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Your Environment. Your Health.

Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT)

Principal Investigator:
Hu, Howard; Peterson, Karen; Hernandez-Avila, Mauricio; Tellez-Rojo, Martha Maria
Institution:
University of Michigan
Location:
Mexico City, Mexico
Number of Participants::
1,653
Brief Description::
This is a group of three sequentially-enrolled, on-going, epidemiologic birth cohort studies in Mexico City with an original aim to investigate the impact of lead on child development. The research aims have since expanded to include a wide range health outcomes and environmental, nutritional, behavioral, genetic, and epigenetic risk factors. More than 1,600 mother-child pairs enrolled in the study beginning in 1994, some of whom have been followed for over two decades.
Lifestage of Participants:
Exposure: Prenatal; Infant (0-1 year); Youth (1-18 years); Adulthood (18+ years); Adulthood (mother)
Assessment: Prenatal; Infant (0-1 year); Youth (1-18 years); Adulthood (18+ years); Transgenerational
Exposures:
Air Pollutants: Particulate matter; Tobacco smoke
Fluorinated Compounds: Not specified
Metals: Arsenic; Cadmium; Chromium; Copper; Lead; Manganese; Mercury/methylmercury; Nickel; Zinc; Other Metals
Mixtures:
Non-Chemical Stress: Psychosocial stress
Nutrition/Diet/Supplements: Not specified
Personal Care/Consumer Products: Bisphenol A (BPA); Phthalates
Health Outcomes:
Birth Outcomes: Birthweight
Immune Outcomes: Allergic response; Autoimmune outcomes; Inflammation
Metabolic Outcomes: Metabolic syndrome; Obesity/body weight
Musculoskeletal Outcomes: Dental health
Neurological/Cognitive Outcomes: Neurobehavioral outcomes; Neurodevelopmental outcomes
Reproductive Outcomes: Premature/delayed puberty; Other Reproductive Outcomes
Biological Sample:
Blood; Cord blood; Fingernails/toenails; Hair; Placenta; Plasma; Saliva/buccal cells; Serum; Teeth; Urine; Other Biological Sample

Related NIEHS-Funded Study Projects

Early Life Exposure to Metal Mixtures and Neuroimaging of Internalizing Behaviors in Childhood

Principal Investigator:
Horton, Megan K
Institution:
Icahn School of Medicine at Mount Sinai
Most Recent Award Year:
2018
Lifestage of Participants:
Exposure: Prenatal; Infant (0-1 year); Youth (1-18 years)
Assessment: Youth (1-18 years, specifically 10-11 years of age)
Exposures:
Metals: Lead; Manganese; Zinc
Mixtures:
Health Outcomes:
Mental Health Outcomes: Internalizing behaviors (depression, anxiety)
Neurological/Cognitive Outcomes: Structural and functional changes in the brain
Biological Sample:
Teeth
Other Participant Data:
Validated self and parental reports of anxiety and depression; MRI to asses structural and functional changes in the brain
Abstract:
Pediatric internalizing disorders, including anxiety and depression, lead to considerable public health burden. Our understanding of internalizing disorders has lagged behind advances in our understanding of other pediatric psychopathologies. The neural circuitry underlying internalizing behaviors, including the prefrontal cortex, lateral orbitofrontal cortex, anterior cingulate cortex, amygdala and hippocampus develop early during developmental processes. Unlike adult neural networks, which are relatively stable, infant and child neural networks are dynamic, and need to be considered as vulnerable developmental trajectories. Even minor environmental disruptions early in life can set in motion deviations from normative trajectories that are not clinically evident for years. Environmental chemicals, such as metals, can exert neurotoxic effects during these critical windows of vulnerability. Advances in neuroimaging (i.e., magnetic resonance imaging; MRI) allow us to non-invasively test the influence of the environmental exposures on the neural circuitry in children. The influence of prenatal and early childhood metal exposure on these internalizing symptoms and the underlying neural circuitry has not yet been examined, even though early exposures to metals has been shown to adversely affect cognitive domains supported by the same circuitry. In the proposed study, we will leverage an ongoing prospective birth cohort study focused on examining associations between early life metal exposure and child cognition. We will introduce new follow-up measures including MRI and behavioral testing to assess internalizing symptoms in a sample of 300 variably exposed children at age 10-11 years. Using an innovative tooth biomarker that reconstructs integrated measures of metal exposure throughout gestation and early childhood, we focus on 3 neuroactive metals including: lead (Pb), a known toxicant; manganese (Mn) an essential nutrient with growing recognition as a neurotoxicant; and zinc (Zn) an essential nutrient with potential to mediate adverse effects of neurotoxicants. Using data-driven statistical models designed to leverage the temporality of the tooth data, we propose to identify and define critical developmental windows of susceptibility to individual metals and to the metal mixture. In addition, exploratory analyses will examine the link between MRI findings and behavioral phenotypes to further understand the mechanisms of metal neurotoxicity. This study bridges the fields of affective neuroscience and neuroimaging with environmental epidemiology. Few environmental health studies have brought together these three fields within a large cohort designed to test risk factors of child neurodevelopment; thus our study will help shape our overall understanding of the long-term effects of early life metal exposure and set the stage for developing effective public health interventions that can improve emotional, behavioral and cognitive functioning in children.
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SPP1, Oxidative Stress, and Lead Toxicity

Principal Investigator:
Lu, Quan
Institution:
Harvard School of Public Health
Most Recent Award Year:
2018
Lifestage of Participants:
Exposure: Prenatal; Infant (0-1 year); Youth (1-18 years)
Assessment: Youth (1-18 years)
Exposures:
Metals: Lead
Health Outcomes:
Neurological/Cognitive Outcomes: Neurodevelopmental outcomes
Genes or Other DNA Products Studied:
Variants in secreted phosphoprotein 1 (SPP1) and associated pathway genes
Abstract:
Exposure to lead (Pb), a pervasive environmental toxicant, at the early stages of brain development has long-lasting effects on neurocognitive function. However, the molecular mechanisms underlying the unique susceptibility of early brain development to Pb remain poorly understood. As the progenitor cells in the central nervous system, neural stem cells (NSCs) play an essential role in shaping the developing brain. We performed global transcriptional profiling and identified genes whose expression is significantly altered by Pb treatment in neural stem cells. Most of the Pb-upregulated genes are targets of NRF2--the master transcriptional factor for the oxidative stress response, including SPP1 (secreted phosphoprotein 1). SPP1 is known to be neuroprotective, and consistent with this, we demonstrated that addition of recombinant SPP1 protein reduces the inhibitory effect of Pb on NSC growth. Using data from existing genome-wide association studies of an environmental epidemiological cohort, we further showed that a genetic variant in the promoter region of SPP1 significantly associates with improved cognitive development in children. Based on these studies, we hypothesize that NRF2-mediated SPP1 upregulation functions as a self-protective response to reduce Pb exposure-induced injury in neural stem cells. We further hypothesize that failure or compromised ability to upregulate SPP1 in response to Pb exposure contributes to neural stem cell dysfunction and consequently the impairment of early brain development. To test these hypotheses, we propose a highly integrative project that combines molecular mechanistic studies in cultured neural stem cells, in vivo mouse models, and human genetic epidemiology in children exposed to Pb. Aim 1 will investigate the mechanisms thorough which SPP1 upregulation protects against Pb toxicity in neural stem cells. Aim 2 will investigate the role of SPP1 in mediating the effect of Pb on neurodevelopment in mice. Aim 3 will determine the functional association of SPP1 variants with neurodevelopment in children exposed to Pb. Results from this study will establish SPP1 upregulation as a critical mechanism linking Pb exposure with neural stem cell function and neurodevelopment in children, and may identify SPP1 as a novel target for preventative and therapeutic interventions against detrimental neurodevelopment effects of Pb exposure in children.
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Stress-Chemical Interactions and Neurobehavior in School Age Children

