Pilot Projects Awarded 2019

Title of Project: Manganese exposure, neuroimaging phenotypes, and gut-microbiome interactions: a pilot study

Principal Investigator: Cheuk Ying Tang, PhD

Co-Investigators: Roberto Lucchini, MD; Jianzhong Hu, PhD; Donatella Placidi, MD; Simona Fiorentini, MD; Andrea L. Deierlein, MPH, PhD; Megan Horton, PhD

Project Period: February 1, 2019 – January 31, 2020

Pilot Award Amount: $70,000


Abstract: Several ongoing studies are investigating the effects of environmental exposure to metals such as Manganese, lead and chromium on human cognition using brain imaging biomarkers and neuropsychological test batteries. In recent years an abundance of research has highlighted the important relationship between the brain and the gut-microbiome. The eubiosis of the gut-microbiome helps in digestion and general balance of neurotransmitters whereas a dysbiosis can lead to depression and other psychiatric conditions. There are limited reports on the effects of environmental toxins on the gut-microbiome. In this proposal we will analyze the relationship between microbiota composition, neuroimaging biomarkers and cognitive assessments in exposed and non-exposed subjects. To study these relationships we will analyze the gut-microbiome of the subjects that are part of one of our ongoing study: Public Health Impact of Manganese Exposure (PHIME). The PHIME study is currently in its second phase where neuroimaging biomarkers are being obtained using MRI. These subjects are from three well-characterized communities in Northern Italy that differ in the timing and intensity of environmental manganese exposure from current or historic ferromanganese alloy plant operations. Other readily available data on these subjects include neuropsychological assessments and extensive imaging scans. This proposal is to request funds to obtain fecal samples, perform sequencing and microbiome analysis. We will be able to leverage all the other readily available data as all collaborators on this application are also co-investigators of the PHIME study. The goal is to investigate the multidimensional relationships between exposure from early life to adolescence, cognition, imaging biomarkers, and the gut microbiome.

Title of Project: Metabolomics analysis to identify functional groups of multiple endocrine disruptor chemical exposures and their associations with childhood growth and development

Principal Investigator: Lauren Petrick, PhD

Co-Investigators: Susan Teitelbaum, PhD; Mary Wolff, PhD; Boris Reva, PhD

Project Period:  February 1, 2019 – January 31, 2020

Pilot Award Amount: $25,000


Abstract: Endocrine disruptor chemicals (EDs) have been associated with alterations in pubertal timing and somatic growth linked with breast cancer risk. However, investigations on the underlying disruptions of metabolic and biologic response pathways have not been undertaken. Furthermore, the effects of multiple ED exposures on pubertal outcomes during adolescence are unknown, even though exposures actually occur as integrated mixtures which may have profoundly different biological impacts as those investigated with a single exposure model. Using plasma from 171 girls in the Growing Up Healthy (GUH) cohort at Mount Sinai, we intend to identify metabolomic profiles associated with multiple exposure groups and outcomes. The GUH cohort is well characterized with over 30 exposure biomarkers and recall exposure data. Because many of the well-studied individual environmental chemical exposures have been found to have similarities in their biological function/activity, we propose to examine whether the combined effect of these similarly functioning chemicals, as multiple-exposure groups, can identify metabolites and mechanistic pathways associated with multiple real-life exposures. We are leveraging pilot funding (CHEAR PF08) for metabolomics analysis on 66 samples from this cohort, and will use this proposal for metabolomics analysis of an additional 105 samples (n=171). With this proposal we intent to 1) evaluate the feasibility of using multiple-exposure groupings to identify metabolomic biomarkers of ED exposure, 2) assess the viability of using these groupings to predict functionality, and 3) generate data on the relationship of identified biomarkers with somatic growth and age of menarche. This pilot data will be used to develop an R01/R21 emphasizing longitudinal metabolomics discovery during this important window of susceptibility of adolescent development in the expanded Breast Cancer and Environment Program (BCERP) national cohort of 1231 girls for whom we have comparable and harmonized data.

Title of Project: Prenatal time windows of vulnerability to interactions of phthalates and allostatic load among low-income women
Principal Investigator: Shelley H. Liu, PhD

Co-Investigators: Julie Spicer, PhD; Annemarie Stroustrup, MD

Project Period:  February 1, 2019 – January 31, 2020

Pilot Award Amount: $25,000


Abstract: Pregnancy is a vulnerable time for all women. But the stakes are even higher for low-income women, who are at greater risk of adverse infant outcomes such as preterm birth. A variety of factors likely contribute to this disparity. Here, we study how environment and stress interact across critical time windows of pregnancy to jointly impact infant outcomes for low-income women. Specifically, we study phthalates, a plasticizer ubiquitous to daily life, with higher exposures in low-income women, and linked to preterm birth. We hypothesize that short-term exposure to phthalates at critical time windows of pregnancy, coupled with long-term dysregulation of multiple inter-related physiological systems due to chronic stress (biologically manifested as allostatic load), can place certain pregnant women at greater risk of adverse infant outcomes. To our knowledge, the interaction of phthalates and allostatic load has not been studied. We capitalize on a new cohort – the Pregnancy, Stress and Infant Outcomes study (PreSIO; PI: Spicer, 5R00HD079668-04; n=68). PreSIO just began enrolling low-income pregnant women at the Mount Sinai Ambulatory OB/GYN practice (10 already recruited). Currently, no environmental exposures are collected in PreSIO; thus, it provides a unique opportunity to fulfill the P30 Center’s mission on increasing the environmental health research portfolio at Mount Sinai. In Aim 1, we collect phthalate metabolites at two prenatal windows (16-21 weeks, 22-29 weeks), and investigate time-varying and cumulative effects of prenatal phthalate exposure on infant outcomes (gestational age at birth, birthweight). In Aim 2, we develop a statistical method to model interactions of phthalate mixtures and allostatic load mixtures, and use it to investigate if allostatic load moderates the association between phthalates and infant outcomes. This pilot will lay the groundwork for future R21/R01 applications in line with NIEHS 2018-2023 Strategic Plan priorities, to study individual susceptibility to environment-stress interactions and reduce health disparities for low-income women.

Title of Project: Improving identification of home-based environmental exposures and social stressors in at-risk families in East Harlem: a community based participatory project
Principal Investigator: Elizabeth J. Garland, MD, MS

Co-Investigators: Erin Thanik, MD, MPH; Elizabeth Howard, MD; Carlos Melendez, PhD; Emily Moody, MD, MS; Luz Claudio, PhD; Maida Galvez, MD, MPH

Project Period:  February 1, 2019 – January 31, 2020

Pilot Award Amount: $25,000


Abstract: This project improves infrastructure and assessment tools at LSA Family Health Services (LSA), a community based organization in East Harlem, and integrates environmental health screening into assessment of high risk families. This community based participatory research project is aligned with the NIEHS Partnerships in Environmental Public Health mission of increasing impacts of emerging research by translating science into programs and policies that prevent and reduce exposures, particularly for high poverty communities who are disproportionately burdened by environmental exposures. With expert support of P30 faculty, input will be provided to LSA on enhanced data capture and management allowing us to work together to examine the association between environmental factors, social stressors and adverse child outcomes. The objectives are: 1) develop a database to capture social stressors and home environmental risks and health outcomes in families served by LSA, 2) identify gaps and redundancies in existing health assessment tools and 3) design an environmental assessment tool. We will conduct semi-structured interviews with LSA public health nurses on codifying anecdotes and client interactions into meaningful assessments, in-agency referral mechanisms and design interventions. We will attend a LSA mothers’ group to discuss environmental concerns and identify themes. Collaboration with LSA will inform new database development to ensure it meets needs for program evaluation and health outcomes research. The new database will be populated with retrospective data for data analysis.This project is innovative as it advances clinical practice of environmental risk identification to improve child health outcomes through enhanced assessment and sets the stage for improved home-based interventions.The innovation is in development of a home-environmental risk assessment tool that addresses gaps and further informs design of replicable home-based interventions. Ultimately, linking identified environmental risks with home-based interventions improves health outcomes while addressing social determinates of health,environmental health disparities and environmental justice.

