), which canbe arrhythmogenic. Indeed, extensive degranu-lation of mast cells is observed in healthy Mexico City dogs (Calderón-Garcidueñas etal.2001a), and arrhythmias have been observed inMexico City children (Calderon-Garcidueñas L, Hazucha MJ, Herbst MC, Reed W, Cascio WE, unpublished data). Taken together, theseobservations suggest that the elevated plasma ET-1 levels observed in this study may fore-shadow the development of clinical cardio-pulmonary disease in Mexico City children. Conclusions Chronic exposure of Mexico City children to a complex mixture of air pollutants was associ-ated with a significant elevation of both plasma ET-1 concentration and MPAP. The prospec-tive health effects of sustained elevations of plasma ET-1 and MPAP in growing childrenare unknown. It is plausible that a chronicexposure to significant levels of air pollutants,especially PM 2.5 , may lead to the developmentof clinically significant adverse health effects ina subpopulation of Mexico City children laterin life. Our results clearly suggest a need forepidemiologic and toxicologic studies that canmore fully characterize the association betweensustained ET-1 and MPAP elevations and thedevelopment and progression of systemichealth effects in this population. R EFERENCES Avogaro A, De Kreutzenberg SV. 2005. Mechanisms ofendothelial dysfunction in obesity. Clin Chim Acta360:9–26.Bonner JC, Rice AB, Lindroos PM, O’Brien PO, Dreher KL,Rosas I, etal. 1998. Induction of the lung myofibroblastPDGF receptor system by urban ambient particles fromMexico City. Am J Respir Cell Molec Biol 19:672–680.Bouthillier L, Vincent R, Goegan P, Adamson IY, Bjarnason S,Stewart M, etal. 1998. Acute effects of inhaled urban par- ticles and ozone: lung morphology, macrophage activity,and plasma endothelin-1. Am J Physiol 153:1873–1884.Brook RD, Brook JR, Urch B, Vincent R, Rajagopalan S,Silverman F. 2002. Inhalation of fine particulate air pollu- tion and ozone causes acute arterial vasoconstriction inhealthy adults. Circulation 105:1534–1536.Calderón-Garcidueñas L, Franco-Lira M, Torres-Jardón R,Henríquez-Roldán C, Barragán-Mejía G, Valencia-SalazarG, etal. 2007. Pediatric respiratory and systemic effects ofchronic air pollution exposure: nose, lung, heart and brainpathology. Toxicol Pathol 35:154–162.Calderón-Garcidueñas L, Gambling TM, Acuña H, Garcia R,Osnaya N, Monroy S, etal. 2001a. Canines as sentinelspecies for assessing chronic exposures to air pollutants:part 2. Cardiac pathology. Toxicol Sci 61:356–367.Calderón-Garcidueñas L, Mora-Tiscareño A, Fordham LA,Chung CJ, Garcia R, Osnaya N, etal. 2001b. Canines assentinel species for assessing chronic exposures to airpollutants: Part 1. Respiratory pathology. Toxicol Sci61:342–355.Calderón-Garcidueñas L, Mora-Tiscareño A, Fordham LA,Chung CJ, Valencia-Salazar G, Gómez S, etal. 2006. Lungradiology and pulmonary function of children chronicallyexposed to air pollution. Environ Health Perspect114:1432–1437.Calderón-Garcidueñas L, Mora-Tiscareño A, Fordham LA,Valencia-Salazar G, Chung CJ, Rodríguez-Alcaraz A, etal.2003. Respiratory damage in children exposed to urbanpollution. Pediatr Pulmonol 36:148–161. Calderón-Garcidueñas et al. 1252 VOLUME 115 | NUMBER 8 | August 2007  • Environmental Health Perspectives
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