Principal Investigator:
Wright, Robert O
Institution:
Icahn School of Medicine at Mount Sinai
Most Recent Award Year:
2017
Lifestage of Participants:
Exposure: Prenatal; Infant (0-1 year); Youth (1-18 years); Adulthood (mother)
Assessment: Infant (0-1 year); Youth (1-18 years, specifically 8-11 years of age)
Exposures:
Air Pollutants: Particulate matter (PM 2.5)
Metals: Arsenic; Cadmium; Chromium; Lead; Manganese; Nickel; Zinc; Barium; Strontium
Mixtures:
Non-Chemical Stress: Psychosocial stress
Health Outcomes:
Immune Outcomes: Inflammation
Metabolic Outcomes: Obesity/body weight
Neurological/Cognitive Outcomes: Neurodevelopmental outcomes; Inhibitory control
Biological Sample:
Cord blood; Deciduous teeth
Other Participant Data:
Inhibitory control using selective attention, self-control, cognitive inhibition; Cortisol rhythms for child and mother; Body mass index, bioimpedance, skin folds; Maternal psychosocial stress (lifetime trauma, current negative life events, depression)
Epigenetic Mechanisms Studied:
Mitochondrial DNA damage
Abstract:
Learning disabilities and child obesity are major public health problems and understanding their root causes is a critical research priority. Inhibitory control has been cross-sectionally linked to obesity, although which disorder arises first is unclear. In addition, there is substantial overlap among fetal/infant environmental risk factors for both learning disabilities and for obesity. This may mean that inhibitory control is part of a shared causal pathway between environment and obesity. To our knowledge, no studies have addressed the upstream environmental causes that could explain the link between inhibitory control and obesity, nor have they addressed the temporal relationship between maladaptive behavior and obesity. A large body of research shows that environmental exposures during sensitive life periods affect key physiological processes and regulatory systems that orchestrate the development of multiple organ systems, including brain development and growth/obesity. The perinatal period is particularly important, as this is when cells and tissues differentiate most rapidly. The role of optimal oxidant balance for proper brain development, as well as its role in obesity is now increasingly recognized. Bringing all these concepts and observations together, we propose that prevalent, perinatal, paradigm pro-oxidant exposures ?air pollution, metals, and psychological stress- program child obesity by first causing maladaptive inhibitory control that ultimately leads to obesity. Furthermore, to better assess the role of oxidative stress (OS) we will measure mitochondrial DNA (mtDNA) damage in cord blood, as mtDNA is highly sensitive to OS and damage to its DNA propagates via mitosis. Damaged mtDNA biomarkers act as cumulative records of past oxidative stress, extending our work to include perinatal OS regardless of its cause. More broadly, our proposed biological framework means that one disease can be a causal risk factor for another, and that longitudinal pathways from environment to a disease should consider other disease states as possible intermediates. We believe this is a paradigm shifting concept that can unify several widely observed relationships. In addition, the path from environment to behavior to obesity may depend as much on exposure timing as on differences in exposure levels. We have therefore developed novel exposure methods that reconstruct perinatal environments in short time intervals. We combine these exposure tools with novel statistical approaches to allow us to objectively define susceptibility windows to air pollution and metals. Finally, we conduct this work in the ELEMENT cohort, a prospective pregnancy cohort study that has collected longitudinal exposure, covariate and phenotype data from pregnancy to age 7 years. In this proposal, we propose to assess inhibitory control and obesity phenotypes from 8-11, an age when child obesity rates rise dramatically, ensuring adequate power for our aims. Our approach will elucidate heretofore unexplained observations that multiple disorders (e.g., anthropometric, metabolic, neurobehavioral) arise from similar exposures and may have their roots in shared vulnerability to early environmental programming.
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E3Gen: Multigenerational Effects of Toxicant Exposures on Life Course Health and Neurocognitive Outcomes in the ELEMENT Birth Cohorts

Principal Investigator:
Peterson, Karen Eileen
Institution:
University of Michigan
Most Recent Award Year:
2017
Lifestage of Participants:
Exposure: Prenatal; Infant (0-1 year); Youth (1-18 years); Adulthood (18+ years)
Assessment: Youth (1-18 years); Adulthood (18+ years); Transgenerational
Exposures:
Endocrine disrupting chemicals:
Metals:
Health Outcomes:
Metabolic Outcomes: Metabolic health during menopause; Infant weight gain
Microbiome Outcomes: Oral health and oral microbiome
Neurological/Cognitive Outcomes: Neurodevelopmental outcomes
Reproductive Outcomes: Premature/delayed menopause
Other Participant Data:
Oral health indicators (caries, fluorosis, images)
Epigenetic Mechanisms Studied:
Transgenerational epigenetic modifications
Abstract:
The impact of environmental toxicants on health and disease risk during sensitive developmental periods has been recognized for nearly 20 years, as highlighted by the developmental origins of adult disease hypothesis and life course epidemiology. Yet, the potential to understand novel mechanisms implicit in these frameworks has not been fully realized. Few environmental cohorts have followed mother-child dyads beyond adolescence, precluding the ability to understand long-term impacts of toxicant exposures in young adulthood and perimenopause?both dynamic life stages characterized by increased risk of metabolic syndrome and potential changes in neurocognitive processes. The E3Gen project, based on our highly successful, 22-year research collaboration with the Instituto Nacional de Salud Pública de Mexico (INSP), comprises three birth cohorts of women originally recruited from 1994- 2004, their children now aged 12-22 years, and the next generation of grandchildren currently being born. This R24 application leverages the research infrastructure of our ongoing studies in the Early Life Exposure in Mexico to ENvironmental Toxicants (ELEMENT) cohorts and of three NIEHS-funded centers at the University of Michigan, creating an unparalleled opportunity launch new research that maximizes use of the existing biorepository and rich database of repeated toxicant exposures and metabolic and neurocognitive outcomes and that promotes accelerated data and resource sharing with the larger environmental health sciences community. Specific Aims are to: 1) Maintain and enhance the scientific integrity of the E3Gen multigenerational cohort and implement strategies to encourage participation and prevent loss to follow up among 850 mothers aged 38-50 years, their children aged 12-22 years, while also recruiting 90 grandchildren currently and projected to be born over the next five years; 2) Prepare for future scientific studies considering the roles of epigenetics, oral health and oral microbiome in mediating the impact of endocrine disrupting chemicals (EDCs) and metals on metabolic and neurocognitive outcomes across three generations of ELEMENT participants; 3) Develop and test novel data management techniques to improve and enrich data integration and harmonization, data sharing, and cross-project data communication.
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Novel Biomarker to Identify Critical Windows of Susceptibility to Metal Mixture