Title of Project: Impact of maternal prenatal stress on composition and function of the infant microbiome

Principal Investigator: Rebecca Campbell, PhD

Co-Investigators:Chris Gennings, PhD; Andrea Baccarelli, MD, PhD (Columbia); Supinda Bunyavanich, MD

Project Period:  February 1, 2019 – January 31, 2020

Pilot Award Amount: $25,000


Abstract: Maternal prenatal psychosocial stress is common, especially in women of low socioeconomic status,with negative consequences for child neurocognitive development. How prenatal stress impacts child neurodevelopment, and why effects are often sex-specific, is not clear, but accumulating preclinical evidence points to the microbiome. An abnormal early-infancy intestinal microbiome can have long-term health consequencessimilar to those of prenatal stress, including immune and metabolic dysfunction and neurocognitive delays. Prenatal stress disrupts normal maternal microbiome shifts during pregnancy, impactingthe microbes that the infant receives at birth.Sex differences in the intestinal microbiome existin infancy and possibly even in the pregnant woman’s microbiome. Thus,the early-infancy intestinal microbiome may yield valuable new insights into intergenerational and sex-specific transmission of prenatal stress. We will investigate compositional and functional characteristics of the infant microbiome within an ongoing multiethnic urban cohort study with comprehensive, high-quality assessments of maternal stress. Stress exposures in pregnant women,including life stressors, trauma history and psychological function,are assessed with validated questionnaires,and hair cortisol measured.Childhealth outcomes including cognitive function are assessed frominfancy through mid-childhood. In this pilot, we will analyzestool samples from a subsample of cohort participants (n=50) at age two weeks, extracting bacterial DNA and RNA for 16S sequencing and transcriptomic analysis, respectively. Stress-associated differences in 16S gene diversity and composition and metagenome expression will be analyzed,and sex-specific effects examined. This proposed pilot will investigate the early-infancy intestinal microbiome as a novel propagator of prenatal stress effects on child health. We will generate preliminary data verifying the feasibility of detecting stress effects on the infant intestinal microbiome, which will support a future study of theroleof the infant intestinal microbiome in prenatal stress effects on child cognitive development. Additional prenatal co-exposures and child health outcomes could be investigated in the future.

Title of Project: Ambient air pollution, lipidomics, and overweight/obesity in an Italian adolescent cohort

Principal Investigator: Elena Colicino, PhD; Megan Niedzwiecki, PhD (Multi-PI)

Co-Investigators: Robert Wright, MD; Roberto Lucchini, MD; Itai Kloog, PhD; Massimo Stafoggia

Project Period: February 1, 2019 – January 31, 2020

Pilot Award Amount: $25,000


Abstract:In the last three decades, the prevalence of overweight and obesity in adolescents tripled. Currently, half of US adolescents are overweight or obese, and rates are increasing around the world, including Italy. Environmental conditions, including ambient air pollution (particulate matter with diameter ≤2.5 μm [PM2.5]), might contribute to the development of overweight and obesity. Air pollution exposure has been shown to affect cellular and systemic lipid processes and lead to abdominal adiposity in adults, but little is known about these relationships in adolescents.Adolescence is a critical developmental period in which the levels, compositionand metabolism of lipids undergo alterations due to major hormonal changes. We hypothesize that adolescents may be more susceptible to lipid perturbations by ambient air pollution. However, the limited availability of lipid biomarkers that reflect detrimental environmental exposures and predict early obesity risk limits opportunities for prevention and therapeutic interventions. To address this gap, we aim to identify novel lipidomic biomarkers that link long-­term exposure to PM2.5 with obesity. We will use plasma lipidomics—a characterization of lipid species, metabolic pathways and networks—to reveal environmentally-­driven alterations of lipid composition and abundance that underlie the onset and progression of adolescent obesity.Our overall goal is to determine whether long-­term exposure to PM2.5is associated with lipidomic alterations that contribute to overweight and obesity in adolescents. We will leverage the prospective Public Health Impact of Mixed element Exposure (PHIME) cohort of 665 adolescents (11-­21 years) living in the greater area of Brescia, Italy. We have daily measurements of PM2.5 since 2006. We will use advanced statistical methods to analyze lipidomics profiles in relation to (i) long-­term metrics of ambient PM2.5 and (ii) BMI, overweight,and obesity.


Pilot Projects Awarded 2018

Title of Project: High dimensional immune profiling of the response to prenatal air pollution
Principal Investigator: Cecilia Berin, PhD

Co-Investigators: Rosalind J. Wright, MD; Chris Gennings, PhD

Project Period: July 2, 2018 – July 1, 2019

Pilot Award Amount: $70,000


Abstract:Prenatal exposure to chemical (air pollution) and non-chemical (psychological) stressors have a negative  impact on child health including birth weight, neurodevelopment, and atopy/asthma. There is a lack of understanding of the mechanistic link between exposure and child health outcome. The immune system is thought to be a key mediator. Immune cells sense and respond to particulate matter (PM) or neuroendocrine signals, and immune processes are critical for diverse health outcomes including atopy, obesity, cardiovascular disease, and psychological function. Studies to date have measured selected serum biomarkers (C-reactive protein, IL-6) and tested for association with exposure. Alternatively, transcriptomics or epigenomics of placenta or cord blood has been performed. This provides the opportunity for discovery research, but provides no information on cell source or confirmation of protein expression. Multi-parametric approaches for immune profiling such as CyTOF provide the opportunity to quantify and phenotype all cells in peripheral blood simultaneously, at single cell resolution, and to examine a dynamic response to immune perturbation. This provides a much richer dataset that is more likely to convey functional changes that underlie susceptibility to immune-mediated disease. We propose to use the existing PRISM cohort to recruit 30 mother-infant pairs. Paired maternal blood and cord blood specimens will be obtained for immune profiling studies. The PRISM cohort collects detailed information on exposure to chemical and non-chemical stressors, including PM2.5. We will use CyTOF and Olink targeted immune proteomics to provide a detailed description of the immune system status at homeostasis and in response to immune and neuroendocrine stimulation. These studies will utilize  the Phenotyping and Environmental Modifiers Facility Core (Co-I Rosalind Wright) and the Biostatistics and Bioinformatics Facility Core (Co-I Chris Gennings). The data from this pilot study will be used to support a multi-PI R01 application to NIH PAR-18-333 (Understanding the Early Development of the Immune System).

Title of Project: Prenatal programming of the male vulnerability phenotype
Principal Investigator: Whitney Cowell, PhD

Co-Investigators: Rosalind J. Wright, MD; Jia Chen, ScD; Elena Colicino, PhD

Project Period: July 2, 2018 – July 1, 2019

Pilot Award Amount: $20,000


Abstract:Prenatal exposure to chemical (air pollution) and non-chemical (psychological) stressors have a negative  impact on child health including birth weight, neurodevelopment, and atopy/asthma. There is a lack of understanding of the mechanistic link between exposure and child health outcome. The immune system is thought to be a key mediator. Immune cells sense and respond to particulate matter (PM) or neuroendocrine signals, and immune processes are critical for diverse health outcomes including atopy, obesity, cardiovascular disease, and psychological function. Studies to date have measured selected serum biomarkers (C-reactive protein, IL-6) and tested for association with exposure. Alternatively, transcriptomics or epigenomics of placenta or cord blood has been performed. This provides the opportunity for discovery research, but provides no information on cell source or confirmation of protein expression. Multi-parametric approaches for immune profiling such as CyTOF provide the opportunity to quantify and phenotype all cells in peripheral blood simultaneously, at single cell resolution, and to examine a dynamic response to immune perturbation. This provides a much richer dataset that is more likely to convey functional changes that underlie susceptibility to immune-mediated disease. We propose to use the existing PRISM cohort to recruit 30 mother-

Title of Project: Lead Exposure and Kidney Function in Genetically Susceptible Ethnic Minorities: A Pilot Study (CBPR)
Principal Investigator: Girish Nadkarni, PhD

Co-Investigators: Robert Wright, MD; Andrea Baccarelli, MD, PHD (Columbia); Joel Schwartz, PHD (Harvard)

