Frederica Perera, Ph.D. - US grants

The aim of this Program Project is to increase understanding of the mechanisms of chemical carcinogenesis in human. Mechanisms will be studied directly in human who have exposures to known environmental carcinogens: cigarette smoke (whose constituents include ethylene oxide, styrene, 4- aminobiphenyl, polycyclic aromatic hydrocarbons or PAHs) and foundry air (which contains high levels of PAHS). All of the laboratories within he Program will evaluate biologic samples from the same individuals, using biologic markers to assess the association between potential markers of genetic susceptibility (P1-450 induction, AHH activity and glutathione-S- transferase activity) on induction of procarcinogenic effects (carcinogen- DNA and -protein adducts, gene mutations at the hprt locus and activation of c-ras, c-myc and c-fes proto-oncogenes). In contrast to these mechanisms of genetic toxicity, associated with cancer initiation and possibly other stages in the carcinogenic process, little is known about the mechanisms involved in tumor promotion. Because these are important determinants of individual cancer risk, novel methods will be developed to measure effects of certain non-genotoxic agents and tumor promotors on the activity of our model populations, who also experiences high exposure to known tumor promotors, will be studied. Thus, the combined resources of the Program will provide comprehensive data on a broad spectrum of events and processes in human carcinogenesis. They will also help to clarify the nature and significance of interindividual variability in response to carcinogens. These studies are an essential prerequisite to incorporating biologic markers into quantitative risk assessment and epidemiologic studies of cancer causation. Our goal, at the end of 5 years, is to carry our a longitudinal epidemiologic study, in order to determine the ability of biologic markers to predict individual risk of cancer.

Prevention of environmentally related cancer will be enhanced by understanding etiologic mechanisms and in particular by identifying genetic, acquired, or developmental factors that place subgroups of the population at greatest risk. The proposed research aims to validate promising biomarkers of exposure, response, and susceptibility in two groups of Polish women and their newborn infants: urban women exposed to polycyclic aromatic hydrocarbons (PAH) and associated air pollutants at levels 1O-fold higher than those found in U.S. cities, but below most workplace levels, and rural women from a non-polluted area. Because many of these carcinogens appear to have no "threshold" for biological effects, once these biomarkers are validated they can be incorporated into epidemiologic studies of industrial and urban air pollution in the U.S. and elsewhere. During the winter of 1992 samples of placental tissue, infant cord blood and maternal peripheral blood were collected from mother/newborn pairs along with information on potential confounding factors. The biological samples were immediately processed, transported on liquid nitrogen or dry ice to Columbia University and stored at -196 degrees C (lymphocytes) or --70 degrees C (buffy coat, plasma and placental tissue). In this interinstitutional laboratory analysis of shared specimens, the biomarkers to be assessed include PAH-DNA adducts by enzyme-linked immunosorbent assay (ELISA) and aromatic-DNA adducts by 32P-postlabeling (markers of biologically effective dose), the frequency of gene mutation at the hprt locus in T-lymphocytes (a marker of biologic response), aryl hydrocarbon hydroxylase (AHM) activity, glutathione-S-transferase genotype (GSTm1),and CYP1A1 MSP1 polymorphism (markers of genetic/metabolic susceptibility). All of the biomarkers are biologically relevant to carcinogenesis in general and are not restricted to cancers of the lung or to the inhalation route. The following research questions will be addressed: 1) the relationship between air pollution exposure and markers of biologically effective dose and biologic response, adjusting for age, smoking, occupational and dietary exposures 2) ability of genetic/metabolic markers (AHH activity, GSTm1 genotype, CYP1A1 Msp1 polymorphism ) to modify these markers 3) comparison of the same biomarkers in maternal and fetal/newborn tissues 4) comparison of DNA adducts in placental tissue versus cord blood from newborns; 5) overall feasibility of each biomarker for future epidemiologic research in environmental carcinogenesis. Answers to these questions will facilitate the development of strategies for preventing environmentally-induced cancers.

DESCRIPTION: (Adapted from the Applicant's Abstract): There is a need for early molecular indicators of the efficacy of chemoprevention and of interindividual variation in potential risk reduciton. A double-blind, placebo-controlled intervention trial is proposed using biologic markers to evaluate whether supplementation with antioxidant micronutrients reduces DNA damage in a cohort of 300 cigarette smokers and whether genetic factors modulate the effects of the micronutrients. Study subjects will be recruited through the New York State Psychiatric Institute and will be randomized into placebo or vitamin treatment groups. The latter will receive 400 IU vitamin E, and 500 mg vitamin C, based on experimental and epidemiologic evidence that these micronutrients inhibit DNA damage and tumor formation. Biomarkers of DNA damage and plasma vitamin levels will be evaluated in blood sample drawn at baseline and at three month intervals over one year of treatment and one year of follow-up. Buccal cells will be stored for future analyses. The study will address three specific issues: 1) whether suppplementation reduces smoking-induced DNA damage (aromatic-DNA adducts and oxidative DNA damage, including 8-hydorxydeoxyguanine and 5-hydroxymethyl-2'deoxyuridine in peripheral mononuclear cells); 2) whether DNA damage increases significantly after cessation fo vitamin supplementation; and 3) whether genetic susceptibility factors (glutathione-S-transferase M1 deletion and CYHP1A1 polymorphisms) modulate the relationship between DNA damage and antioxidant micronutrients. This type of validation study is a prerequisite to incorporating markers of DNA damage and plasma micronutrients into large-scale, long-term intervention studies designed to look at reduction of cancer incidence in smokers and ex-smokers. Once validated in this model population, these biomarkers would also have applicability in evaluating interventions in occupational cohorts and other populations highly exposed to carcinogens.