Principal Investigator:
Arora, Manish
Institution:
Icahn School of Medicine at Mount Sinai
Most Recent Award Year:
2016
Lifestage of Participants:
Exposure: Prenatal; Infant (0-1 year); Youth (1-18 years, specifically 1-8 years of age)
Assessment: Youth (1-18 years, specifically through 8 years of age)
Exposures:
Metals: Arsenic; Cadmium; Lead; Manganese; Zinc
Mixtures:
Health Outcomes:
Neurological/Cognitive Outcomes: Neurodevelopmental outcomes
Biological Sample:
Deciduous teeth
Abstract:
Neurodevelopment and cognitive function are among the most important outcomes in public health, particularly with the rise of knowledge-based economies. While it is widely believed that the simultaneous presence of several toxic exposures can alter developmental trajectories of the central nervous system, studies designed to address mixed chemical exposures are rare, and represent a critical need in the field of public health. Multiple barriers are inherent to conducting mixtures research and must be overcome if this field is to progress. Obvious barriers include the need for large sample sizes and prospective data to assess exposure timing (i.e. critical developmental windows). Two additional barriers include exposure misclassification and lack of statistical approaches available for higher dimensional interactions. Our proposal addresses all of these barriers directly and will establish a framework for the study of chemical mixtures that can be applied broadly in environmental health. We have developed a novel biomarker that can objectively reconstruct the dose and timing of past chemical exposure using deciduous teeth. This biomarker differs from standard tooth biomarkers as it combines sophisticated histological and chemical analyses to precisely sample dentine layers corresponding to specific life stages, generating integrated, longitudinal weekly exposure estimates in the second and third trimesters and during early childhood. Our proposal will address mixed metal exposure, as a first step. We note, however, that our approach can and will be applied to organic chemicals in the future, and we are in parallel developing methods for their analysis in teeth. On another front, we will also apply cutting-edge statistical machine learning methods. In this study, we will focus on five metals/metalloids that are of public health significance, manganese (Mn), lead (Pb), arsenic (As), zinc (Zn) and cadmium (Cd). We will conduct this study in the Early Life Exposures in MExico and NeuroToxicology (ELEMENT), a prospective birth cohort using advanced methods in social science, genetics and toxicology to assess transdisciplinary risk factors impacting neurodevelopment.
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The Environment and Epigenome: Interplay of Toxicants and Transposons in Mammals

Principal Investigator:
Faulk, Christopher Don
Institution:
University of Minnesota
Most Recent Award Year:
2015
Lifestage of Participants:
Exposure: Prenatal
Exposures:
Metals: Lead
Personal Care/Consumer Products: Bisphenol A (BPA)
Health Outcomes:
Biological Sample:
Human fetal liver cells
Epigenetic Mechanisms Studied:
DNA Methylation
Abstract:
There are fifty times as many transposons as there are genes in the human genome, and through interaction of the environment and the epigenome, they can become a disruptive force in gene regulation. Since the inception of the field of epigenetics, only a handful of genes have been definitively identified as epigenetically modifiable by environmental exposures. Such loci are termed "metastable epialleles". Most of these epigenetically labile regions are linked to chance insertions of repetitive elements, causing for example, the varying fur colors of genetically identical Agouti viable yellow (Avy) mice. Early exposure to the common environmental toxicants bisphenol A (BPA) and lead (Pb) has been shown to alter the epigenome through global changes in DNA methylation at repetitive elements in mammals. Consequently, the interaction between these toxicants and the epigenome at repetitive elements can have dramatic and long lasting effects. We do not know the governing features underlying the capacity for metastability, nor do we understand how toxicant exposure affects methylation instability in transposons. The candidate's research strategy is designed to discover the extent to which environmental toxicants disrupt the necessary silencing of these selfish elements. Intriguingly, the candidate's preliminary evidence shows that two intracisternal A particle (IAP) transposons associated with metastable epialleles in mice have a higher sequence similarity to each other than to any other transposon in the genome. Thus the overall objective in this study is to determine if phylogenetic similarity predicts the instability of DNA methylation at transposons and whether early environmental insults shift the methylation pattern in mice and humans. The proposed work presents opportunity to merge repetitive element genomics with environmental epigenetics and establish good biomarkers to test exposed populations of mice and humans. First the candidate will test variability in DNA methylation of genetically similar and dissimilar transposons to determine whether sequence identity is a controlling factor in epigenetic instability (Aim 1). Those transposons found to be variably methylated will be validated in mice exposed to environmentally relevant levels of BPA or Pb throughout gestation and early life. Second, using fetal liver samples stratified by BPA exposure that have undergone next-generation sequencing, the candidate will develop an unbiased methodology to identify potentially metastable transposons in humans (Aim 2). Finally, human metastable loci candidates identified with this approach will be validated in a well-characterized ongoing epidemiological birth cohort, the Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT) study (Aim 3). The successful completion of this project will result in more accurate tests of prior environmental exposures and the identification of metastable transposons susceptible to modification by environmental toxicants in both mice and humans.
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The Toxic Environment and the Epigenetics of Fetal Growth