Project Period:  July 2, 2018 – July 1, 2019

Pilot Award Amount: $20,000


Abstract: Chronic kidney disease (CKD) affects up to 15% of the US population; persons of African ancestry (AAs) have threefold times the prevalence than people of European ancestry (EAs). Reasons for this disparity are multifactorial, and include genetic, socioeconomic, environmental and healthcare factors. Recent discoveries reveal that a significant proportion of this disparity is genetic. High risk Apolipoprotein L1 (APOL1) genotypes, found nearly exclusively in AAs are associated with a ten-fold higher risk of end stage renal disease (ESRD).2 However, only not all individuals with APOL1 highrisk genotype develop kidney disease, indicating suggesting a role for environmental modifiers. There is an established link between cumulative heavy metal exposure, particularly lead, and incidence and progression of CKD. There are also substantial disparities in lead exposure between AAs and EAs due to differing environmental exposures. This raises the interesting hypothesis that cumulative lead exposure and APOL1 genotype may interact (a gene-environment interaction) for the outcome of CKD. We propose to explore this hypothesis using the unique BioMe biobank and the resources of the Mount Sinai Transdisciplinary Center on Health Effects of Early Environmental Exposures. This study will be conducted in full partnership with our community board who have been conducting APOL1 research for 4 years, and have specific interest in gene-environment interactions, will be full partners in the conduct, analysis and dissemination of this study. This pilot study will allow us to explore the ‘second-hits’ needed for CKD to develop in persons with high-risk APOL1 genotype and generate valuable preliminary data and sample size needs for a grant proposal to more fully elucidate geneenvironmental influences on development of kidney disease and related racial-disparities in a much larger population. This may lead to improved insights, enabling us to target the persistent disparities in renal disease.

Title of Project: Effect of Gestational Exposure to Fine-size Particulate Matter 2.5 on Placental Gene Expression in Relation to Birth Weight
Principal Investigator: Jia Chen, ScD

Co-Investigators: Judith Zelikoff, PhD (NYU); Carmen Marsit, PhD (Emory)

Project Period:  July 2, 2018 – July 1, 2019

Pilot Award Amount: $20,000


Abstract: Numerous epidemiological and animal studies have demonstrated that exposure to ambient fine particulate matter <2.5um in diameter (PM2.5) during gestation is associated with adverse obstetric outcomes like preterm birth, intrauterine growth restriction and deviation from normal birth size. The placenta provides the crucial link between the intrauterine environment and fetal growth/development. We have previously demonstrated that dysregulation of gene expression in placenta was associated with abnormal fetal growth both under- and over-growth. However, how the placenta genome responds to environmental stimuli, such as PM2.5, is much less known. The present study aims to investigate causal relationships between PM2.5 exposure and changes in the placental transcriptome and whether disruption of the transcriptome is subsequently linked to changes in birth weight (BW). We will employ a hybrid study design combining a mouse model and a population study. First, the placental transcriptome from mice exposed to concentrated ambient PM throughout the full term of gestation will be profiled by RNAseq; co-expression gene networks will be constructed by weighted gene co-expression analysis (WGCNA). The PM2.5 -responsive genes in the mouse model will be validated in human placentas obtained from the Rhode Island Child Health Study (RICHS), a population-based birth cohort, using RT-PCR. We will also evaluate how placental gene expression mediates the association between maternal PM exposure and BW in the RICHS. Understanding the mechanisms by which PM2.5 alter the placental transcriptome leading to abnormal growth is invaluable in developing interventions to offset the impact of exposure.

Title of Project: Does study participation and receiving feedback on her child’s EDC exposure alter mother’s risk perception and behavior?
Principal Investigator: Sarah Evans, PhD

Co-Investigators: Shanna Swan, PhD; Emily Barrett, PhD; Katrina Korfmacher, PhD

Project Period:  July 2, 2018 – July 1, 2019

Pilot Award Amount: $20,000


Abstract: Perception of risks posed by environmental exposures influences behaviors that affect those exposures. Interventions that modify risk perception should therefore lead to behaviors that result in reduction of potentially harmful exposures. In this pilot study we will investigate whether participation in The Infant Development and Environment Study (TIDES), a multicenter prospective birth cohort study designed to assess associations between phthalate and other chemical exposures and child development, modifies environmental risk perception and behaviors and whether mother’s behaviors impact child phthalate exposures. We will also explore whether knowledge of one’s child’s urinary phthalate levels increases behaviors that have the potential to reduce exposure. 50 subjects will be randomly selected from families enrolled in the TIDES study at University of Rochester Medical Center who completed a first trimester environmental risk survey and whose child provided urine at age 4 and asked to complete the same survey they completed during pregnancy. Half of subjects will be given their child’s 4-year urinary phthalate metabolite levels plus aggregate data from the pilot cohort, and half will receive aggregate data only. All subjects will receive information on phthalate health effects and exposure reduction strategies. After three months, subjects will be re-surveyed about their attitudes and behaviors towards environmental risk and pre- and post-intervention responses compared. Responses given before the receipt of phthalate data will be compared to responses given during pregnancy. We hypothesize that perception of risk and frequency of exposure-reduction behaviors will have increased since pregnancy, in part due to continued participation in TIDES and that knowledge of child phthalate exposure will lead to a further increase in exposure-reduction behaviors. Findings from this pilot will be used to improve the usability and efficacy of biomonitoring report-back methods and provide pilot data to support a R21 application to expand this study to the entire TIDES cohort.

Title of Project: Lead exposure during pregnancy, serum metabolomics, and postpartum
Principal Investigator: Megan Niedzwiecki, Lauren Petrick (Multi-PI)

Co-Investigators: Robert Wright, MD; Elena Colicino, PhD

Project Period:  July 2, 2018 – July 1, 2019

Pilot Award Amount: $20,000


Abstract: Lead (Pb) exposure is associated with detrimental health effects, even at low levels. While the neurotoxiceffects of Pb exposure during pregnancy have been widely studied in children, the neurotoxicity of Pb during this critical window in mothers is not well delineated, especially in postpartum depression (PPD), a serious mental condition affecting 10-­20% of new mothers. Further, there remains a great need to identify novelbiomarkers of Pb exposure to better understand mechanisms of Pb-­mediated toxicity. The application of untargeted high-­resolution mass spectrometry (HRMS), in which thousands of metabolites are simultaneously measured in a biospecimen, holds great promise for this task, but challenges in HRMS metabolite identification have restricted the widespread application of HRMS in epidemiological studies. We expect that employing an integrated approach to identify the biological response to Pb exposure with HRMS will uncover novel metabolites and/or metabolic pathways associated with Pb toxicity and PPD risk. To address this, we first propose a novel bioinformatics workflow for metabolite identification of untargeted HRMS data in which MS1-­based accurate mass identifications are paired with MS2 data-­independent acquisition (DIA), which will improve the speed and accuracy of annotation. This method will be integrated into the Integrated Health Sciences Facility Core (IHSFC) Lab methods for use in future Center studies and distributed to the public. Second, we will identify metabolomic signatures of prenatal Pb exposure in serum
samples collected during the 2nd and 3rd trimesters from mothers enrolled in the Programming Research on Obesity, GRowth, Environment and Social Stress (PROGRESS) cohort in Mexico City, a region with a wide range of Pb exposures. Identifications of Pb-­associated metabolites will be aided by our MS1/DIA approach. Further, we will look for metabolomics signatures of PPD diagnosed 6 months and 1 year postpartum, as well as associations of Pb and Pb-­associated metabolites with PPD.