There is increasing evidence that people of color are disproportionately exposed to numerous environmental hazards, including hazardous air pollutants such as polycyclic aromatic hydrocarbons (PAH) and environmental tobacco smoke (ETS). The Washington Heights and Harlem neighborhoods in Manhattan are typical of other Hispanic and African American communities in that they are located in a large sprawling metropolitan area characterized by elevated air pollution. The incidence of low birth weight is higher among African Americans living in Central Harlem and Hispanics living in Washington Heights than in Caucasians in the U.S. Cancer rates are also higher in African Americans than in Caucasians. Environmental risks to the developing infant are of particular concern, given the likelihood of increased susceptibility during this period. A molecular epidemiologic cohort study of African American and Hispanic mothers and newborns is proposed to investigate the role of PAH and ETS in procarcinogenic and developmental damage. A combination of personal monitoring, questionnaire and biomarkers in peripheral blood will be used to quantify individual exposure to the toxicants of concern. The biomarkers include PAH-DNA adducts in white blood cells (an indicator of PAH exposure and procarcinogenic genetic damage) and plasma cotinine (a metabolite of nicotine and internal dosimeter of ETS). Measures of development will be assessed in the infants at birth and at 6 and 12 months. The proposal is responsive to concerns about environmental justice and to the recommendation of the National Research Council that risk assessment and public health policy pay special attention to the protection of young infants and children.

This is a double-blind, placebo controlled intervention trial that uses biologic markers to evaluate whether supplementation with antioxidant micronutrients will lower DNA damage in a cohort of 300 current cigarette smokers. The study will also evaluate the effect of genetic susceptibility factors on DNA damage. Volunteers will provide a blood and saliva sample every three months while they are in the trial.

environmental toxicology; chemical carcinogenesis; cancer risk; environmental health; biomedical facility; DNA damage; embryo /fetus toxicology; carbopolycyclic compound; biomarker; air pollution; adduct; congenital disorders; clinical research; urban area; Caribbean; human subject; African American;

The goal of the etiologic study is to examine the influence of selected ambient and indoor pollutants (polycyclic aromatic hydrocarbons and environmental tobacco smoke) on fetal growth and early childhood development (at 6,7,12, and 24 months) in a cohort of inner-city, minority children. The study is undertaken because of growing concern that exposures to this widespread environmental toxicants, disproportionately concentrated in low-income urban areas, have particularly adverse effects on fetal and early childhood development. We combine expertise in molecular epidemiology, state of the art ambient and indoor pollutant monitoring techniques, use of geographical information system, attention to the role of nutrient status in toxicant susceptibility (essential fatty acids and antioxidants), and a framework for assessment of child growth and developmental effects within the context of the social environment. Exposure data (from personal indoor and ambient air monitoring, and questionnaire) will be collected from 480 pregnant women residing in low- income areas of norther Manhattan. Blood samples will be collected at delivery (umbilical cord blood and maternal blood) and at 24 months (infant blood). Biomarkers (PAH-DNA adducts, cotinine, lead antioxidants, and essential fatty acids) will be analyzed in those samples. Fetal outcomes include birthweight, length, head circumference, and size for gestational age. Developmental outcomes will be assessed at 6,7, 12, and 24 months, using the Fagan Test and the Bayley Scales. A questionnaire (administered prenatally, 6,12 and 24 months) collects information on environmental exposure on environmental exposure, social disadvantage, daily activities, infant feeding practices, health status, and level of maternal distress. An observational measure of he quality of physical stimulation and mother-child interaction is conducted in the home at 24 months. Collectively, these measures permit control for poverty-related confounders of the association between toxicant exposures and growth/developmental outcomes, improving our estimates of the proportion of development deficit/delay that can be attributed to the toxic study factors. We will also provide data to the Data Management Statistics and Community Impact Modeling Core for multi-level analysis of whether or not the strength of the associations between toxic exposures and individual developmental child outcomes varies as a function of broader social conditions.

environmental toxicology; epidemiology; mother /infant health care; carbopolycyclic compound; passive smoking; biomarker; clinical research; questionnaires; human subject; Hispanic Americans; African American;

The aim of this study is to lower the risk of asthma in young African American and Hispanic children living in northern Manhattan through two interventions, one at the community level and one at the household level. For the Community Education Intervention (CEI) the Center and its community partners, coordinated by West Harlem Environmental Action, Inc (WE ACT) will join with other community based organizations, including Alianza Dominicana, to develop, implement, and evaluate a community wide intervention to increase awareness of environmental health hazards, particularly airborne pollutants and allergens, and educate community members to take action and events held throughout Northern Manhattan. The CEI will be delivered through a combination of written and audiovisual materials, and public meetings and events held throughout Northern Manhattan. The CEI will be evaluated with data from maternal questionnaires from the cohort of 400 mothers enrolled in the developmental studies (see Ford and Perera projects). Using a single group pre-test-post-test research design, we hypothesize that from baseline to follow-up 24 months later the CEI intervention will: 1.1 Reach 10% of the wp,em aged 18-35 living in Northern Manhattan; and 1.2 Increase the percentage pf wp,em aged 18-35 who take steps to prevent or reduce environmental hazards in their households or in the community. The household intervention will consist of an Indoor Pollution and Allergen Control childhood. When the cohort of 400 children research their second birthday, we will enroll the 120 children (30%) with the highest total IgE levels--the best predictor of asthma at any age--for a one year trial of environmental strategies to prevent asthma. Enrolled families will be randomly assigned to treatment or control studies, and we will intervene in treatment group households to (a) clean and seal the preparation that includes antioxidant vitamins A, C, and E and selenium (Se), and (c) provide the child's mother with written materials and one-to-one counseling by the health educator about the importance of and methods for reducing environmental tobacco smoke (ETS) in the home. Control group families will be given a placebo intervention that includes a multi- vitamin preparation for children that does not contain the anti-oxidant vitamins and written materials about reducing exposure to ETS. Baseline data will be collected at each child's second birthday (24 months) and follow up data will be collected at 30 months (household allergen levels) and 36 months (all measures). We hypothesize that from baseline to follow up the treatment group will have, relative to controls: 2.1 reduced plasma levels of cotinine in children; 2.2 reduced household levels of cockroach and dust mite allergen; 2.3 higher plasma levels of vitamins A, C, and E and Se in children; 2.4 lower sera levels of total, cockroach-specific, rodent-specific, and dust mite-specific IgE in children; 2.5 fewer clinical signs or symptoms of asthma or allergies in children.