Principal Investigator:
Burris, Heather Herson
Institution:
Beth Israel Deaconess Medical Center
Most Recent Award Year:
2013
Lifestage of Participants:
Exposure: Prenatal; Adulthood (mother)
Assessment: Prenatal; Infant (0-1 year)
Exposures:
Metals: Arsenic
Health Outcomes:
Birth Outcomes: Birthweight
Biological Sample:
Umbilical cord blood leukocytes
Other Participant Data:
General diagnostics/Medical exam
Genes or Other DNA Products Studied:
Inflammatory cytokine genes; Glucocorticoid receptor gene
Epigenetic Mechanisms Studied:
DNA methylation
Abstract:
This application for a K23 Mentored Patient-Oriented Research Career Development Award includes a 5-year plan for training and research activities that will provide the skills and experience needed to achieve success as an independent investigator studying the role of the environment and epigenetic mechanisms in birth outcomes. The candidate has completed research and clinical fellowships that prepared her for an academic career studying perinatal social epidemiology and is currently a full-time faculty member in the Department of Neonatology at Beth Israel Deaconess Medical Center. The candidate is a core member of the Division of Newborn Medicine at Harvard Medical School serving as an Instructor in pediatrics, which is the standard entry level academic position at Harvard. This K23 award will provide her with the structure and support necessary to accomplish the following goals: (1) assess the role that arsenic plays in fetal growth; (2) assess the role arsenic plays in the DNA methylation of genes involved in fetal growth such as inflammatory cytokine genes and the glucocorticoid receptor gene, and explore whether arsenic affects fetal growth through such epigenetic mechanisms; (3) gain expertise in environmental toxicology and environmental epigenetic analyses; and (4) learn the administrative skills needed to manage a large cohort study so that transition to an independent research career running her own birth cohort is accomplished. The candidate's goal is to examine the role the toxic chemical environment plays in birth outcome disparities in the US. To achieve these goals, Dr. Burris has assembled a mentoring team comprised of a primary mentor, Robert Wright, MD MPH, Associate Professor of Pediatrics and Environmental Health who is an expert in pediatric environmental health and toxicology, and co-mentor Andrea Baccarelli, MD PhD, the Mark and Catherine Winkler Associate Professor of Environmental Epigenetics, who has expertise in epigenetic analyses. Although chemicals like arsenic are known to affect birth outcomes and known to affect DNA methylation, it remains unknown whether DNA methylation mediates arsenic-birth weight associations. The study proposed is designed to test the hypothesis that arsenic impairs fetal growth, that arsenic causes alterations in the DNA methylation of inflammatory cytokine genes and the glucocorticoid receptor gene. The candidate will explore whether DNA methylation disturbances mediate arsenic-birth weight associations. These analyses will be performed within a previously established, currently funded cohort in Mexico City (ELEMENT) directed by Dr. Wright. The candidate will use the abundant resources available at Beth Israel Deaconess Medical Center, the Harvard Catalyst (Clinical and Translational Science Center) and the Harvard School of Public Health to obtain the training and coursework necessary to supplement the practical training attained through these analyses to become an independent investigator with a research program studying the environmental impact on birth outcome disparities.
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Metal Mixtures, Children's Cognition, and Sensitive Developmental Windows

Principal Investigator:
Henn, Claus; Gunhild, Birgit
Institution:
Harvard University
Most Recent Award Year:
2013
Lifestage of Participants:
Exposure: Prenatal; Infant (0-1 year); Youth (1-18 years)
Assessment: Youth (1-18 years)
Exposures:
Metals: Chromium; Copper; Lead; Manganese
Mixtures:
Health Outcomes:
Neurological/Cognitive Outcomes: Neurodevelopmental outcomes
Biological Sample:
Blood; Fingernails/toenails; Hair; Deciduous teeth; Urine
Abstract:
Mixtures are a common exposure scenario but are rarely studied. Metals comprise a class of chemicals to which co-exposure is common and whose neurotoxic effects, particularly, can be severe, making them a potentially paradigm class of chemicals for mixtures research. Research on individual metals, such as lead, has been robust; but research on metal mixtures is lacking. Major challenges impeding progress in mixtures research include the lack of sufficient exposure data for multiple metals. Even when multiple metal exposure biomarkers are collected, there remains a lack of analytical tools to fully evaluate interactions. Under the mentorship of Drs. Coull and Lucchini, Dr. Claus Henn (principal investigator) will overcome barriers in mixtures research by using cutting-edge statistical learning methods, combined with robust data on host exposure to mixed metals. By doing so, she will evaluate the joint effects of multiple metals on neurodevelopment. This K99/R00 application builds upon Dr. Claus Henn's experience in environmental epidemiology and exposure science to cross train her in child development and biostatistics and prepare her to become an independent investigator specializing in chemical mixtures and pediatric environmental health. In the K99 phase of the award, Dr. Claus Henn will use tutorials, didactic instruction, and seminars/conferences to receive training in: 1) advanced quantitative methods for use in analyzing combined exposures, and 2) childhood neurodevelopment from the prenatal period through adolescence. These areas of training represent a new cross-disciplinary goal for Dr. Claus Henn. Her training will subsequently be applied in an existing cohort of 750 Italian adolescents in the Public Health Impact of Mixed Element exposure (PHIME) study. Dr. Claus Henn will apply structural equation models, random forests, and kernel regression machines to examine cognitive effects of concurrent exposure to combinations of metals. In the R00 phase, Dr. Claus Henn will evaluate whether cognitive effects of exposure to combinations of metals depend on exposure timing. Using data from the Early Life Exposure in Mexico to Environmental NeuroToxicants (ELEMENT) longitudinal birth cohort, she will apply the aforementioned methods at multiple exposure time points, across the prenatal period and childhood. This cross-disciplinary proposal represents a unique opportunity to efficiently use existing data in an innovative yet cost-effective manner. The proposed training and research will provide Dr. Claus Henn with the skills to study the joint effects of multiple chemicals and multiple time points on neurodevelopment in future research. This research will 1) address the large data gap on health effects of chemical mixtures, and 2) help characterize critical windows of susceptibility to neurotoxicants; both are NIEHS strategic goals and public health priorities. Public Health Relevance: Research on chemical mixtures is a critical public health need, because the neurotoxicity of an individual chemical is likely modified in the presence of other chemicals; yet research on the effects of metal mixtures is lacking. Further complicating this issue is that timing of exposure to mixtures may also result in differential toxicity. This application will use an integrated training plan in neurodevelopment and advanced biostatistics to train Dr. Birgit Claus Henn, an environmental epidemiologist and exposure assessment expert, to conduct high-level research in metal mixtures and children's neurodevelopment at several critical time points of development, from the prenatal period through adolescence.
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Project 1: Perinatal and Peripubertal Mixtures, Physical Growth and Sexual Maturation

Parent Title:
Lifecourse Exposures & Diet: Epigenetics, Maturation & Metabolic Syndrome
Principal Investigator:
Meeker, John D (Contact); Padmanabhan, Vasantha
Institution:
University of Michigan
Most Recent Award Year:
2013
Lifestage of Participants:
Exposure: Prenatal; Youth (1-18 years); Adulthood (mother)
Assessment: Prenatal; Infant (0-1 year); Youth (1-18 years)
Exposures:
Metals: Cadmium; Lead
Mixtures:
Personal Care/Consumer Products: Bisphenol A (BPA); Phthalates
Health Outcomes:
Metabolic Outcomes: Obesity/body weight
Physical growth:
Reproductive Outcomes: Premature/delayed puberty
Biological Sample:
Blood (mother, child); Urine (mother, child)
Other Participant Data:
Testicular volume; Tanner stage; Height; Weight
Abstract:
There is great concern regarding the potential developmental and reproductive effects resulting from environmental exposure to endocrine disrupting compounds (EDCs). Recent population trends showing shifts in the age of puberty onset and progression have contributed to this concern, as has evidence for interrelationships between EDC exposures, overweight and obesity, and easier onset of puberty. Early and late puberty onset are associated with social and psychological challenges and may indicate risk of current or future endocrine-related disorders. EDCs, such as phthalates and BPA, have been hypothesized to be associated with earlier puberty, while animal and human studies suggest exposure to lead and cadmium may be associated with delayed growth and puberty onset via endocrine-mediated pathways. There are a lack of longitudinal studies that have considered exposure to these agents, individually and as mixtures, and at multiple sensitive stages of development, in relation to physical growth and sexual maturation. The proposed study will address these gaps by expanding on pilot work of the University of Michigan (UM) Formative P20 Children's Center to undertake a more robust (N = 400) prospective assessment of the relationship between exposure to a select mixture of EDCs (phthalates, BPA, lead, and cadmium) and the tempo of physical growth and timing of sexual maturation in a long-standing longitudinal cohort study in Mexico. Existing data on life stage lead exposure and anthropometry (height, weight, BMI) 6-month intervals between birth and 5 years of age will be utilized, along with newly collected data. In the proposed study, children in the ongoing cohort will be re-recruited for two clinic visits (18 months apart) between the ages of 8 and 15 where Tanner stages (along with testicular volume among boys), anthropometry, and skin fold thickness will be assessed by a clinician, a blood sample will be collected for analysis of lead and reproductive and thyroid hormones, and a urine sample will be collected for analysis of phthalates, BPA and cadmium. These same exposure measures will additionally be analyzed from samples collected at all 3 trimesters of pregnancy when the children were in utero. Four years of repeated self-reported Tanner stage
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Project 2: Metabolic Consequences of In Utero and Peripubertal Toxicant-Diet Exposures

Parent Title:
Lifecourse Exposures & Diet: Epigenetics, Maturation & Metabolic Syndrome
Principal Investigator:
Peterson, Karen Eileen (Contact); Padmanabhan, Vasantha
Institution:
University of Michigan
Most Recent Award Year:
2013
Lifestage of Participants:
Exposure: Prenatal; Infant (0-1 year); Youth (1-18 years); Adulthood (mother)
Assessment: Infant (0-1 year); Youth (1-18 years)
Exposures:
Metals: Cadmium; Lead
Mixtures:
Nutrition/Diet/Supplements: Not specified
Personal Care/Consumer Products: Bisphenol A (BPA); Phthalates
Health Outcomes:
Metabolic Outcomes: Metabolic syndrome
Biological Sample:
Blood; Cord blood; Serum; Collected cells
Epigenetic Mechanisms Studied:
Epigenetic changes involved in altered metabolic function
Abstract:
The developmental origins hypothesis relates early exposures to endocrine disrupting chemicals (EDCs) to the development of chronic diseases, including metabolic syndrome, a condition affecting up to 25% of US adults and 30% of obese adolescents. Limited research in humans has considered the mechanisms by which exposures to EDCs mixtures interact with diet to alter maternal and child metabolic homeostasis, nor considered whether subsequent exposures during adolescence exacerbate risk of metabolic syndrome. Pilot human and animal data from our Formative CEHC: 'Perinatal exposures, epigenetics, child obesity and sexual maturation" (P20 ESDI 8171/ RD834800, Pl: Peterson) suggest that the disruptive effects of representative maternal EDCs on metabolic and epigenetic markers may differ across sensitive periods of child development. Drawing on unparalleled institutional resources including the UM NIEHS Center of Excellence Epigenetics Laboratory (P30 ES017885) and the Michigan Nutrition and Obesity Research Center (MNORC, P30 DK089503), this project will test the hypothesis that EDC mixtures (BPA, phthalates, lead, cadmium) via epigenetic mechanisms induce oxidative stress (tyrosine oxidation products), disrupt metabolic homeostasis (free fatty acids, amino acids, Acyl-carnitine) and lead to changes in gene transcription and metabolic function. We further hypothesize that dietary macro- and micronutrient intake and dietary patterns during pregnancy and adolescence will modify the impact of EDC mixtures on these outcomes. Study participants include the Michigan Mother-Infant Pairs (MMIP) cohort (n=80) (extension of R01 ES017005, PI: Padmanabhan) and 400 children followed from pregnancy to 8-15 years of age through our 18-yr Early Life Exposures in Mexico to ENvironmental Toxicants (ELEMENT) collaboration with Mexico's Instituto Nacional de Salud Publica (INSP). Findings will: 1) provide proof of concept that EDC mixtures perturb metabolic homeostasis, 2) clarify the role of diet in amplifying or negating such effects, 3) illustrate the epigenetic and transcriptional changes involved and 4) inform the design of future interventions to modify metabolic consequences of EDC exposures both in utero and during the pubertal transition.
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Stress-Lead Interactions and Child Development

Principal Investigator:
Wright, Robert O
Institution:
Icahn School of Medicine at Mount Sinai
Most Recent Award Year:
2013
Lifestage of Participants:
Exposure: Prenatal; Infant (0-1 year); Youth (1-18 years, specifically 1-8 years of age)
Assessment: Youth (1-18 years, specifically 7-8 years of age)
Exposures:
Metals: Manganese
Health Outcomes:
Neurological/Cognitive Outcomes: Neurodevelopmental outcomes, attention, executive function, and memory
Biological Sample:
Blood; Deciduous teeth
Other Participant Data:
Computerized versions of established animal research behavioral tasks: Visual spatial memory using the Virtual Radial Arm Maze, Attention using the Rapid Visual Information Processing test and Choice Reaction Time test
Abstract:
Manganese (Mn) is an emerging neurotoxicant. Two critical issues in the neurotoxicology of Mn include the 1) extrapolation of animal results to humans, and 2) limitations in defining/assessing critical exposure windows in epidemiologic studies. Because randomized trials cannot be conducted for neurotoxic agents, research translation in neurotoxicology involves epidemiologic observational studies that rely on parallel research in animals to determine mechanisms of action. However, such studies seldom measure the same functional domtheains or address exposures at the same life stages, at least not in a coordinated fashion. Although there are several caveats when extrapolating results from animals to humans, one caveat, the use of different neurophenotypes, can now be overcome, given the development of computerized tests of animal/human behavior, such as the virtual radial arm maze and temporal response differentiation test (a fixed interval response). The investigators will employ these tests and others in children in parallel to conducting animal toxicology studies that also address Mn exposure in specific life stages. Their team has also developed a method to reconstruct past Mn exposure using deciduous teeth that expands upon prior work by measuring Mn in specific growth rings corresponding to discrete life stages. In effect, the investigators can now reconstruct past exposure to Mn at multiple developmental windows, a technique that may even be superior to prospective blood Mn levels. In this supplement, the investigators will leverage an ongoing cohort study in Mexico City to assess Mn exposure and child neurodevelopment, while tightly coupling our findings to animal toxicology studies measuring the same neurophenotypes. This ViCTER application is a new transdisciplinary collaboration among investigators with expertise in animal toxicology (Smith) and manganese epidemiology/exposure assessment (Lucchini/Arora), bringing them together to form a unique virtual consortium to study Mn toxicity in children.
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Stress-Lead Interactions and Child Development