Title of Project: Structural and functional brain imaging in ferromanganese workers to assess the impact of manganese exposure on neurophenotypes from early life to adulthood

Principal Investigator: Roberto Lucchini, MD

Co-Investigators: Robert Wright, MD; Cheuk Tang Ying, PhD; Megan Horton, PhD; Elena Colicino, PhD; Donatella Placidi, MD; Roberto Gasparotti, MD

Project Period:  July 2, 2018 – July 1, 2019

Pilot Award Amount: $20,000


Abstract:Cognitive functioning can be impacted by exposure to neurotoxicants occurring from early life to the old age, with major public health implications. Manganese exposure can cause cognitive impairment in early life and memory dysfunctions in adults, by targeting critical brain areas including frontal and parietal cortex, and the caudate nucleus in the striatum. High quality neuroimaging tools provide insights on the structural and functional changes associated with environmental exposures. In this proposal we will assess cognitive functioning in workers with lifetime exposure to manganese and other metals, and with extensive longitudinal air monitoring data, biomarkers and neurofunctional testing. Structural and functional brain magnetic resonance imaging will be used to assess the association of cumulative exposure with the neuroimaging phenotypes. Functional cognitive assessment will be also piloted, using MoCA (Montreal Cognitive Assessment), CogState and novel testing batteries, such as the NIH toolbox, to examine the association with the neuroimaging phenotypes. The presence of amyloid deposition will be tested using PET scan, as a highly innovative exploratory aim. To our knowledge this is the first study exploring β-amyloid brain deposition as a predictor of clinical neurodegenerative disease in manganese exposed individuals. Teeth will also be collected from the workers to assess lifetime and exposure and different exposure windows through laser ablation ICPMS analysis. With this proposal, we will leverage the existence of the multiple cohorts of the PHIME (Public Health Impact of Metal Exposure) study, which includes different age groups residing in the same impacted areas in Italy, and extend our current imaging studies on adolescents to the adult workers’ cohort. This pilot study will yield preliminary data for larger grant applications, which will further increase the available data of the PHIME study on metal exposure and neurological impacts from early life to the old age.

Title of Project: Metal exposure, Brain Autoantibodies in pregnancy and child

Principal Investigator: Uri Laserson, PhD; Elena Colicino, PhD (Multi-PI)

Co-Investigators: Robert Wright, MD

Project Period:  July 2, 2018 – July 1, 2019

Pilot Award Amount: $20,000


Abstract:The role of neuroimmunology and anti-brain autoantibodies in the pathogenesis of developmental disorders such as autism and schizophrenia has recently become a topic of intense interest. Concurrent to this work, neurotoxic metals such as lead and mercury have been linked to these diseases, as well as to the development of anti-brain autoantibodies. Despite these hints in the literature, no prior study has prospectively assessed lead and mercury exposure in pregnancy, linked them to the development of autoantibodies nor determined whether this represents a mechanistic pathway explaining the metals’ neurotoxicity. In this proposal we will use the phage immunoprecipitation sequencing (PhIP seq) assay to comprehensively measure antibodies against all possible autoantigens in maternal serum collected during pregnancy in the PROGRESS longitudinal birth cohort. We will test associations of these autoantibodies with blood lead and mercury exposure as well as with measures of executive function and IQ in children between ages 4-6. PROGRESS has been ongoing since 2007, and all neurobehavioral data and necessary biosamples already exist, rendering this study highly cost- and time-efficient. Data generated through this project will serve for both future publications and, most importantly, for a future R01 proposal expanding these measures to multiple time points and testing the relationship with metal mixtures. The multi-PI’s are early stage investigators with expertise in immunology and biostatistics. The proposal uses all 3 facility cores of the P30 Center as well.

Pilot Projects Awarded 2017

Title of Project: “Air Pollution Exposure During Pregnancy and Sleep Health in Childhood”
Principal Investigator: Sonali Bose, MD MPH

Co-Investigators: Rosalind J. Wright, MD

Project Period: October 2017 – September 2018

Pilot Award Amount: $50,000


Abstract: In utero exposure to ambient air pollution may have adverse effects on fetal growth and development, increasing the risk of a variety of health disorders in childhood. Using novel hybrid satellite- and ground-based exposure methods to estimate daily pollutant exposures at high spatial resolution in a longitudinal birth cohort, we have previously demonstrated that exposure to particulate air pollution during specific periods of gestation is linked to adverse respiratory and neurocognitive outcomes in childhood, potentially through mechanisms involving immune, inflammatory, and autonomic pathways. However, less is known regarding the direct influence of prenatal air pollution upon sleep quality in children, which may occur through similar inflammatory or autonomic processes. While limited epidemiologic studies do suggest that airborne pollutant exposures are associated with alterations in sleep patterns in several populations, none have specifically examined the early life period, when sleep is most critical for growth and development. Indeed, inadequate sleep has already been linked to a range of health problems in childhood and later life, highlighting the need for a better understanding of environmental risk factors for altered sleep in early childhood. We propose a feasibility pilot, in which we will leverage our existing prenatal pollutant exposure models and ongoing longitudinal birth cohort to determine optimal methods of assessing sleep in a subset of preschool children. Within the parent study, we will add subjective and objective measurements of sleep variables through validated questionnaires, 24-hour accelerometers, and EEG-based polysomnographic testing, as well as in-home measures of autonomic function (e.g. low-frequency heart variability and respiratory sinus arrhythmia) during sleep, to inform a larger study powered to examine associations between sleep patterns and air pollution. Ultimately, we predict that children with higher prenatal particulate matter exposure will have reduced sleep duration, increased sleep disturbances, and/or heightened autonomic dysfunction, compared to less exposed children.

Title of Project: Biomarkers of Lead Exposure and a Novel Form of DNA Methylation in the Human Genome
Principal Investigator: Gang Fang, PhD

Co-Investigators: Robert Wright, MD; Andrea Baccarelli, MD, PHD (Columbia); Joel Schwartz, PHD (Harvard)

Project Period: October 2017 – September 2018

Pilot Award Amount: $50,000


Abstract: DNA methylation at 5-methylcytosine (5mC) is a well-known epigenetic mark that regulates gene expression. Recent research by our group identified N6-methyladenine (N6mA) in human DNA as a newly discovered epigenetic mark that also regulates gene expression, in particular transposable element expression. There is a growing interest in the role of transposable elements in predicting health effects as their expression would induce predictable cellular toxicity. Increasing evidence suggests that changes in methylation of the transposable element LINE-1 (L1) secondary to environment exposures may have significant impacts on health. Thus L1 expression and its epigenetic marks have great potential for the development of novel epigenetic biomarkers. Our lab recently contributed to the discovery of N6mA in mouse genome, while also demonstrating that it is over represented in regulatory regions of L1s. Before this study, the prevailing dogma was that N6mA exclusively occurs in unicellular organisms. Since this breakthrough, our lab has been leading the genome-wide N6mA mapping in humans revealing that N6mA events are enriched at L1s. This exciting discovery motivated this application, in which we aim to achieve three milestones. First, we will examine the whether N6mA methylation at L1 is responsive to environmental exposures by quantifying their relationship with lead exposures rigorously measured in bone and blood in multiple cohorts at different life stages. Lead is a paradigm toxicant and has already been shown to alter 5mC levels in L1 making it a logical starting point for this work. Second, we will characterize the relationship between the two forms of DNA methylations (N6mA and 5mC) in their joint association with lead exposure. Third, to discover more precise biomarkers, we will develop a genomics method that can simultaneously map N6mA and 5mC events on individual L1s in order to perform high- resolution association analysis between both forms of methylations and lead exposure.

Title of Project: Development of a novel genome-wide method for mapping UV-induced DNA lesions
Principal Investigator: Aneel Aggarwal, PhD

Co-Investigators: Gang Fang, PhD

Project Period: October 2017 – September 2018

Pilot Award Amount: $20,000


Abstract: Exposure to UV radiation is a major detriment to human health. However, despite the known etiological effects of UV exposure, methods for detecting initial UV-DNA damage and the mutational processes that follow are severely limited. There is an urgent need for a high-throughput method that can directly detect UV-DNA damage at the genome level in human cells. Our long-term goal is to develop a method that will permit direct detection of UV radiation-damaged DNA bases at a single nucleotide resolution based on damaged DNA immunoprecipitation (DDIP) followed by single-molecule, real-time (SMRT) DNA sequencing. The development of the method depends critically on the ability to enrich for damage- containing genomic DNA fragments. We propose here a method based on the use of bacteriophage T4 endonuclease V (EndoV) to enrich for UV-damaged DNA. Specifically, DNA from melanocytes exposed to UV radiation will be isolated, sheared, and enriched for UV-induced lesions by EndoV. A catalytically deficient mutant (E23Q) of EndoV will be expressed, purified, and conjugated with magnetic beads for pull- down of DNA fragments containing UV-induced lesions. These enriched DNA fragments will be directly used for SMRT DNA sequencing of both strands for detection of DNA lesions based on the kinetic “signature” that we have already derived. The development of DDIP-SMRT seq will have a major impact on our ability to directly assess the effects of UV-radiation and other environmental DNA damaging agents on cellular DNA and will form the basis of an R01 application to NIEHS.