DESCRIPTION (Adapted from the Applicant's Abstract): There is growing concern about adverse developmental effects in infants and young children from prenatal exposure to environmental air pollutants, including polycyclic aromatic hydrocarbons (PAH), particulate matter (PM2.5), and environmental tobacco smoke (ETS). The proposed study combines expertise in molecular epidemiology and biomarkers, state-of- the-art pollutant monitoring techniques' and a strong theoretical framework to guide assessment of the impacts of these pollutants on fetal and child growth and development The specific aims are: 1. To test the hypothesis that prenatal exposure to airborne polycyclic aromatic hydrocarbons (PAH) adversely affects fetal growth and early childhood growth and development, after controlling for non-PAH components of PM2.5 ETS, nutritional status (essential fatty acids and antioxidants) and other potential confounders; 2. To explore whether non-PAH components of PM2.5, and ETS have an independent effect on birth outcomes and childhood growth and development, after controlling for PAH, and to explore possible interactions between PAH, PM2.5 and ETS; and 3. To estimate the relative contribution of ambient PAH pollution vs. ETS and other indoor PAH sources to a) personal PAH exposure and PAH-DNA adducts and b) impairment of fetal growth and early child development. To achieve these aims, the international team of researchers will carry out a prospective cohort study of 400 nonsmoking pregnant women living in Krakow, Poland, and will follow their newborns for 12 months postnatally. Fetal growth will be assessed at birth by weight, length head circumference, and size for gestational age. Childhood growth and developmental outcomes will be measured using the Fagan Test and the Bayley Scales. Strengths of the research include the combination of personal inhalation monitoring of PAH and PM2 5 with biomarkers (umbilical cord blood levels of PAH-DNA adults, cotinine, essential fatty acids antioxidants and lead) to estimate in utero exposure to the pollutants of interest and potential confounders. The Polish cohort provides a valuable model for study since emissions from coal burning and traffic are relatively high. However, the results will be broadly applicable since exposures to PAH, ETS and PM25 during pregnancy are common in virtually all industrialized regions of the world It is anticipated that this research will provide relevant data to policymakers concerned with protecting the health of young children.

DESCRIPTION (provided by applicant): The continuation proposed here extends a prospective cohort study using biomarkers to examine the effects of in utero and postnatal exposure to environmental pollutants on the health of African American and Latina children in NYC. That study is now following subjects for 2 years postnatally to assess the relationship between exposure to ambient and indoor pollutants (PAR, particulate matter, environmental tobacco smoke/ETS, allergens) and risk of developmental impairment, asthma and cancer. The continuation has important new components: (1) an extension of the follow-up period from the currently funded 2 years to 5 years: (2) the measurement of maternal and infant exposure to non-persistent pesticides (NPP): (3) the measurement of infant and child exposure to endotoxins; 4) the evaluation of biomarkers of genetic susceptibility to the toxicants studied; (5) the assessment of cognitive development, behavioral adjustment, asthma and genetic damage through age 5; and (6) the recruitment of additional subjects so that a cohort of 400 mother/child pairs will remain in the study for the full five years, ensuring us adequate power to test our main hypotheses. AU of these new analyses will be done on the full cohort, as the relevant samples from the initial cohort have been processed and stored appropriately. The extended follow up allows periodic reassessment of health, development, and behavioral functioning in order to track cascading effects and identify damage that might become manifest only after age 2, when more complex physical and developmental demands arise. Moreover, follow up of children through age 5 permits definitive clinical diagnosis of health outcomes such as attention-deficit/hyperactivity disorder (ADHD) and asthma, not possible in younger children. Primary aims are: 1) to quantify the impact of prenatal and/or postnatal exposures to indoor and outdoor air pollutants on fetal and child growth and neurobehavioral development through 5 years of age, controlling for known physical and psychosocial confounders; 2) to assess the degree to which prenatal and/or postnatal exposure to air pollutants and home allergens contribute to risk of childhood asthma from birth through five years of age, controlling for known confounders; and 3) to quantify associations between prenatal and/or postnatal exposures to PAH/aromatic pollutants and ETS on procarcinogenic genetic damage (PAH/aromatic-DNA and 4-ABP-Hb adducts) in umbilical cord and child?s blood cells.

environmental exposure; disasters; embryo /fetus toxicology; air pollution; epidemiology; psychological stressor; human morbidity; congenital disorders; infant mortality; child physical development; child psychology; pregnancy disorder; physiologic stressor; clinical research; infant human (0-1 year); human pregnant subject; human subject;

DESCRIPTION (provided by applicant) The overall theme of the Columbia Center for Children's Environmental Health (CCCEH) is the identification and prevention of risks of neurodevelopmental impairment and childhood asthma from prenatal and postnatal exposure to urban pollutants. Since it was established in 1998, the Center has forged a successful partnership with West Harlem Environmental Action, Inc. (WE ACT), and nine other community organizations to identify and prevent environmental causes of childhood disease in Northern Manhattan and the South Bronx. The Center has enrolled and retained a unique cohort of mothers and children of color who belong to one of the most at-risk urban populations in this country with respect to environmental exposures, social adversity, and childhood health problems. Using molecular epidemiologic approaches, Center investigators have developed a rich body of knowledge about this vulnerable and disadvantaged urban population. They have documented substantial prenatal exposure to indoor and outdoor urban pollutants, including the combustion byproduct polycyclic aromatic hydrocarbons (PAH), environmental tobacco smoke (ETS), pesticides, and pest allergens. The research has demonstrated significant associations between prenatal exposures to those pollutants and adverse birth outcomes and/or neurodevelopmental, immunological, and respiratory health outcomes in children studied through age two. Building on its achievements of the past five years, the Center proposes several important new initiatives. These include follow-up of the mother and child cohort through ages five to seven, as the children enter school, with links to school performance data at age eight. Additional exposure, biomarker, and outcome assessments will allow testing of new etiologic hypotheses in the community based participatory research (CBPR) projects on asthma and growth and development. A new laboratory-based mechanistic research project will elucidate possible mechanisms of in utero sensitization by co-exposure to PAH/diesel exhaust particles and allergens, directly complementing the CBPR asthma project. A CBPR Intervention project on integrated pest management and health-related housing improvements will be conducted in partnership with the New York City Departments of Health and Mental Health and the New York City Housing Authority. A new Community Outreach, Translation, and Application Core (COTAC) will ensure that the Center's findings have local and national public health impact. COTAC initiatives will include: education of medical students, medical residents, and pediatricians about children's environmental health; a new community campaign to improve air and housing quality in New York City, co-led by WE ACT; and risk assessment, cost, and risk prevention analyses on the Center's findings regarding the health effects of environmental exposures and the cost-effectiveness of IPM. In summary, it is important that the Center as an institution be continued as an established and valued resource to the community, scientific researchers, and policymakers.

disease /disorder proneness /risk; embryo /fetus toxicology; growth /development; mother /infant health care

DESCRIPTION (provided by applicant) This proposal is submitted in response to the RFA-ES-06-001 DISCOVER initiative. The fetus and young child have physiologic, developmental, metabolic, and behavioral patterns that make them uniquely vulnerable to hazards in their environments. Ambient air pollution has been implicated as a major risk factor for asthma and asthma exacerbation, however epidemiological studies have been hampered by uncertainties in exposures and the nature of airway responses. The Columbia Center for Children's Environmental Health (CCCEH) Disease Investigation through Specialized Clinically-Oriented Ventures in Environmental Research (DISCOVER) seeks to understand when and how airborne polycyclic aromatic hydrocarbons (PAHs) and diesel exhaust particles (DEP) increase the risk for childhood asthma and airway inflammation, develop new biomarkers to identify children at risk and improve clinical treatment, evaluate the success of a public policy intervention, and implement physician education initiatives as a mode of intervention. This proposal includes four closely linked projects and Administrative and Data Management and Biostatistics Cores each ensuring the seamless coordination of the multiple research activities involved in this proposal. The cores play vital roles in the quality of research information and statistical analyses and the administrative/financial oversight and translational components of the four main DISCOVER research project initiatives. The four project aims are: 1) Take advantage of repeat PAH measurements pre- and post-natally to distinguish between the biological effects of prenatal PAH exposure versus postnatal exposure during early childhood and pre-adolescence;2) To advance the understanding of the influence of diesel exhaust exposures, which include PAHs, in acute asthma exacerbations by linking innovative exposure and outcome measures;3) To determine whether epigenetic changes related to PAH exposure are involved in the pathogenesis of childhood asthma;4) To ascertain if traffic related PAHs affect ?2AR function in airway smooth muscle cells in vitro, alter (?2AR function following in utero and early life exposures, affect (?2AR expression and function in airway epithelial cells in vitro. The research is translational to asthma prevention, clinical treatment, physician education, and policy. INTEGRATED (clinical and basic) and INTERDISCIPLINARY NATURE OF PROGRAM Description: The goal of the DISCOVER Center submitted by Dr. Perera, Columbia University, is to expand the work of the existing Columbia Center for Children's Environmental Health (CCCEH) to understand how and when airborne polycyclic aromatic hydrocarbons (PAHs) and diesel exhaust particles (DEP) increase the risk for childhood inflammation and asthma. The Center will also develop new biomarkers to identify children at risk and improve clinical treatment, evaluate the success of a public policy intervention and implement physician education initiative as a mode of intervention.

[unreadable] DESCRIPTION (provided by applicant): The major objective of the proposed research is to study the impact of early-life exposures to common urban pollutants on neurobehavioral development and asthma in a sample of children living in three low-income, minority communities of New York City (Central Harlem, Washington Heights and the South Bronx). Using a molecular epidemiologic approach with monitoring, biomarkers, and clinical assessments at serial time points, we will extend our study of African-American and Latina urban mothers and children in order to follow the cohort through child age 11 years to assess the longer-term impact of exposures on child health and developmental outcomes. The exposures of concern include airborne polycyclic aromatic hydrocarbons (PAHs) and orgnaophosphate pesticides such as chlorpyrifos (CPF). The first Specific Aim (Neurodevelopmental) builds on our prior findings and proposes to evaluate relationships between early exposures (PAHs and CPF) and longer-term neurodevelopment, in order to assess the persistence of neurotoxic effects into the school years, identify effects that may emerge over time, and delve more deeply into the behavioral domains to better understand the significance of behavior problems observed in the preschool years. The second aim (Asthma) also builds on our previous findings with respect to risk factors for asthma. We will repeat the assessment of immunoglobulin (lg)E at ages 5, 7, and 9 and obtain measures of lung function and airway inflammation, and a physician-diagnosis of asthma between ages 5 and 7 years. We will also assess the association between becoming overweight in the first 5 years of life and the development of IgE, airway inflammation, and asthma in childhood. The research will consider the effect of known determinants of disease and potential confounders, including other toxic exposures and demographic factors. By using a multidisciplinary approach to understand the complex pathogenesis of developmental disorders and asthma that impose such a heavy burden on inner-city children, we anticipate that the proposed research will have important implications for prevention. [unreadable] [unreadable] [unreadable] [unreadable]

This highly innovative project addresses the role of epigenetic changes in the pathogenesis of childhood asthma. There is growing evidence, some from our own research, that prenatal exposure to polycyclic aromatic hydrocarbons (PAHs), common urban pollutants from traffic and other combustion sources, may be a risk factor for asthma in childhood. Following up on a recent pilot study that demonstrated proof of orinciple, the proposed research will determine whether epigenetic changes related to prenatal PAH exposure are involved in the pathogenic process of childhood asthma. The first study will utilize banked human cord white blood cells, paired placental tissue, and clinical outcome data from children, now aged 9/10 years) who are participants in a prospective cohort study in minority communities in New York City (CCCEH cohort). Analysis of DNA methylation in cord blood DMA and gene expression in placental tissue from these children will be used to identify candidate genes that may be involved in the mechanistic pathway between prenatal PAH exposure and childhood asthma at age 9-10 (i.e., that are differentially methylated and expressed in the high vs. low PAH exposure groups). The set of candidate genes will then be tested as potential biologic markers predictive of childhood asthma in this study sample. Those genes that are found to be predictive will then comprise a "candidate epigenome" to be confirmed in a closely linked animal model. In this complementary animal model, pregnant mice will be exposed to a PAH mixture of similar composition to that measured in air samples from the CCCEH cohort. Blood, placenta and target tissue (lung and spleen) collected from offspring at delivery will be examined for PAH-related changes in gene methylation and gene expression, respectively. A group of offspring prenatally exposed will be followed for 4 weeks to determine asthma-like phenotype. Criteria for selecting the final biomarker(s) will be a) high concordance between gene methylation in white blood cells and gene expression in target tissue and b) significant association with asthma-like phenotype. It is anticipated that this research will provide valuable new data on the role of epigenetic changes in the pathogenesis of childhood asthma. If specific methylation changes induced in utero are found to predict asthma and ultimately validated, we will have identified clinically relevant biomarkers for predicting asthma risk in children.

DESCRIPTION (provided by applicant): The broad objective of the proposed study is the early detection of lung cancer through the identification of patterns of protein expression with the potential to identify early disease. The research "nests" a case-control study within the prospective Harvard Physicians Health Study (PHS) to determine whether biomarkers in blood of healthy individuals can detect early disease that would manifest itself years or decades later. Specific Aims: Our aims are to test the following hypotheses: 1) The baseline blood samples from subjects who later develop lung cancer (cases) will differ significantly with respect to their patterns of protein expression from samples of subjects who are followed for the same period of time and have the same smoking status at enrollment but do not develop lung cancer (controls), such that an "overall" discriminating pattern can be identified that has adequate sensitivity and specificity (>80%) to serve as a potential biomarker of early disease. 2) The baseline blood samples from subjects who later develop Non-Small Cell Lung Cancer (NSCLC) will differ significantly with respect to their patterns of protein expression from samples of controls, such that a "specific" discriminating pattern can be identified that has higher sensitivity and specificity (>85%) to serve as a potential biomarker of early NSCLC. While a number of studies have demonstrated the potential of proteomics in early detection of lung cancer, the sample sizes have been small, none have involved well characterized prospective cohorts, and the specific markers, when identified, have been inconsistent from study to study. None has systematically assessed biomarker validity in terms of the sensitivity and specificity of the patterns under different circumstances of time from blood draw to diagnosis, histology, stage, or smoking status. This research is an essential step in their validation as tools in early detection of lung cancer. Research design and methods: Baseline blood samples from 350 cases and 700 matched controls will be selected from stored "enrollment" samples from the PHS and analyzed for patterns of protein expression. Detailed smoking, environmental, health and dietary histories (baseline and follow-up) have been obtained on each subject. Preliminary studies have demonstrated the feasibility of this collaboration between Columbia University, Harvard University, and the NCI/FDA and have generated data directly supporting all of the research aims. Lung cancer is the leading cause of death from cancer in the U.S. and worldwide and claims over 162,000 lives every year in the U.S. The proposal fits within the mission of the NIH, NCI, and NIEHS to reduce the burden of illness and within the NCI's and NIEHS'strategic areas highlighted for advancement: cancer prevention, early detection and prediction, molecular epidemiology, and validation of new biomarkers of preclinical risk.

The role of the Administrative Core will be to oversee and coordinate all administrative and financial aspects of the Center, facilitate internal and external communications including scientific interactions via the External Advisory Committee, and monitor and ensure progress toward the faculty development goals for the Center's junior faculty members. With support from Core staff, the Core Leader will lead monthly Executive Committee meetings, weekly meetings of project leaders, External Advisory Committee meetings, and supervise all Center administrative and financial activities. Core staff will also collaborate with the the Pediatric Health Specialist and the Community Outreach and Translation Core to translate research findings and disseminate best clinical practices to physicians, health educators, community practice settings, and community groups through Continuing Medical Education, Grand Rounds, and other presentations at local hospitals and community practice settings; outreach to local physician groups, and community stakeholders. Core staff will also monitor and ensure progress toward the Faculty Development Investigator's career development goals, and facilitate overall career development opportunities by ensuring that Columbia University's training opportunities are available to all Center junior investigators. The Administrative Core has the capacity and expertise to administer the three scientific research projects and two other cores, and will operate in a timely and efficient manner, ensuring regular exchanges of information between investigators, external advisors, and other stakeholders. The Core has been a well-functioning team for the past ten years.

Description (provided by applicant): The role of the Administrative Core will be to oversee and coordinate all administrative and financial aspects of the Center, facilitate internal and external communications including scientific interactions via the External Advisory Committee, and monitor and ensure progress toward the faculty development goals for the Center's junior faculty members. With support from Core staff, the Core Leader will lead monthly Executive Committee meetings, weekly meetings of project leaders, External Advisory Committee meetings, and supervise all Center administrative and financial activities. Core staff will also collaborate with the Pediatric Health Specialist and the Community Outreach and Translation Core to translate research findings and disseminate best clinical practices to physicians, health educators, community practice settings, and community groups through Continuing Medical Education, Grand Rounds, and other presentations at local hospitals and community practice settings; outreach to local physician groups, and community stakeholders. Core staff will also monitor and ensure progress toward the Faculty Development Investigator's career development goals, and facilitate overall career development opportunities by ensuring that Columbia University's training opportunities are available to all Center junior investigators. The Administrative Core has the capacity and expertise to administer the three scientific research projects and two other cores, and will operate in a timely and efficient manner, ensuring regular exchanges of information between investigators, external advisors, and other stakeholders. The Core has been a well-functioning team for the past ten years.

DESCRIPTION (provided by investigator): Further research is needed to inform new policy initiatives to reduce the burden of developmental impairment in children. We propose to extend and enrich a molecular epidemiologic prospective cohort study launched in 2000 to assess the longer-term neurobehavioral effects of prenatal exposure to PAHs in children. PAHs are ubiquitous in urban air from combustion of fossil fuel. The study population is unique, comprising more than 400 Caucasian mothers and children residing in Krakow, Poland who have been followed since pregnancy. Follow-up of the cohort is required because we have observed significant adverse effects of prenatal exposures to PAHs on child development among children followed through age five. We have also observed marked inter-individual variation in response to the same levels of exposure, indicating susceptibility due to genetic or nutritional factors. Because the retention rate in this cohort has been high, we are readily able to extend the study through school age (age nine), allowing us to diagnose neurodevelopmental problems that may ultimately impact learning and academic performance. Our primary aim is to determine the effect of prenatal exposures to airborne PAHs on neurobehavioral development from birth through age nine years of age, after controlling for the effects of postnatal PAH exposure, known determinants of child development, and potential confounders. Our secondary aims will be to explore the modifying roles of a) genetic polymorphisms in metabolic activation and detoxification genes and b) lipid- soluble micronutrient concentrations in cord and maternal blood on the associations between prenatal PAH exposure and neurobehavioral development through age nine years. We will also compare results from this cohort study in Caucasians with those from African Americans and Dominicans in our parallel study being conducted in New York City. There are few such comprehensive cohort studies beginning in pregnancy that can provide needed policy-relevant information on neurodevelopmental risks from common urban pollutants. We anticipate that this study will provide a sound evidence-base not only on air pollution exposures, but also on susceptibility factors which may contribute to the risk of neurodevelopmental disorders. PUBLIC HEALTH RELEVANCE: Rates of developmental disorders have increased in children over the past decade and prenatal exposure to environmental contaminants such as polycyclic aromatic hydrocarbons (PAHs) has been implicated. The results of this cohort study will address a major gap in knowledge. The exposures we are studying are not unique to Poland but are ubiquitous worldwide;our results will thus be generalizable to other geographic and ethnic populations.

? DESCRIPTION (provided by applicant): This grant application requests support for a new training program in Environmental Life Course Epidemiology. The training program will be directed by Drs. Pam Factor-Litvak and Robin Whyatt. It requests funds for two pre-doctoral trainees and one post-doctoral trainee in year 1, and gradually increases to a total of four pre doctoral and two post-doctoral trainees by year 5. The proposed mentors are well funded and well published investigators with considerable experience in training Master's, pre-doctoral and post-doctoral students. The theme of the program is to train a new generation of scientists in the life course approach to environmental epidemiology and population health that is to investigate early environmental exposures and outcomes which may not manifest themselves until later in the life course and to study the possible biologic, social, behavioral and psychological mechanisms behind such exposure - outcome relationships. The proposed program builds upon the long, distinguished and ongoing history of life course and molecular epidemiology approaches at Columbia. Pre doctoral trainees will complete the requirements for a PhD in epidemiology or environmental health sciences, including specific course requirements in the life course track and dissertation research related to the life course, and will be offered funding for a period of 5 years. Post-doctoral trainees will pursue research in environmental life course epidemiology under the guidance of experienced mentors. Thus, trainees will be uniquely prepared to perform environmental life course research in a variety of academic and public health settings.

Project Summary: Over the past 16 years, under the direction of Dr. Frederica Perera, the CCCEH has grown into a major resource within the institution and in the field, with many collaborations and partnerships that have required a skilled support staff for effective functioning. Dr. Perera will serve as corresponding Program Director (PD) and will be joined by Dr. Bradley Peterson (PD). Dr. Perera is an internationally recognized expert in children?s health, environmental health sciences and molecular epidemiology. Dr. Peterson is an international leader in the area of early brain development, Magnetic Resonance Imaging (MRI), translational neuroscience, and child and adolescent psychiatry. The Administrative Core, led by Dr. Perera, will serve as the central coordination entity for ensuring the successful implementation and coordination of CCCEH?s research and community outreach and translation activities in a timely and efficient manner. The aims of the Administrative Core (AC) are to: 1. Provide scientific and financial oversight and coordination of the Center?s projects and cores by convening regular meetings of an Executive Committee composed of the two PDs and project and core leaders; coordinate reporting of progress to funding agencies; facilitate submission of IRB protocols and monitor compliance; and serve as the central mechanism for approval of release of data by the Data Management Core (DMC) and review of draft manuscripts prior to submission. 2. Manage the formation and involvement of the External Advisory Committee (EAC) composed of experts in environmental health sciences, polycyclic aromatic hydrocarbons (PAH), neurodevelopment, obesity, and MRI; plan an annual meeting of the EAC; and communicate regularly with the EAC to keep advisors abreast of developments in the Center?s research. 3. Monitor and facilitate progress of the career development investigator (CDI) toward her career development plan goals; and coordinate training for graduate and post-doctoral students who will be future environmental and public health professionals. 4. Coordinate with the Community Outreach and Translation Core (COTC) and the Center?s Pediatric Health Specialists (PHS) to facilitate the translation of scientific findings and dissemination to key stakeholders; develop fact sheets and written materials to ensure that the Center's expertise and findings are an accessible resource for families, community members, policy-makers and other key children's health stakeholders; and maintain the Center's children's environmental health website with input from the PHS and COTC. This Core has the proven capacity and expertise to successfully administer the three proposed research projects, the Data Management Core (DMC), and the COTC and ensure that the program achieves its goals.

? DESCRIPTION (provided by applicant): Protein markers originating in the lung and measurable in the circulating plasma have the potential to complement low-dose computed tomography (LDCT) within a comprehensive risk assessment and screening process. Based on integrative analysis of data from several quantitative plasma profiling platforms (glycomics, metabolomics, immunomics, and proteomics), we have previously identified a set of circulating protein biomarker candidates that, in initial validation studies, had the ability to discriminate between pre-diagnostic plasmas of lung cancer cases from those of control subjects in the Beta-Carotene and Retinol Efficacy Trial (CARET) cohort. The main goal of our proposed study is to determine if the candidate biomarkers identified in the CARET cohort also can detect cancer before clinical diagnosis in the Physicians' Health Study (PHS) cohort. A unique feature of the PHS cohort is the long duration of follow-up, with a lapse of 0.5 to 25 years between baseline blood collection and diagnosis of cases. This allows us to determine the performance of the markers in relation to time to diagnosis; i.e., whether they are most useful as markers of risk, signaling pre-malignant changes, or as early detection markers that signal the emergence of malignancy. The primary aim of this study is to validate a panel of previously identified candidate protein biomarkers for lung cancer by testing these biomarkers in a set of blinded samples drawn from the PHS cohort. Baseline plasma samples drawn at enrollment will be analyzed for each candidate protein biomarker using an enzyme-linked immune-sorbent assay (ELISA). We will then compare cases (n=182) and controls (n=325), matched on age, smoking, and duration of follow-up, with respect to the biomarkers, individually and in combination (panel). The second aim of this study is to determine the biomarker panels appropriate for each of two modalities: 1) risk assessment, in which we will determine a panel with high sensitivity to predict lung cancer > 8 years before diagnosis and help guide decisions regarding the need for follow up with LDCT; and 2) early detection, in which we will determine a panel with high specificity to predict lung cancer < 8 years before diagnosis as a complement to LDCT, which is costly and has very high sensitivity but low specificity. The third aim of this study is to utiliz nanoparticle technology to develop sensitive, low-cost multiple reaction monitoring (MRM) assays for the application of validated biomarkers in the clinical setting. Conclusion: If validated, a panel of protein biomarkers that can be feasibly measured in blood will offer a new tool to assess risk and/or screen for early lung cancer so that chemoprevention, lifestyle changes, and treatment measures can be applied as appropriate, reducing the burden of lung cancer.

PROJECT SUMMARY: The goal of the Columbia Center for Children?s Environmental Health (CCCEH) is to contribute to the ECHO consortium and to develop, validate, and implement an urgently needed new biomarker measurable in an easy-to-obtain, small-volume cord blood sample that reflects prenatal exposure to widespread environmental pollutants, polycyclic aromatic hydrocarbons (PAH), and is predictive of risk of adverse outcomes in the domains of obesity and neurodevelopment. Identification of newborns at increased risk will allow for needed early interventions. Once validated in CCCEH cohorts for PAH, this approach will be scalable to the ECHO Consortium and can be applied to the prevention of risks from other environmental exposures. The Columbia Center for Children?s Environmental Health (CCCEH) birth cohorts, comprised of mothers and children who are low income and minority (largely African-American and Latino), will make a unique contribution to the ECHO Consortium (?Virtual Cohort?). They include the Mothers and Newborns, Sibling, and Fair Start birth cohorts, for a total of 886 children presently enrolled, current funding allows for a total of 1,048 children to be enrolled by 2018. This project will leverage the comprehensive dataset already acquired by CCCEH on the associations between prenatal exposure to a widespread toxic pollutant, polycyclic aromatic hydrocarbons (PAH), and adverse outcomes including reduced IQ and ADHD as well as obesity in childhood. In a series of feasibility studies in UG3, extensive data on prenatal PAH exposure (via personal air monitoring, PAH urinary metabolites and PAH-DNA adducts) and DNA methylation in cord blood will be used to develop and validate a novel epigenetic biomarker that will identify newborns who had high prenatal PAH exposure. The PAH-related methylome will then be tested to determine whether it can be used to predict adverse postnatal neurodevelopmental and obesogenic outcomes (?PAH-related risk methylome?). A mechanistic aim will assess whether PAH-related structural brain changes are mediating the effect of the PAH-related methylome on neurodevelopmental outcomes. In addition, to better understand the contribution of various emission sources to overall PAH exposure estimated by the PAH methylome, a variety of metrics will be used including modeled black carbon (BC) exposure, modeled residential distance to roadways, PAH-hemoglobin adducts in cord blood and PAH measured via passive wristband samplers. In the UH3 phase of the grant, the methylomic approach will be tested in the larger ECHO cohort to cross-validate and evaluate the prediction models in different populations across the country. The cohorts of the CCCEH will extend the value by the ECHO consortium to answer critical questions relating to the role of the early life environment on children?s health.

PROJECT SUMMARY/ABSTRACT Within the ECHO consortium, Columbia Center for Children?s Environmental Health (CCCEH) has three longitudinal pregnancy cohorts comprised primarily of African American and Hispanic mothers and their children, who were recruited during pregnancy beginning in 1998. The three cohorts span all ECHO life stages and represent an urban, minority population that is typically under-represented in scientific research. The 2019 novel coronavirus (COVID-19) pandemic has had worldwide impact; during the ?first wave?, New York City (NYC) was identified as the U.S. epicenter. There are many early indicators suggesting that urban minority communities were among the most affected by the COVID-19 pandemic; and effects of exposure to the pandemic vary by life stage. To develop strategies to mitigate these disparities and to more fully understand the impact of COVID-19 on the health and welfare of children living in the most affected communities during this pandemic, our group is contributing to 3 ECHO supplement concepts. Collectively, these concepts address the impact of the COVID-19 pandemic on nearly every outcome domain within ECHO: perinatal; respiratory; neurodevelopmental; and positive health outcomes. Specifically, the aims address the impact of infection; the broader impact of the pandemic and its associated policies (e.g., lockdowns) on environmental determinants of health; and the impact on social determinants of health. In complete alignment with the ECHO mission, this proposal addresses the impact of exposure to the COVID-19 virus and concurrent pandemic- related changes in the environmental chemical and psychosocial environments on child health, development, and well-being overall and within urban, minority communities. Given the long-lasting impact of the COVID-19 pandemic, it is critical to understand how these factors influence child outcomes measured in ECHO, particularly among a subgroup of the study population that may be among the most highly impacted. Collectively, our proposal seeks to learn from the pandemic, using it as an opportunity to inform the future development of more effective programs and policies that protect and support all children, especially the most vulnerable.

PROJECT SUMMARY: The Columbia Center for Children?s Environmental Health (CCCEH) requests support to maintain retention and engagement of its unique environmental cohorts, enhance basic laboratory and data management resources, increase community outreach, and set the stage for new partnerships and training opportunities to evaluate cumulative oxidative damage from prenatal exposure to mixtures of environmental pollutants. Currently, over 1,000 children are enrolled in the CCCEH cohorts, including the Mothers and Newborns cohort, the Sibling/Hermanos cohort, and the Fair Start cohort; we expect that we will have a total enrollment of 1,500 children by 2023. The CCCEH cohorts are comprised of mothers and children who are low income and minority (largely African-American and Latino). Therefore, it is of critical importance to retain these participants, their associated biorepositories, and the environmental health data they have provided through increased engagement activities, more laboratory resources, and enhanced data management, preparation, and sharing. Impressively, over the past 20 years, the Center has collected over 4,100,416 for 31,742 variables and 8,478 standardized derived variables. The exposures studied in these cohorts include diverse toxic pollutants and chemicals, including polycyclic aromatic hydrocarbons (PAH), phthalates, pesticides, bisphenol A (BPA), environmental tobacco smoke (ETS), and polybrominated diphenyl ethers (PBDE) flame retardants. The Center has also collected a wealth of outcome data from anthropometric measures, neurodevelopmental assessments, magnetic resonance imaging (MRI), and health records. The support will facilitate the Center?s outreach efforts to guide behaviors and inform policies to reduce exposures of pregnant women and children to toxic chemicals and pollutants. It will lay the groundwork for new collaborations across cohorts by incorporating novel biological measures that can provide new insight on the mechanisms of exposure-related disease. To develop a novel biomarker for assessing cumulative damage in mtDNA, the Center will integrate information from high-throughput screening programs (such as Tox21 and ToxCast?) to inform mixture models based on mitochondrial toxicity. The Center will also develop a new inter-institutional collaboration with Mount Sinai School of Medicine that will compare mtDNA measures in our CCCEH cohorts with the same measures in their birth cohort from Mexico City. Given the urgent need to prevent environmentally related diseases and neurodevelopment disorders in children, strong infrastructure support is warranted to maintain and preserve our Center?s unique resources, prepare for future research directions, and ensure effective communication of our findings.

PROJECT SUMMARY Within the Columbia Center for Children?s Environmental Health (CCCEH) Environmental influences on Children?s Health Outcmes (ECHO) award (UG3/UH30D023290), we follow three longitudinal pregnancy cohorts comprised primarily of Black and Latina mothers and their children, who were recruited during pregnancy beginning in 1998. At the time of pregnancy, all women reside in/around New York City (NYC) and represent an urban, minority population that is typically under-represented in scientific research. The research program in our birth cohorts aims to study the impacts of prenatal chemical and social exposures on children?s health outcomes. In this administrative supplement which aims to promote diversity within the ECHO consortium workforce, Ms. Amarelis Raudales is our candidate. She is a predoctoral student in clinical psychology and her clinical coursework at the City College of New York (CCNY) will be complemented by practical research experience within the CCCEH ECHO cohorts. The goal of her project is to understand how to better assess peripartum depression (periPD) in ethnic and minority women. PeriPD is characterized by a major depressive episode during the prenatal period or within four weeks. Depressive symptoms may continue and studies often extend up to one-year postpartum and has been shown to adversely affect children?s health. Latina and Black women are at especially high risk for PeriPD and screening measures for PeriPD are sensitive to the unique experiences of Latina and Black women. Better screening measures are needed for early detection, diagnosis, and treatment. This information will benefit our cohort and the ECHO community, as the ECHO wide cohort aims to include representation from multicultural populations.

Abstract The Columbia Center for Children?s Environmental Health (CCCEH) has three multi-ethnic birth cohorts contributing to the ECHO Consortium. Children in our cohorts live in the lower income Northern Manhattan and South Bronx neighborhoods of New York City and are comprised of African American and Hispanic women and their children. As described in this supplemental application, we respectfully request additional funding in year 6 to achieve our EWCP milestones and goals. These funds would go principally to increase our staff effort--many of whom are bilingual (English/Spanish) and from the same cultural background, ethnicity, and neighborhoods in which the participants live. The additional funds requested in this supplement will ensure that we can continue to provide extant and newly collected EWCP data from our three cohorts and will create a more equitable situation among all of the ECHO cohorts. With the provision of these additional resources, we will preserve our ability as ECHO members to exert a sustained, powerful influence on the research fields involved and will support the inclusion and representation of diverse participants in ECHO who are traditionally under-represented in research.