Principal Investigator:
Wright, Robert O
Institution:
Brigham and Women's Hospital
Most Recent Award Year:
2012
Lifestage of Participants:
Exposure: Prenatal; Infant (0-1 year); Youth (1-18 years); Adulthood (mother)
Assessment: Prenatal; Infant (0-1 year); Youth (1-18 years)
Exposures:
Metals: Lead
Mixtures:
Non-Chemical Stress: Psychosocial stress
Health Outcomes:
Neurological/Cognitive Outcomes: Neurobehavioral outcomes; Neurodevelopmental outcomes
Biological Sample:
Saliva/buccal cells
Other Participant Data:
Behavioral/Cognitive tests; Questionnaire
Abstract:
Previous studies on lead have typically analyzed covariate markers of social stress as independent predictors of neurodevelopment, considering them potential confounders. There are biological reasons to believe that psychosocial stress potentiates the toxicity of lead. If so, then understanding this relationship may be the key to designing effective public health interventions designed to improve neurodevelopment in children. The ELEMENT cohort has created the infrastructure for such a study and is uniquely positioned to address these important neurotoxicological questions. In this competing renewal, we hypothesize that lead exposure and social stressors experienced jointly in pregnancy and infancy will have multiplicatively increased deleterious effects on neurodevelopment (i.e. environment X environment interactions). Based on work conducted by others in animals, this should result in selective impairments in memory (hippocampus) and fixed interval responses (nucleus accumbens) due to the established vulnerability of these structures to stress and lead. Our results thus far have established a consistent pattern of adverse effects to both lead and social stress, as well as disturbed salivary cortisol rhythms following high levels of stress. We also find multiplicative changes in cortisol rhythms when these exposures occur in the context of high lead exposure. Cortisol may thus represent a mechanistic link between lead and stress. We have already enrolled 1000 infants in Mexico City measuring stress and lead exposure longitudinally beginning in the 2nd trimester through age 2 years. To date, we have measured only infant development via Bayley Scales. In this renewal we propose to measure more detailed neurophenotypes as the children age (behavior, cognition, memory) as well as tests specific to hippocampal and nucleus accumbens function. Social and educational interventions, if targeted properly, could be effective treatments. This research will identify those interventions.
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Prenatal and Childhood Exposure to Fluoride and Neurodevelopment

Principal Investigator:
Hu, Howard
Institution:
University of Toronto
Most Recent Award Year:
2012
Lifestage of Participants:
Exposure: Prenatal; Youth (1-18 years); Adulthood (mother)
Assessment: Youth (1-18 years)
Exposures:
Metals: Lead
Mixtures:
Nutrition/Diet/Supplements: Fluoride
Health Outcomes:
Neurological/Cognitive Outcomes: Neurobehavioral outcomes; Neurodevelopmental outcomes
Biological Sample:
Fingernails/toenails; Plasma (mother); Urine (mother, child)
Environmental Sample:
Food sample; Drinking water sample
Other Participant Data:
Behavioral/Cognitive Tests (BSID II, MSCA, WASI); Questionnaire
Abstract:
In this new R01, we will capitalize on the unique resources of our Early Life Exposure in Mexico to ENvironmental Toxicants (ELEMENT) program, a molecular environmental epidemiology birth cohort study that won the 1999 NIEHS Progress and Achievement Award, to conduct a rigorous study of the potential impact of population-wide levels of exposure to fluoride on neurodevelopment. This effort addresses a 2007 US National Research Council report which concluded that more research is needed to address the possibility that population-wide levels of fluoride exposure may pose a significant threat to neurobehavior. The exceptional data and resources of ELEMENT has allowed our team to publish over 40 papers related to the impact of prenatal and childhood exposure to lead and other toxicants on neurobehavioral and physical development. Using levels of fluoride measured in our archived urine, fasting plasma and toenail specimens, validated measures widely recognized as being the best available biomarkers of fluoride exposure, we propose to study the impact of prenatal and childhood fluoride exposures on widely used and validated measures of neurobehavior at 2 to 14 years of age utilizing 3 of the 4 cohorts of ELEMENT. Our pilot research on archived urine and plasma samples from 40 randomly chosen mother-offspring pairs using rigorous and cross-validated laboratory methods indicates that our ELEMENT subjects have a distribution of fluoride levels that will enable us to pursue our specific aims. Further, our pilot data shows evidence of an inverse relationship between prenatal biomarkers of fluoride exposure and general cognitive function at 2 years (Bayley Scales of Mental Development), 4 years (McCarthy Scales of Children's Abilities) and 7-14 years (Wechsler Abbreviated Scales of Intelligence). Our overall goals will be to conduct a full investigation to () address hypotheses on the potential impact of pre- and postnatal exposures to fluoride on measures of overall neurobehavioral function; (B) explore the potential impacts of fluoride exposure on specific domains of neurobehavioral function, the shape of the dose-response relationships, differential susceptibility in relation to time windows of exposure (prenatal v. childhood), and, using archived data, potential interactions with lead exposure, another widely- distributed neurotoxicant; and (C) conduct a study of offspring to examine the drinking water, dietary, dentifrice, lifestyle, and other determinants of current urinary and toenail fluoride levels. Given the power of our archived resources and sample sizes, we will be able to accomplish this research at a small fraction of the cost and time required of a new study.
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Immune Dysfunction Associated with Early Life Heavy Metal Exposure

Principal Investigator:
Somers, Emily Catherine
Institution:
University of Michigan
Most Recent Award Year:
2011
Lifestage of Participants:
Exposure: Prenatal; Infant (0-1 year); Youth (1-18 years); Adulthood (mother)
Assessment: Infant (0-1 year); Youth (1-18 years)
Exposures:
Metals: Mercury/methylmercury
Health Outcomes:
Immune Outcomes: Allergic response; Autoimmune outcomes
Epigenetic Mechanisms Studied:
DNA methylation
Abstract:
The overarching goal of this K01 proposal is for the candidate to acquire the expertise necessary to lead a research program in environmental epidemiology applied to immune-mediated disorders. Dr. Somers is trained as an epidemiologist, with significant expertise in the clinical epidemiology of lupus, public health surveillance of chronic disease, and descriptive epidemiology of autoimmune diseases. Immediate career goals are to expand on this background by acquiring comprehensive training in relevant areas in environmental health sciences, including molecular epidemiology, immunotoxicology, and epigenetics. Long-term career goals are to unravel the etiologies of autoimmune and other immune-mediated disorders, an in particular, to identify the role of potentially modifiable early life exposures. The proposed training and research will be conducted under the mentorship of Howard Hu, M.D. MPH Sc.D. and Bruce Richardson, M.D. Ph.D. Dr. Hu is a recognized leader in environmental epidemiology and health effects of heavy metals. Dr. Richardson is a rheumatologist and immunologist, and has performed groundbreaking laboratory research related to epigenetics and lupus. The Career Development Plan will include both structured and informal learning activities that together will provide in depth training in the following growth areas for the candidate: (a) Environmental health science and molecular epidemiology, including exposure assessment, gene-environment interactions, and immunotoxicology; (b) developmental and maternal-fetal immunology; (c) assessment and interpretation of biomarkers of immune phenotype and function; (d) epigenetics methods, including DNA methylation, related to health and human disease. The proposed research will be a birth cohort study investigating the association between early life heavy metal exposure and immune dysregulation. The study population will be the Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT) birth cohort (PI: Dr. Hu), which has been extensively characterized in terms of heavy metal exposures, including mercury (prenatal and childhood measurement). This proposal will be the first to investigate immunologic endpoints in this birth cohort. Emphasis will be exploration of the association between in utero and early childhood exposure to mercury and immune perturbations, which may be relevant in terms of autoimmune and allergic disease. Immune parameters will include auto-antibodies, cytokines, and gene-specific methylation levels relevant to T helper cell differentiation. Balance of Th subsets is important in directing host immune responses, and clearly influenced by microbial stimuli. This project addresses a critical gap in knowledge in the role of non-microbial exposures in immune modeling, and will represent a significant career enhancement opportunity for the candidate.
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Early Life Environmental Toxicant Exposure and Oral Health

Principal Investigator:
Arora, Manish
Institution:
Mount Sinai School of Medicine
Most Recent Award Year:
2011
Lifestage of Participants:
Exposure: Prenatal; Infant (0-1 year); Youth (1-18 years); Adulthood (18+ years); Adulthood (mother)
Assessment: Youth (1-18 years); Adulthood (18+ years)
Exposures:
Metals: Arsenic; Cadmium; Lead; Manganese; Zinc
Health Outcomes:
Musculoskeletal Outcomes: Dental health
Biological Sample:
Blood; Shed deciduous teeth
Other Participant Data:
Dental caries and periodontal disease
Genes or Other DNA Products Studied:
Genes that regulate metal or calcium metabolism
Abstract:
Oral diseases are amongst the most common chronic diseases in the US and result in significant disability in the most vulnerable sections of the population, especially children and the poor. The effects of dental diseases extend beyond the oral cavity, with evidence linking poor oral health to diminished quality of life and systemic disorders including cardiovascular disease and cancer. It is, therefore, important that the environmental determinants of oral diseases are systematically investigated to identify their risk factors. Furthermore, metals are deposited in teeth and can be used as biomarkers of fetal/childhood exposure. The use of laser ablation to tease out concentrations within dental layers that correspond to fetal vs childhood development would be a major innovation as it would allow for reconstructing fetal exposure as opposed to cumulative exposure. One of the major barriers to this field of research is the lack of dentists who specialize in environmental health. Dr. Arora is among the few dentists who have previously undertaken studies on the oral health effects of metal toxicants. For this award, during the K/Mentored phase, Dr. Arora will receive structured training in environmental epidemiology, toxicology, genetics, biostatistics and laboratory methods, and he will also lay the foundation for research to be undertaken in the latter stages of this award. In the R/Independent phase of this award, Dr. Arora will study prospectively the oral health effects of metal exposure in a well-established cohort of mother-child pairs residing proximal to a large Superfund site contaminated with metals in Tar Creek, Oklahoma. He will also collect shed deciduous teeth from children in this cohort as well as two others - the CHAMACOS cohort, Salinas Valley, CA (University of Berkeley), and Mexico cohort, Mexico City (Harvard School of Public Health). He will address two Specific Aims: i) to investigate the prospective relationship of environmental metal exposure with dental caries in children, and the association between metals and dental caries/periodontal disease in adults; and ii) to validate the use of tooth-metal concentrations as a biomarker of exposure to metal toxicants capable of reconstructing prenatal vs early childhood exposure, a major advancement in exposure biology. The PI, Dr. Arora, is a dentist and is well-positioned to carry out the proposed training program and research studies because of his prior training in oral biology and the unique resources available through his mentorship team including access to a large established prospective birth cohort that will provide the necessary exposure assessment data, genetic material, newborn measurements and covariate data during this award period; access to state-of-the-art molecular biological laboratories; and advanced coursework in environmental epidemiology and genetics. The proposed training and career development will enable Dr. Arora to become an independent investigator and position him to play a leadership role in the field of environmental dentistry.
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Environment, Fetal Tissue DNA Methylation & Birthweight

Principal Investigator:
Baccarelli, Andrea; Wright, Robert O (Contact)
Institution:
Mount Sinai School of Medicine
Most Recent Award Year:
2011
Lifestage of Participants:
Exposure: Prenatal; Adulthood (mother)
Assessment: Infant (0-1 year)
Exposures:
Air Pollutants: Tobacco smoke
Metals: Lead
Non-Chemical Stress: Psychosocial stress
Health Outcomes:
Birth Outcomes: Birthweight
Biological Sample:
Cord blood; Placenta
Epigenetic Mechanisms Studied:
DNA methylation in target tissues critical for fetal growth
Abstract:
Previous studies on impaired fetal growth have identified multiple risk factors including environmental tobacco smoke (ETS), social stress, lead exposure and air pollution. In parallel, a growing body of literature has demonstrated that all 4 of these risk factors can alter DNA methylation, suggesting a common pathway by which such environmental factors impair fetal growth. The key to understanding the role of environment in impairing fetal growth is to 1) measure environmental risk factors prospectively in pregnancy, to ensure that exposure and subsequent epigenetic changes are temporally associated and 2) to measure epigenetic changes in the correct target tissues. While a case control design may be more efficient, such a design could not tease out whether methylation changes were due to environmental factors or were constitutive in impaired growth. This point is critical as reducing risk by intervening on environmental factors requires knowledge of their mechanisms. To this end, this proposal will utilize the existing infrastructure of the ELEMENT birth cohort study in Mexico and a second ongoing study of similar design in Boston-PRISM. ELEMENT and PRISM have archived umbilical cord vessels and placenta as well as ETS, stress, air pollution and lead exposure measured prospectively beginning in the early 2nd trimester and data on fetal growth. We are therefore uniquely positioned to address these important questions. In this proposal, we hypothesize that common environmental risk factors that impair fetal growth will alter methylomic marks in target tissues critical for fetal growth. Fetal growth depends on maternal transport of nutrients as well as the transport and excretion of toxicants and waste products. Logical target tissues for fetal growth would be tissues of the vascular system (vessels, blood and placenta). Perhaps the greatest strength of our proposal is that we can assess multiple "target tissues" and can compare and contrast 450,000 unique methylation sites across these tissues in the context of environmental exposures. This study will make substantial contributions to our understanding the role of environment in fetal growth.
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Project 1: Prenatal Lead Exposure, Early Childhood Growth, and Sexual Maturation

Parent Title:
Perinatal Exposures, Epigenetics, Child Obesity & Sexual Maturation
Principal Investigator:
Peterson, Karen
Institution:
University of Michigan
Most Recent Award Year:
2010
Lifestage of Participants:
Exposure: Prenatal
Assessment: Youth (1-18 years)
Exposures:
Metals: Lead
Health Outcomes:
Metabolic Outcomes: Obesity/body weight
Reproductive Outcomes: Premature/delayed puberty
Biological Sample:
Cord blood
Other Participant Data:
Maternal bone lead
Genes or Other DNA Products Studied:
Genes associated with early growth (e.g., imprinted loci IGF2 and HI 9; non-imprinted genes IGF2R and 11ss-HSD)
Epigenetic Mechanisms Studied:
DNA methylation
Abstract:
The 'early origins' hypothesis postulates that environmental factors influence plasticity during the perinatal period, altering susceptibility to adult chronic diseases. This emerging field of research points to the epigenome as a modifier of disease susceptibility. Less is known about mechanisms by which adverse exposures in utero may affect physical growth and development during sensitive periods in early and mid-childhood. Among these outcomes, child weight gain and weight status and the tempo of maturation can increase the risk of adult diseases, e.g., diabetes, obesity, cardiovascular disease, and some cancers. Interactions among a representative maternal toxicant, prenatal lead exposure, child growth and epigenetic mechanisms nevertheless remain largely unexplored. Our preliminary studies suggest that the epigenome of the developing fetus can be affected by maternal cumulative lead burden and may influence long-term epigenetic programming. This research project capitalizes on synergies among epigenetics, environmental health and nutrition newly available at the University of Michigan School of Public Health and strengths of the Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT) research collaboration with Mexico's Instituto Nacional de Salud Publica. Longitudinal data on ELEMENT cohorts and new information on physical and hormonal biomarkers of adolescent development will be used to describe the relationship of prenatal lead exposure, assessed by maternal bone lead, to child weight gain and status and to sexual maturation among 200 youth aged 8-17 yr. Examining whether prenatal lead exposure affects cord blood DNA methylation levels in four key genes associated with early growth (imprinted loci IGF2 and HI 9; non-imprinted genes IGF2R and 11ss-HSD) will support consideration of DNA methylation as a mediator the associations of early lead exposure with growth and development. Using prenatal lead exposure as a representative maternal toxicant, this longitudinal study and a P20 pilot study in animals can provide invaluable insights into epigenetic regulation of early exposures affecting childhood health outcomes that confer long term disease risk. The recent emergence of the epigenome as a modifier of perinatal environmental exposures offers a unique opportunity to understand mechanisms that alter susceptibility to adult chronic diseases. This study will yield insights into interactions among in utero exposure to a representative maternal toxicant (bone lead), child growth & maturation and epigenetic mechanisms that confer long-term disease risk.
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Fetal Lead Exposure, Genes, and Neurodevelopment

Principal Investigator:
Hu, Howard
Institution:
University of Michigan
Most Recent Award Year:
2006
Lifestage of Participants:
Exposure: Prenatal; Infant (0-1 year); Youth (1-18 years, specifically up to 2 years of age); Adulthood (mother)
Assessment: Youth (1-18 years, specifically 2-15 years of age)
Exposures:
Metals: Lead
Health Outcomes:
Neurological/Cognitive Outcomes: Attention deficit hyperactivity disorder (ADHD); Neurobehavioral outcomes; Aggression
Biological Sample:
Plasma (mother, child)
Other Participant Data:
Bayley Scales of Mental Development and Cambridge Automated Neuropsychological Test Battery to measure cognition and behavior; Pre-pulse inhibition tests; School performance; Measures of cholesterol metabolism in mother and child
Genes or Other DNA Products Studied:
Polymorphic gene variants of cholesterol metabolism (APOE, lipoprotein E2 receptors, lipoprotein lipase and CYP46)
Abstract:
The Harvard-Mexico Project on Fetal Lead Exposure, Risks and Intervention Strategies (FLERIS), a collaboration between investigators at Harvard University and the National Institute of Public Health in Mexico, has been a model of international teamwork and environmental epidemiology using state-of-the-art methods that won the 1999 NIEHS Progress and Achievement Award. FLERIS established three birth cohorts using similar methods that we continue to follow. In this revised competitive renewal of our R01, we propose to follow-up, collect and analyze new data and samples on all three cohorts and fully capitalize on its rich associated bank of archived data and samples to address two major themes representing novel hypotheses with critical implications for public health: (A) the potential of fetal neurotoxicant exposure to negatively impact on child behavior (aggression and attention deficit/hyperactivity); and (B) the potential for the impact of fetal neurotoxicant exposures on both cognition and behavior to be modified by gene-environment interactions involving candidate genes critical to CNS cholesterol metabolism. Our primary fetal exposure of concern will remain environmental lead exposure, because of its continuing primacy as an environmental hazard in the United States and Mexico. We have chosen specific genes because of growing evidence for the centrality of cholesterol metabolism to neurodevelopment, intriguing preliminary data pointing to cholesterol gene-lead interactions recently published by our group, and new unpublished but supportive data produced for this re-submission. We will also examine several exploratory hypotheses that attempt to develop pre-pulse inhibition as an early predictor of lead's impact on behavior and that assess the potential for measures of maternal circulating cholesterol, maternal dietary cholesterol, and infant 24S-hydroxy cholesterol (a novel plasma biomarker of CNS cholesterol) to modify the lead-gene interactions with respect to cognition and behavior. Finally, we will use our data to compare the relative impacts of prenatal with postnatal lead exposure. This research promises to provide key insights into mechanisms of neurotoxicity, individual susceptibility, and both behavior and cognition as toxic endpoints.
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Metal Mixtures and Neurodevelopment

Principal Investigator:
Wright, Robert O
Institution:
Brigham and Women's Hospital
Most Recent Award Year:
2006
Lifestage of Participants:
Exposure: Prenatal; Adulthood (mother)
Assessment: Youth (1-18 years)
Exposures:
Metals: Arsenic; Lead; Manganese
Mixtures:
Health Outcomes:
Neurological/Cognitive Outcomes: Neurodevelopmental outcomes
Biological Sample:
Blood (mother, child); Cord blood
Other Participant Data:
Behavioral/Cognitive tests
Genes or Other DNA Products Studied:
Iron metabolism gene variants (e.g., HFE, Transferrin, Transferrin receptor, Divalent metal transport protein-1, GST-M1, T1, and P1)
Abstract:
The developing central nervous system is particularly vulnerable to environmental toxicants. While lead poisoning has been extensively studied and public health measures to reduce exposure implemented, exposure is still high in some populations. Other toxic metals (arsenic and manganese for example) remain elevated in the environment, and the effects of arsenic and manganese on neurodevelopment remain poorly understood. Critical questions also remain regarding individual differences in susceptibility to metals (even lead) and whether combinations of neurotoxicants are synergistically toxic. Given this, the effect of joint exposure to combinations of metals is a critical public health issue, as this exposure scenario is more reflective of the real world situation. The role of iron metabolism genes, which may regulate the metabolism of multiple neurotoxic metals, may also play a key role in understanding the mechanisms by which metal mixtures produce neurotoxicity. In this project we will establish a new birth cohort in Mexico City to measure biomarkers of internal dose for manganese, arsenic and lead and analyze their interactions in predicting associations between metal exposure and neurodevelopment. Furthermore, we will study the modifying effects of iron metabolism gene variants (HFE, Transferrin, Transferrin Receptor, and Divalent Metal Transport Protein-1) on the neurotoxicity of these metals and their influence on placental transfer of metals. We will also explore the effect of variants in the GST-M1, T1 and P1 genes on Arsenic neurotoxicity. Our research team is particularly well situated to conduct this work as we have a long-standing collaboration with the National Institute of Public Health in Mexico, enabling us to quickly assemble highly skilled field teams for sample collection and phenotyping. Furthermore, our pilot data suggest that exposure to Mn, As and Pb are elevated in the target population, and that biomarkers of internal dose may be associated with poorer developmental outcomes.
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