Title of Project: Exploring Transcriptome and Endocrine Effects of Glyphosate-based Herbicides in Early Life
Principal Investigator: Corina Lesseur, MD, PhD; Jia Chen, ScD (Multi-PI)

Co-Investigators: Susan L Teitelbaum, PhD

Project Period: October 2017 – September 2018

Pilot Award Amount: $20,000


Abstract: Glyphosate is the most commonly used herbicide worldwide. Human exposures to glyphosate-based herbicides (GBHs) are rising rapidly as their presence in water and food grows. There is significant controversy regarding the safety of GBHs due to conflicting findings. Most of the current knowledge comprises studies performed in adults with particular focus on cancer; little data exist on potential effects of GBHs in children and on non-cancer outcomes. Moreover, traditional risk assessment studies have not interrogated GBHs as complex chemical formulations (e.g., Roundup® weed killer) that could be more toxic than glyphosate alone. Thus, there is an impending need to investigate possible health-related effects of chronic exposure to low-level glyphosate alone and GBH formulations especially during highly susceptible windows of development from the in utero period to early adulthood. We hypothesized that chronic low-level exposure to glyphosate or Roundup® during fetal development through early adulthood results in detectable changes in the transcriptome of multiple target tissues (brain, kidney and liver) as well as imbalances of plasma pituitary hormones. We will leverage banked samples from an existent study that exposed Sprague-Dawley rats to glyphosate or Roundup® through drinking water from gestation day 6 to post-natal day 70. The exposure dose used, 1.75mg/kg bw/day, is relevant to human exposure levels and corresponds to the “acceptable daily intake” (ADI) for glyphosate in the US. Our approach has multiple strengths: 1) we will obtain information on multiple tissues and endocrine markers to assist on a comprehensive evaluation of GBHs safety; 2) we will evaluate the effects of glyphosate and GBH exposure using a relevant dose during a sensitive exposure window.

Title of Project: Examining windows of vulnerability for prenatal heavy metal programming of infant autonomic function

Principal Investigator: Ashley J Malin, PhD; Rosalind Wright, MD, MPH (Multi-PI)

Co-Investigators: Ghalib Bello, PhD

Project Period: October 2017 – September 2018

Pilot Award Amount: $20,000


Abstract:Heavy metal exposures have been linked to autonomic dysfunction and consequent cardiovascular risk in adults. However, the effects of such exposures on the developing autonomic nervous system (ANS) are less understood. Therefore, in the current study we aim to examine the impact of prenatal heavy metal exposure on infant cardio-respiratory functioning. Additionally, in testing this relationship we aim to identify windows of vulnerability for heavy metal programming of infant autonomic function. In addition, maternal prenatal stress has been linked with infant ANS programming. Therefore, we will also explore whether maternal stress modifies effects of prenatal heavy metal exposures on infant ANS functioning.

We will measure a panel of metals (including: arsenic, lead, mercury, cadmium, aluminum, manganese, chromium and cobalt) in maternal hair at delivery using novel methods that reconstruct exposure over gestation implemented using laser ablatation inductively coupled plasma mass spectrometry (LA-ICP-MS). Additionally, we will validate hair metal biomarkers against metal levels in maternal whole blood at 26-28 weeks gestation. LA-ICP-MS provides weekly exposure estimates over pregnancy. It will be coupled with data driven statistical methods to identify windows of vulnerability by testing the relative impact of heavy metal exposures at different prenatal time points on infant ANS function (assessed at rest and during an in-laboratory stressor at 6 months) using the BioRadio Wireless Physiology Monitor (Great Lakes NeuroTechnologies, Cleveland, OH). Analyses will consider ANS parameters including respiratory sinus arrhythmia (RSA, uncorrected and corrected for respiratory rate and tidal volume), and T-wave amplitude (TWA). Maternal lifetime stress will be measured using the Life Stressor Checklist Revised (LSC-R) administered prenatally.

We expect our findings to enrich our understanding of early life environmental factors that contribute to ANS dysfunction. Furthermore, we anticipate that the invaluable information obtained regarding windows of vulnerability will have important implications for prevention and treatment of cardiorespiratory disorders

Title of Project: Development of Placental Cell Culture System to Test Metal Mixture- Induced Perturbations in Placental Function
Principal Investigator: Maya Deyssenroth, DrPH; Jia Chen, ScD (Multi-PI)

Co-Investigators: Chris Gennings, PhD; Ke Hao, ScD

Project Period: October 2017 – September 2018

Pilot Award Amount: $20,000


Abstract: Using a systems biology approach, we recently delineated the transcriptome-wide gene network and identified unique network modules, enriched for genes involved in gene expression and metabolic hormone secretion, in the human placenta. We also reported perturbations of some of these modules in fetal growth restriction. Concurrent efforts are also being made to develop innovative means to integrate whole-genome network data and exposure data to discover novel loci linking environmental exposures to health outcomes.
Using weighted quantile sum (WQS) regression analysis, we identified several placenta gene modules that are susceptible to metal exposure predominated by arsenic and cadmium (As/Cd). However, biological verification of these empirical observations is urgently needed to validate the in silico approach and to offer insight into the underlying biologic mechanism. In this pilot study, we propose to develop an in vitro placenta cell culture system to assess network-derived hub gene expression changes in response to As/Cd exposure, assess As/Cd induced changes in placental phenotypes, including proliferation, migration and invasion, and measure As/Cd induced changes in metabolic hormone secretion. The successful development of a placental cell culture system has the potential to be leveraged in additional P30 studies assessing the influence of environmental agents on placental biomarkers.

Title of Project: MY NYC AIR: Environmental Health Citizen Science (CBPR)
Principal Investigator: Maida Galvez, MD, MPH

Co-Investigators: Nancy Loder Jeffery, RN, MPH (NYCDOHM); Grant Pezeshki, MS (NYCDOHM); Carol M. Horowitz, MD, MPH

Project Period: October 2017 – September 2018

Pilot Award Amount: $20,000


Abstract: Air quality in New York City has improved over the past several decades, but concentrations of multiple air pollutants remain at harmful levels, particularly for seniors, children, and those with pre-existing health conditions. Objective: We aim to establish meaningful collaborations between local government agencies, academic and medical institutions, and community groups to enhance the capacity of at risk communities to proactively identify local sources of outdoor air pollutants in high risk NYC neighborhoods that often suffer from a disproportionate burden of environmental exposures. Methods/Innovation: Together with diverse stakeholders, we plan to pilot the air quality app “My NYC Air”, developed by the NYC Department of Health and Mental Hygiene in collaboration with technology consultants (Mount Sinai App Lab) to conduct the necessary user interface testing needed prior to publicly launching. This work will help inform the type and quality of data that could be collected, determine methods to best manage crowdsourced data, and will allow us to refine analysis and visualization techniques needed for effectively communicating crowd-sourced data. Use of “MY NYC Air” literally places the ability to collect air quality concerns at people’s fingertips, through use of their smartphones which are now in routine use by families of diverse socioeconomic backgrounds. Significance: “My NYC Air” has the potential to increase citizen participation in acquiring, interpreting and communicating air quality data, which can inform community based organizations, clinicians, researchers, public health officials and policy-makers on air quality issues as identified by NYC residents.

Title of Project: Statistical methods to assess prenatal exposures to metal mixtures and associations with latent patterns of neurodevelopmental trajectories
Principal Investigator: Shelley H. Liu, PhD

Co-Investigators: Qixuan Chen, PhD, MS; Brent Coull, PhD; Chris Gennings, PhD; Robert Wright, MD

Project Period: October 2017 – September 2018

Pilot Award Amount: $18,000


Abstract: Neurodevelopmental delay is a complex public health problem, affecting up to 15% of children in the general population. As genetic factors only explain a small percentage of these delays, environmental factors likely play a larger role. Prenatal exposures to metal mixtures, such as lead and arsenic, can potentially injure the fetal brain. Accordingly, the NIEHS has prioritized the study of both complex chemical mixtures and early childhood neurodevelopment. Typically, studies of metal mixtures and neurodevelopment use models that assume metals impact each child’s health to the same degree. In reality, there may be latent, or underlying, population subgroups of infants with distinct neurodevelopment trajectories over time, and the impacts of exposure to metal mixtures may differ across these subgroups. To our knowledge, studies have not addressed if infants in latent classes with distinct neurodevelopmental trajectories – particularly those in the delayed latent class – are differentially vulnerable to metal mixtures, and if interactions among the metal mixture components differ across latent classes. If we identify subpopulations with greater vulnerability to mixtures, we can potentially help public health practitioners target early interventions.
We propose to develop a two-stage statistical model to investigate these questions, and conduct a secondary data analysis of the Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) prospective cohort study. PROGRESS contains extensive data on prenatal exposures to metal mixtures, and neurodevelopment assessed through the Bayley Scales of Infant and Toddler Development measured over time. Our two-stage model will first use growth mixture modeling to identify latent classes of infants with distinct patterns of neurodevelopmental trajectories. Second, we will separately study each latent class, using a flexible Bayesian approach to model how metal mixtures, and their interactions, are associated with neurodevelopmental trajectories. We will create an R package for researchers to implement this two-stage model for other datasets.

Pilots Awarded in 2016

Title of Project: Children’s Urinary miRNAS as Biomarkers of Early Life Metal Exposure
Principal Investigator: Alison P Sanders, PhD

Co-Investigators: Lisa Satlin, MD; Robert Wright, MD, MPH; Chris Gennings, PhD

Project Period: October 2016 – September 2017

Pilot Award Amount: $70,000


Abstract: Toxic metals including cadmium (Cd), mercury (Hg), and lead (Pb) are known renal toxicants in adults; however, their renal toxicity in developing children is understudied. Prenatal and early childhood are potential susceptibility windows for renal toxic metals as these life stages are associated with development and differentiation of renal transport systems. Urinary microRNAs (miRNAs) serve as early biomarkers of renal health, and may mediate metal-associated health effects. The aims of this study are to compare miRNA expression in children’s whole urine and urinary exosomes, and determine whether early life toxic metal exposure contributes to altered miRNA expression. To accomplish our goals, we will leverage an existing and established longitudinal birth cohort in Mexico City – the Programming Research in Obesity, GRowth Environment and Social Stress (PROGRESS) study – which has measured prenatal and childhood levels of metals (Cd, Hg, and Pb) longitudinally in blood and nails, and collected urine from mother-child pairs at each visit. This proposal therefore need only measure miRNA expression as well as concurrent metal and creatinine levels in urine. The research team includes expertise in pediatrics, metals toxicology, epidemiology, biostatistics, and epigenetics, including Drs. Alison Sanders, Lisa Satlin, Chris Gennings, and Robert Wright. This proposal leverages P30 Core Center expertise in children’s environmental health and biostatistics (Preventive Medicine) with specialization in renal physiology and epigenetics (Pediatrics and Pittsburgh Center for Kidney Research). This work will advance our ability to assess miRNAs as biomarkers and/or specific mechanisms that may contribute to metal-altered pathophysiology of renal health. The proposed research activities will provide substantial pilot data for future R01 applications to assess the functional impacts of early life metal exposure on miRNAs that maymediate renal/cardiovascular outcomes, and lead to future interventions designed to prevent or treat renaltoxic metal exposure.

Title of Project: Prenatal manganese exposure, placental imprinting, and fetal growth: a pilot study

Principal Investigator: Jia Chen, ScD

Co-Investigators: R. Colin Carter, MD, MMSc; Sandra Jacobson, PhD; Joseph Jacobson, PhD; Pei Wang, PhD; Christopher Molteno, MD

Project Period: October 2016 – September 2017

Pilot Award Amount: $25,000


Abstract: Manganese (Mn) is both an essential nutrient and a toxicant, with environmental exposure via air, water, and soil, particularly in areas where Mn is either mined, transported, or added to gasoline as methylcyclopentadienyl manganese tricarbonyl (MMT), an anti-knocking agent. Prenatal exposure to both high and low levels of manganese has been shown to impair fetal growth and neurodevelopment. Recent evidence has implicated alterations in epigenetic programming as a potential mechanism in these effects, and alterations in the expression profiles of imprinted genes in the placenta may be of particular importance, given the critical roles of these genes in fetal growth and neurodevelopment. We hypothesize that prenatal Mn exposure modulates imprinted gene expression that leads to deficits in fetal growth. We will test this hypothesis in banked placenta samples obtained from 68 mother-infant pairs in a prospective longitudinal cohort study examining the effects of prenatal alcohol exposure on growth and development, including both drinkers and abstaining controls. Placental Mn content (mg/g dried placental tissue) will be measured using ICP-MS, and placental expression of imprinted genes will be assayed using a validated, multiplexed imprintome assay by nanoString. This cohort was recruited in Cape Town, South Africa, where Mn exposure levels are particularly high due to Mn mining and the addition of MMT to gasoline. A major strength of our approach is the measurement of Mn content directly in the target tissue, the placenta, as blood concentrations of Mn may not correlate with degree of environmental exposure. The placenta is an ideal target tissue for this study because it is fetally-derived, and imprinted genes are highly expressed in the placenta. Furthermore, prospectively obtained data regarding prenatal alcohol exposure will provide a unique opportunity to explore potential interactions between Mn and
alcohol, which have similar effects on fetal growth and neurobehavior.

Title of Project: Air Pollution and Psychosocial stress exposure during pregnancy, telmere length and respiratory health in childhood

Principal Investigator: Maria José Rosa, DrPH

Co-Investigators:  Rosalind Wright, MD, MPH; Allan Just, PhD; Andrea Baccarelli, MD, PhD

Project Period: October 2016-September 2017

Pilot Award Amount: $25,000


Abstract: In utero exposure to ambient pollution and psychosocial stress may adversely affect the developing respiratory system. Despite the long history of research on these 2 issues, the underlying mechanism of their effects has not been completely elucidated. Telomeres play a critical role in cellular aging and appear to be particularly sensitive to reactive oxygen species (ROS) damage. Decreased length may represent a common underlying mechanism connecting fetal programming and subsequent adverse respiratory outcomes shared by both exposures. Newborn telomere length may be of particular importance. Our group has estimated daily predicted values of particulate matter <2.5 microns in diameter (PM2.5) during pregnancy for each of the participants enrolled in the Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) cohort. We have also collected prospective measures of stress during pregnancy and children’s respiratory health. In this proposal we will measure leukocyte telomere length (LTL) in cord blood DNA, as an index of cumulative ROS and cellular aging during pregnancy. We predict that children with higher exposure to prenatal PM2.5/stress will have shorter LTL, and shorter LTL will be associated with greater risk of asthma/wheeze in childhood, with LTL potentially mediating the effects between air pollution/stress and asthma/wheeze.


Principal Investigator: Alison P. Sanders, PhD

Co-Investigators: Lisa Satlin, MD; Annemarie Stroustrup, MD; Chris Gennings, PhD; Andrea Weintruab, MD; Robert Wright, MD, MPH;

Project Period: October 2016-September 2017

Pilot Award Amount: $25,000


Abstract: Emerging evidence suggests that renal disease can develop from subclinical insults in fetal life or early childhood. During these critical periods for differentiation of the renal filtration, secretion, and reabsorptive systems, environmental exposures may alter the developmental trajectory of the kidney resulting in hypertension and renal disease. Most research on Pb nephrotoxicity has been conducted in adults; Pb nephrotoxicity in developing children remains understudied. Preterm infants are particularly susceptible to renal damage, because birth occurs prior to the completion of nephron formation. We recently noted that prenatal Pb exposure among preterm infants is associated with increased blood pressure at 4 years of age. We also know that, unexpectedly, Pb exposure is common in the NICU environment. We propose to build upon these important findings by measuring prenatal and NICU-based Pb exposure and examining both clinical AND preclinical biomarkers of renal dysfunction among a susceptible population of preterm infants. We hypothesize that early life Pb exposure contributes to renal dysfunction in preterm infants. We are poised to address the impact of prenatal and early childhood Pb exposure during critical windows of renal development using the NICU Hospital Exposures and Long-Term Health cohort (NICU-HEALTH). Preterm infants born between 28 and 33 weeks gestation are enrolled in NICU-HEALTH and followed through early childhood. We will use maternal blood and neonatal urine samples to measure Pb and selected biomarkers of renal dysfunction, and will collect other renal parameters (serum creatinine and blood pressure). We will analyze associations between Pb exposure and renal outcomes individually and in combination. This work will: i) inform our understanding of biomarkers for subclinical renal toxicity, and ii) identify risk factors for early life origins of kidney disease and hypertension, potentially leading to future interventions designed to prevent or treat nephrotoxic Pb exposure in susceptible populations.

Title of Project: Early-life exposure to inorganic arsenic exacerbates the development of fatty
liver disease

Principal Investigator: Kathryn Bambino, PhD

Co-Investigators: Christine Austin, PhD; Jaime Chu, MD; Manish Arora, BDS, MPH, PhD; Christoph Buettner, MD, PhD

Project Period: October 2016-September 2017

Pilot Award Amount: $25,000


Abstract:Prenatal and childhood exposure to inorganic arsenic (iAs) leads to increased risk of mortality, cancer andmetabolic disease, putting iAs at the #1 position on the American Toxic Substances and Disease Registry(ATSDR) watch list. However, despite solid epidemiological evidence demonstrating the adverse and long-termhealth effects of early life exposure to iAs, the mechanism by which iAs causes disease are relatively unknown.Surprisingly, only a few studies in animals have examined specific outcomes associated with iAs exposure. While the idea that environmental exposures modify the severity of common diseases, such as diabetes and obesity, has been widely discussed, few studies have addressed this possibility directly. Here, we will do this using zebrafish to identify the mechanistic basis of iAs toxicity in metabolic disease. Fatty liver is the hepatic manifestation of metabolic syndrome and is also caused by alcohol abuse. However, not all people who drink excessively develop fatty liver disease (FLD). A widely proposed but untested hypothesis is that additional environmental exposures synergize with ethanol to cause FLD. Our preliminary data shows that iAs is sufficient to cause FLD accompanied by activation of the unfolded protein response, a pathway that has been shown to be a common, causative mechanism to alcoholic and non-alcoholic fatty liver. We found that exposure to a low dose of iAs during early development synergistically interact with ethanol to cause steatosis, activate the UPR, and cause severe toxicity and lethality. In summary, our work promotes the idea that iAs toxicity is mediated by activation of a pathological UPR. Moreover, an exciting potential outcome of our findings is the idea that iAs synergizes with alcohol, thereby providing a basis to understand the diverse outcomes of alcohol abuse. Further studies will seek to elucidate the mechanism by which early-life exposure to iAs leads to progressive liver disease.


Title of Project: Psychosocial motivations, behavioral patterns, and health effects of metal, hydroquinone, and steroid exposure associated with skin bleaching among African and Afro-Caribbean women in New York City
Principal Investigator: Bian Liu, PhD

Co-Investigators: Emma Benn, DrPH, Nihal Mohamed, PhD, Andrew Alexis, MD, MPH

Project Period: October 2016 – September 2017

Pilot Award Amount: $25,000


Abstract: Skin bleaching practices, such as using skin creams and soaps to achieve a lighter skin tone, are common throughout the world, and are triggered by cosmetic reasons that oftentimes have deep historical, economic, sociocultural, and psychosocial roots. Exposure to chemicals in the bleaching products, notably, mercury (Hg), hydroquinone (HQ), and steroids, has been associated with a variety of adverse health effects, such as mercury poisoning and exogenous ochronosis. In New York City (NYC), skin care product use has been identified as an important route of Hg exposure, especially among Caribbean-born blacks and Dominicans. However, surprisingly sparse information is available on the epidemiology of the health impacts of skin bleaching practices among these populations. This pilot project serves as the necessary initiation of a future research agenda to address the knowledge gaps surrounding skin bleaching practices and health outcomes among African and Afro-Caribbean women in NYC. To that end, we will identify a study population with typical clinical presentations indicative of skin bleaching through reviews of the pathology database and medical charts of patients who visited the Skin of Color Center at Mount Sinai. Detailed interviews will be conducted to explore skin practices (i.e., type and frequency of products used), self-reported health problems commonly resulting from skin bleaching, and psychosocial factors that may influence this behavior. Exposure assessment will be conducted based on laboratory measurement of metals, HQ, and steroids in skin bleaching products, and questionnaire responses. We expect a heterogeneous pattern of the skin bleaching practices; and hypothesize that chronic users are at a higher risk of having more severe symptoms. Results from this pilot study will serve as preliminary data to obtain extramural funding for an in-depth investigation of the health effects of skin bleaching practices among non-White populations, and to identify effective and culturally sensitive strategies for intervention.

Title of Project: Exposure Characterization to Crumb Rubber used in Artificial Turf Fields: A

Principal Investigator: Homero Harari, ScD

Co-Investigators: Sarah Evans PhD, Maida Galvez MD MPH, Robert Wright MD MPH

Project Period: October 2016-September 2017


Abstract: Crumb rubber infill, generated by grinding recycled rubber automobile tires into small pellets, is utilized on thousands of athletic playing surfaces worldwide. Several reports showed that recycled tires contain known carcinogens, neurotoxins, and other chemicals of concern, yet comprehensive exposure and risk assessment has not been conducted. Existing studies have not characterized exposures during realistic play conditions or addressed dermal and oral routes of exposure to potentially harmful chemicals. Concerns about the health risks associated with exposures to chemicals resulting from play on crumb rubber are mounting. As a result, the Mount Sinai Children’s Environmental Health Center (CEHC) and Region 2 Pediatric Environmental Health Specialty Unit (PEHSU) receive numerous calls for consultation about the risk of artificial turf surfaces; however gaps in the scientific data make it difficult to guide communities in risk reduction. Recent media reports of young soccer goalies diagnosed with lymphomas and other cancers have prompted a federal study of the safety of crumb rubber, on the basis that existing studies are limited. The aims of this proposal are to 1) characterize chemicals of concern in crumb rubber used in turf fields, and 2) characterize exposure in real playing conditions. The project will be conducted via partnership with a community partner who regularly utilizes crumb rubber turf fields. Individual and aggregate exposure assessment findings will be reported back to participants. Based on our exposure assessment findings, we will work closely with users to develop feasible and effective risk reduction methods and associated communication strategy. This proposal will serve as a pilot for future grant applications to examine exposures on a larger number of crumb rubber fields as well as exposures in children. Future studies will examine the risks of exposure to identified chemicals of concern both individually and in aggregate. In addition, our findings will provide a framework for effective communication with communities regarding the safety of crumb rubber artificial turf.

Title of Project: Prenatal Ambient Air Pollution Exposure And Long Noncoding Rnas In Breast Milk Extracellular Vesicles

Principal Investigator: Alison Lee, MD


Project Period: October 2016-September 2017


Abstract: Air pollution is a major health concern and accounts for 3.7 million deaths annually. The developing lung is particularly susceptible to air pollution exposures. In utero exposure to ambient air pollution has been associated with childhood wheeze, asthma onset and morbidity as well as reduced lung function. Psychosocial stress, a risk factor that may co-vary with exposure to air pollutants in high-risk urban communities, can enhance air pollution effects. However, the mechanisms by which air pollution alters lung development and predisposes children to increased future risk of respiratory disease are largely unknown. Extracellular vesicles (EVs) and their cargo, specifically long noncoding RNA (lncRNA), play central roles in cell-to-cell and inflammatory signaling and have been demonstrated to both be modified by preceding air pollution exposures and predict future lung function decline. Our group has identified a number of developmentally-related EV lncRNAs in human breastmilk supporting the hypothesis that these EV lncRNAs may mediate the association between prenatal air pollution and stress exposures and future child respiratory disease risk. Using our Perinatal Environmental and Development Study (PEDS) cohort with state of the art characterization of prenatal ambient fine particulate matter mass (PM2.5) and maternal stress exposures in addition to important covariates, we are uniquely poised to address this question. We predict that prenatal ambient PM2.5 and maternal stress are independently associated with specific profiles of breast milk lncRNAs and that the association between prenatal ambient PM2.5 and breast milk lncRNAs is modified by prenatal maternal stress

Pilots Awarded in 2015

The Center’s mission is to increase the Environmental Health (EH) research portfolio at Mount Sinai and to bring non-EH researchers into the field through new transdisciplinary collaborations.

Title: “Predicting Neurotoxic Perturbations of Developmental Neuroplasticity via an Integrative Bioinformatics Approach”

PI: Joel Dudley

Neurodevelopment is marked by periods of activity-dependent neuroplasticity wherein neural circuitry is optimized by the environment. If these critical periods are perturbed, optimization of function (i.e. visual acuity or language) can be permanently disrupted. A major clinical and scientific gap is knowledge of environmental neurotoxicants that disrupt critical period biology. Historically, this knowledge has been limited by a lack of a comparable data shared between perturbagens and in vivo neuroplasticity and a lack of methods to systematically identify connections between the data. Here, we propose a novel integrative bioinformatics approach that leverages the exponential growth in public molecular data. Our goal is to systematically identify toxicants that suppress networks and pathways regulating critical periods of developmental neuroplasticity. In our preliminary study, we derived in vivo neuroplasticity signatures from mice with elevated plasticity in visual cortex, a well-established model of critical period plasticity. We then computationally matched these transcriptional signatures of in vivo neuroplasticity to >2500 curated toxicant gene set modules. We found overrepresentation of known (i.e. lead, toluene, arsenic, chlorpyrifos, methlymercury, PCBs) and novel neurotoxicants with neuroplasticity signatures. These results have led us to hypothesize that known (and novel) neurotoxicants will disrupt critical period neuroplasticity and result in molecular and functional consequences to neurological and cognitive development. We will test this hypothesis by first developing and applying an integrative informatics approach to identify and prioritize neurotoxicants based on transcriptional profiles (Aim1). We will then assess effect of known neurotoxicant (Pb2+) on developmental neuroplasticity using a well-characterized in vivo model of neuroplasticity (mouse visual system) (Aim2). Lastly, we will validate transcriptome-wide effect of anti-plasticity toxicants (Aim3). This work will establish the detrimental role of known neurotoxicants in developmental neuroplasticity and lay the groundwork for systematic, data-driven prediction and screening of novel neurodevelopmental toxicants.


Title: “Assessment of past phthalate exposure in adult rats using teeth microstructure analysis”

PI: Syam Andra

In this project we will use teeth microstructure analysis as a biomarker of past phthalate exposure in adult rats exposed in early life during critical windows for reproductive and metabolic programming. Wistar rat dams (N=12 litters/group) will be treated with vehicle control and 3 doses of either di-2(ethylhexyl) (DEHP) or di-nbutyl phthalate (DnBP) (0.018, 0.18, and 1.8 mmol/kg/day) from gestation day 13 to postnatal day 21 (weaning). Using an innovative approach based on tooth ontogeny and histological landmarks we will determine the concentrations of DEHP and DnBP metabolites in time-specific dentine layers of adult offspring rats reflecting in utero and lactational exposure. The techniques will combine fine microdissection of first mandibular rat teeth and analysis of phthalate metabolites by state-of-the-art high performance liquid chromatography-tandem mass spectrometry (HPLC/MS-MS). In addition, we will examine dose-responses for reproductive and metabolic effects in male rats, in particular disruption of androgen-dependent development and altered glucose homeostasis, and possible associations between these endpoints and internal phthalate doses assessed by teeth analysis. Overall, the transdisciplinary team of researchers involved in this project will combine unique expertise in the fields of developmental toxicology, epidemiology and analytical chemistry to establish an animal model that will validate the use of teeth as exposure biomarker that can assess longterm/late-onset effects of phthalates in relation to past exposure. The results obtained will reinforce the use of teeth as a potential biomarker of exposure in both animal and human studies, including ongoing birth cohort studies coordinated by the Department of Preventive Medicine at Mount Sinai.


Title: “Lead Exposure And Addictive Diseases: A Pilot Study Of The Association Between Tibia-Lead And Cocaine Addiction”

PI: Megan Horton

While researchers recognize several known risk factors for adult drug addiction (i.e., family history of addiction, physical and sexual abuse, depression and other co-morbidities), the role exposure to environmental chemicals may play in drug addiction has not been well studied. In this study, we propose to examine the association between environmental exposure to the heavy metal, lead, and cocaine addiction. The welldocumented neurotoxic cognitive and behavioral effects of environmental lead (Pb) exposure are attributed, in part, to disruption of the mesolimbic dopaminergic (DA) system. Animal studies demonstrate that low level Pb exposure results in excess synaptic DA, with consequent down-regulation of postsynaptic DA receptors. Disrupted DA function is a major player in mediating drug reward behaviors and the development of addiction to drugs of abuse, such as cocaine. Cocaine produces its immediate psychological effect by causing a build up of synaptic DA. We hypothesize that cumulative exposure to Pb is associated with increased drug seeking behaviors and a greater likelihood of cocaine addiction in humans. To test this hypothesis, we propose to pilot a case-control study of cocaine addicts and healthy controls enrolled in the ongoing Neuroimaging of Addiction and Related Conditions (NARC) Research Program. Using 109Cd-based K-shell X-Ray Fluorescence (XRF), we will measure cumulative Pb exposure in cases and controls and examine associations between Pb exposure and the neuropsychological and neuroimaging phenotypes of cocaine addiction. This study will help elucidate a novel toxicology-related mechanism of addiction, with potential applications to other disorders of self-regulation that are similarly characterized by compromised DA signaling, as well as to other environmental chemicals that act on the DA system. Results could inform insight into interventions addressing the environmental risk factors associated with vulnerability to addiction.



PI: Annemarie Stroustrup

Each year in the United States, over 300,000 neonates require admission to a neonatal intensive care unit (NICU) where they are exposed to a chemical-intensive hospital environment. Preterm infants spend a particularly vulnerable developmental period corresponding to the third trimester in the NICU. It is known that exposure to air pollutants including volatile organic compounds (VOCs) during fetal and early postnatal life can permanently alter pulmonary and neurobehavioral outcomes in children born at term. We also know that NICU graduates experience pulmonary and neurodevelopmental abnormalities at higher rates than the general population and may represent a highly vulnerable subpopulation for toxic chemical exposure. Neurodevelopmental and pulmonary disorders among NICU graduates are incompletely predicted by degree of prematurity or neonatal illness. There are no comprehensive studies of chemical exposure in the NICU. We do not understand the impact of hospital-based chemical exposure on clinical outcomes of NICU graduates. Specific source(s) and types of exposure need to be identified in order to mitigate potential adverse outcomes. We propose to leverage the NICU-Hospital Exposures And Long-Term Health (NICU-HEALTH) study to characterize inhalational chemical exposure in the NICU. The NICU-HEALTH study is an active prospective birth cohort study of moderately preterm infants in the Mount Sinai NICU. Information on exposure to medical materials and stress as well as serial biospecimens are collected from each infant throughout the NICU hospitalization. Short-term outcomes include growth and neurodevelopmental progress; long-term outcomes of neurodevelopment and pulmonary function are planned. No measures of air quality (AQ) are currently included in the NICU-HEALTH protocol. In the proposed study we will (1) evaluate both ambient AQ in the NICU and AQ inside the neonatal incubator; and (2) evaluate the association of AQ in the neonatal incubator with concurrent oxidative stress in hospitalized moderately preterm infants.


Title: “In utero chemical and non-chemical stressors, sex hormones, and infant neurodevelopment”

PI: Rosalind J. Wright

Despite increasing evidence that developing males and females respond differently to chemical and nonchemical stressors, few studies directly examine sex-specific effects of neurotoxicants. Moreover, the mechanisms underlying sex-specific effects of these toxicants are poorly understood. