Grantee Research Project Results
Final Report: Berkeley/Stanford Children’s Environmental Health Center
EPA Grant Number: R834596Center: UC Berkeley/Stanford Children’s Environment Health Center
Center Director: Tager, Ira
Title: Berkeley/Stanford Children’s Environmental Health Center
Investigators: Hammond, S. Katharine , Tager, Ira , Gale, Sara L , Shaw, Gary M. , Balmes, John R. , Padula, Amy , Eisen, Ellen , Mann, Jennifer , Nadeau, Kari
Institution: University of California - Berkeley , Stanford University
EPA Project Officer: Callan, Richard
Project Period: May 7, 2010 through May 6, 2013 (Extended to May 6, 2014)
Project Amount: $1,091,783
RFA: Children's Environmental Health and Disease Prevention Research Centers: Formative Centers (with NIEHS) (2009) RFA Text | Recipients Lists
Research Category: Children's Health , Human Health
Objective:
The overall goal of the Berkeley/Stanford Children's Environmental Health (Pre-)Center was to study the effects of in utero and childhood exposure to ambient air pollutants on birth outcomes (low birth weight [LBW] and structural birth defects), T-cell regulatory function, and the relation of these early life exposures on the occurrence of asthma in the lower half of the Central Valley of California (the San Joaquin Valley). The following are the specific aims expressed as hypotheses:
Project 1 (C001): Effect of multilevel environmental exposure on birth outcomes
Hypothesis: The associations between adverse pregnancy outcomes (LBW, preterm and small for gestation age) and exposure to ambient air pollutants and endotoxin are increased in women who reside in impoverished neighborhoods and are socially disadvantaged at the individual level.
Project 2 (C002): Exposure to air pollutants and risk of birth defects
Hypothesis: Exposure to specific air pollutants and mixtures of air pollutants during critical periods of fetal organogenesis are associated with structural birth defects (so-called congenital anomalies or birth defects).
Birth defects are the leading cause of infant mortality in the United States. Our Centers research efforts will enhance scientific understanding of the potential environmental etiologies of birth defects, which will undoubtedly have important implications for risk assessment and prevention of these common, costly and often deadly outcomes of pregnancy. Specifically, in this project we are conducting a rigorous population-based epidemiologic study to address this research aim.
Project 3 (C003): Ambient pollutants/bioaerosol effects on Treg function
Hypothesis: The reported associations between ambient air pollution and endotoxin and asthma onset and exacerbation are mediated through pollutant/endotoxin alterations of regulatory T-cells (Treg) and these effects on Treg are related to exposure in the year prior to specimen collection and exposure during the late first and early second trimesters when T-cell differentiation and function begin to develop.
This project's goal is to further understand the link between indicators of exposure and outcomes on human health by studying immune system changes in subjects exposed to elevated levels of ambient air pollution. The researchers hypothesized that immunological indicators linked to environmental exposure and health outcomes will elucidate the role and mechanism of air pollution in asthma. This link is theoretically understood, circumstantially clear, but not yet proven. The investigators have developed a comprehensive novel indicator of immune function that can be performed on one drop of blood. This method will be used to examine cellular, serological and epigenetic biomarker changes in peripheral blood that can be broadly applied to an individual health outcome. The objectives of the research were (1) to examine the link between specific immune indicators and ambient air pollution exposures (level of exposure, chronicity of exposure, and type of exposure [ozone, NO, NO2, CO, particulate matter < 10 μg/m3 (PM10), PM < 2.5 μg/m3 (PM2.5), elemental carbon, polycyclic aromatic hydrocarbons (PAH), daily naphthalene, endotoxin]) through a database collected in a large population in Fresno, CA; and (2) to characterize the relationship between immune indicators and health outcomes of asthma.
Summary/Accomplishments (Outputs/Outcomes):
The specific aims posed for this precenter were completed. The Exposure Core estimated exposures to air pollution (O3, NO2, NO, CO, PM10, PM2.5 and PAHs) and traffic density for each of the three projects at the relevant time periods. The Community Outreach and Translation Core both informed the participants and the community about the research findings and engaged the community through a Community Advisory Board that was active and contributed to the research.
Project 1 (C001): Effect of multilevel environmental exposure on birth outcomes
The results of Project 1 showed associations between air pollution at the maternal residences during the entire pregnancy and for specific periods and adverse birth outcomes. This project used data from the Study of Air Pollution, Genetics and the Environment, which include birth certificates in the four most populous counties of the San Joaquin Valley of California from 2000 to 2006.
For Project 1, researchers used land use regression to assign PAH (rings 4,5,6) estimates for the entire pregnancy (and the last 6 weeks) of each of the maternal residences with 20 km of Fresnos central site monitor for births between 2000 and 2006. These exposure metrics are being analyzed further to identify the relationship between PAH exposure during pregnancy and preterm birth.
Using targeted maximum likelihood estimation to examine the relationship between traffic and term LBW, the results showed that if a population lived near high volume freeways (estimated by 4th quartile of traffic density), the estimated probability of term LBW would be 2.27 percent (95% confidence interval: 2.16, 2.38) compared to 2.02 percent (95% confidence interval: 1.90, 2.12) if the same population lived near smaller local roads (1st quartile of traffic density). These findings were published recently in the American Journal of Epidemiology.
The principal investigators have drafted a manuscript on traffic-related air pollution and four levels of prematurity based on gestational age at birth (20-27 weeks, 28-31 weeks, 32-33 weeks and 34-36 weeks) versus term (37-42 weeks). There were increased odds of prematurity at 20-27 weeks gestation for those exposed to the highest quartile of each pollutant during the second trimester of pregnancy with adjusted odds ratios ranging from 1.6 to 2.5. The associations were substantially stronger in those with low neighborhood socioeconomic status (SES) with adjusted odds ratios ranging from 1.8 to 3.7. Exposure to particulate matter, particularly during mid to late pregnancy, was associated with all gestational definitions of prematurity with the strongest associations for the earliest premature births. These results confirm previous studies that have found associations between traffic-related air pollution and prematurity. This study adds an important new finding: that very early preterm births and low SES underlie the association.
To further explore these findings of neighborhood SES as a modifier in the relationship between air pollution and prematurity, future research will include development of a more robust indicator of neighborhood deprivation. The investigators have constructed the 1/2-mile neighborhood surrounding each of the maternal residences for births between 2000 and 2006 in Fresno County (N = 90,196). Preliminary work on neighborhood deprivation factors was conducted on the neighborhood factors in the FACES cohort (N = 315) to pilot the program of the IRT analysis. GIS data of attributes of these neighborhoods were collected (road network and traffic, alcohol and cigarette sales, wildfires, Superfund sites, grocery stores and farmers markets, schools and daycares, hospitals, water quality, crime). To understand the complex neighborhood environment, we used item response theory to help characterize the variables that make up a deprived neighborhood. The item parameters are all of the covariates, which were converted to be positive and negative (0 = negative neighborhood influence, 1 = positive neighborhood influence). The next step is to examine neighborhood deprivation as an effect modifier in the relationship between traffic-related air pollution and adverse birth outcomes in the CHAPS study population.
Project 2 (C002): Exposure to air pollutants and risk of birth defects
For Project 2, investigators examined a total of 2,455 cases of 36 birth defects and their relationship with air pollution and traffic density, all of which were assigned by the Exposure Core to each of the geocoded residences reported by the study subjects during the first and second months of pregnancy.
Investigators used data from the largest case-control study conducted to date in the United States on birth defects—the National Birth Defects Prevention Study. The researchers limited inquiries to the California study site in the San Joaquin Valley—an area with demonstrated poor air quality. The first analysis targeted specific birth defect phenotypes that appear to be more environmentally sensitive in their etiologies (e.g., neural tube defects, cleft lip with or without cleft palate, cleft palate only, gastroschisis) and included 802 cases and 849 controls. The second analysis focused on 822 congenital heart defects, which were categorized into 19 specific defects. The most recent analysis evaluated the remaining defects for which there were sufficient power to detect associations (12 defects and 830 cases).
Ambient air pollution measurements and traffic metrics were assigned to each of the geocoded residences reported by the study subjects during the first and second month of pregnancy. The exposures included: O3, NO2, NO, CO, PM10, PM2.5 and traffic density. The station-specific daily air quality data from the U.S. Environmental Protection Agency (EPA) Air Quality System were spatially interpolated using inverse distance-squared weighting. Traffic density indicators were calculated to represent the amount of traffic counts within a 300 m radius of the early pregnancy residence.
Analyses showed that higher exposure to traffic-related ambient air pollutants CO, NO and NO2 and lower exposure to O3 during the first 2 months of pregnancy appear to be associated with increased odds of neural tube defects in the San Joaquin Valley of California after adjusting for maternal race-ethnicity, education and multivitamin use. In contrast, higher ozone was associated with increased odds of gastroschisis and higher CO was associated with decreased odds of cleft lip with/without cleft palate. Exposure to increased levels of traffic density (and in some cases PM10) during the first 2 months of pregnancy was associated with ventricular septal defects, hypospadias, hydrocephaly and esophageal atresia.
The researchers have incorporated the ambient air pollution exposures from this project into an investigation of residential pesticide exposures to allow a more comprehensive assessment of risks to environmental exposures and birth defects. Several papers will emerge from this work and will partially credit this funding program, such as the publication by Yang, et al.
Project 3 (C003): Ambient pollutants/bioaerosol effects on Treg function
Project 3 recruited 402 children for immune and pulmonary function testing. Significant immunotoxic effects were observed using in vivo and ex vivo studies.
Work on the project aims proceeded smoothly and according to project timelines. All subjects have been enrolled in the study, and the researchers have performed all cellular and molecular analyses on the blood samples obtained from the subjects. A manuscript for this project has been published (Hew, et al., CEA 2014).
Significant immunotoxic effects were observed using in vivo and ex vivo studies. The data demonstrated that: (1) DNA methylation of the Foxp3 gene results in decreased Foxp3 protein levels in Treg and that the levels of Foxp3 decrease are associated with increased levels of exposure to polycyclic aromatic hydrocarbons; (2) downregulation of chemokine receptor/cognate ligand pairs (CCR8/CCL1) is worsened by exposure to PAH; (3) decreases in Treg-associated (TGF-α and IL-10) and increases in Th2-associated plasma markers (IL-4 and IL-13) correlate with increased levels of exposure to ambient air pollution; and (4) higher degrees of Treg impairment are associated with severity of asthma, and lower levels of Treg immune indicators can be detected in nonasthmatic children exposed to elevated levels of ambient air pollution.
The study results were expected to (1) provide sufficient evidence to help understand the link between the environmental hazard, exposure (individual estimate exposures), and the health outcomes (asthma) through the database collected in a large population in Fresno, CA; and (2) characterize the relationship between ambient air pollution exposure and biomarkers that can be used to indicate the health outcomes of asthma.
Conclusions:
Elevated air pollution levels and higher traffic density have been implicated as having adverse effects on the health of children and adults. Outcomes include reduced birth weight and gestational duration, decreased pulmonary function and coronary heart disease. Project 1 demonstrated associations between specific air pollutants and premature birth, with stronger associations observed in 20-27 weeks gestation and among those in lower SES neighborhoods.
The etiologies of most structural birth defects are unknown. A few observations have pointed toward ambient air pollutants as risk factors for human birth defects; however, this important public health hypothesis has not been thoroughly investigated because of a lack of good exposure and outcome data. Thus, Project 2 uniquely fills an important gap in our understanding of the role of environmental exposure on the risk of human birth defects.
The associations observed in Project 3 among chronic ambient air exposures, the health outcomes of individual children, and changes in the immune system are essential for understanding the underlying immune mechanisms. The results can be used to help decrease and prevent the burden of asthma and allergy, and to reduce exposure to air pollution. Overall, the project took an innovative approach to investigating whether chronic ambient air exposures, the health outcomes of individual children, and changes in the immune system are correlated. The results are essential for understanding immune mechanisms that could be related to exposure and health outcomes. The results can be used to help decrease and prevent the burden of asthma and allergy, and to reduce exposure to air pollution.
Many of the outcomes are more common within communities with lower SES and more ethnic diversity; these are the same communities that tend to have higher air pollution and traffic density, at least in the United States, and this conjunction of risks is especially apparent in Fresno and the San Joaquin Valley of California. These findings suggest a case of environmental justice with important health consequences.
Journal Articles: 15 Displayed | Download in RIS Format
Other center views: | All 50 publications | 15 publications in selected types | All 15 journal articles |
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Balmes JR. How does diesel exhaust impact asthma? Thorax 2011;66(1):4-6. |
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Gale SL, Noth EM , Mann J, Balmes J, Hammond SK, Tager IB. Polycyclic aromatic hydrocarbon exposure and wheeze in a cohort of children with asthma in Fresno, CA. Journal of Exposure Science & Environmental Epidemiology 2012;22(4):386-392. |
R834596 (2010) R834596 (2011) R834596 (2012) R834596 (Final) R834596C003 (2012) |
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Hew KM, Walker AI, Kohli A, Garcia M, Syed A, McDonald-Hyman C, Noth EM, Mann JK, Pratt B, Balmes J, Hammond SK, Eisen EA, Nadeau KC. Childhood exposure to ambient polycyclic aromatic hydrocarbons is linked to epigenetic modifications and impaired systemic immunity in T cells. Clinical & Experimental Allergy 2015;45(1):238-248. |
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Kohli A, Garcia MA, Miller RL, Maher C, Humblet O, Hammond SK, Nadeau K. Secondhand smoke in combination with ambient air pollution exposure is associated with increased CpG methylation and decreased expression of IFN-γ in T effector cells and Foxp3 in T regulatory cells in children. Clinical Epigenetics 2012;4(1):17 (16 pp.). |
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Liu J, Zhang L, Winterroth LC, Garcia M, Weiman S, Wong JW, Sunwoo JB, Nadeau KC. Epigenetically mediated pathogenic effects of phenanthrene on regulatory T cells. Journal of Toxicology 2013;2013:967029. |
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Mann JK, Balmes JR, Bruckner TA, Mortimer KM, Margolis HG, Pratt B, Hammond SK, Lurmann FW, Tager IB. Short-term effects of air pollution on wheeze in asthmatic children in Fresno, California. Environmental Health Perspectives 2010;118(10):1497-1502. |
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Nadeau K, McDonald-Hyman C, Noth EM, Pratt B, Hammond SK, Balmes J, Tager I. Ambient air pollution impairs regulatory T-cell function in asthma. Journal of Allergy and Clinical Immunology 2010;126(4):845-852.e10. |
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Noth EM, Hammond SK, Biging GS, Tager IB. Mapping and modeling airborne urban phenanthrene distribution using vegetation biomonitoring. Atmospheric Environment 2013;77:518-524. |
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Padula AM, Mortimer K, Hubbard A, Lurmann F, Jerrett M, Tager IB. Exposure to traffic-related air pollution during pregnancy and term low birth weight: estimation of causal associations in a semiparametric model. American Journal of Epidemiology 2012;176(9):815-824. |
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Padula AM, Tager IB, Carmichael SL, Hammond SK, Yang W, Lurmann F, Shaw GM. Ambient air pollution and traffic exposures and congenital heart defects in the San Joaquin Valley of California. Paediatric and Perinatal Epidemiology 2013;27(4):329-339. |
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Padula AM, Tager IB, Carmichael SL, Hammond SK, Lurmann F, Shaw GM. The association of ambient air pollution and traffic exposures with selected congenital anomalies in the San Joaquin Valley of California. American Journal of Epidemiology 2013;177(10):1074-1085. |
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Padula AM, Tager IB, Carmichael SL, Hammond SK, Yang W, Lurmann FW, Shaw GM. Traffic-related air pollution and selected birth defects in the San Joaquin Valley of California. Birth Defects Research, Part A: Clinical and Molecular Teratology 2013;97(11):730-735. |
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Padula AM, Mortimer KM, Tager IB, Hammond SK, Lurmann FW, Yang W, Stevenson DK, Shaw GM. Traffic-related air pollution and risk of preterm birth in the San Joaquin Valley of California. Annals of Epidemiology 2014;24(12):888-895e4. |
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Padula AM, Balmes JR, Eisen EA, Mann J, Noth EM, Lurmann FW, Pratt B, Tager IB, Nadeau K, Hammond SK. Ambient polycyclic aromatic hydrocarbons and pulmonary function in children. Journal of Exposure Science & Environmental Epidemiology 2015;25(3):295-302. |
R834596 (2012) R834596 (Final) R835435 (2014) R835435 (2015) R835435 (2016) R835435 (Final) |
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Yang W, Carmichael SL, Roberts EM, Kegley SE, Padula AM, English PB, Shaw GM. Residential agricultural pesticide exposures and risk of neural tube defects and orofacial clefts among offspring in the San Joaquin Valley of California. American Journal of Epidemiology 2014;179(6):740-748. |
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Supplemental Keywords:
air pollution, low birthweight, LBW, preterm births, neighborhood effects, cumulative impact, congenital abnormalities, pregnancy, birth defects, immune function, Foxp3, immune system, epigenetic effectsRelevant Websites:
Children's Health & Air Pollution Study - San Joaquin Valley (CHAPS-SJV) ExitProgress and Final Reports:
Original Abstract Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
R834596C001 Effect of Multi-Level Environmental Exposure on Birth Outcomes
R834596C002 Exposure to Air Pollutants and Risk of Birth Defects
R834596C003 Ambient Pollutant/Bioaerosol Effects on Treg Function
The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.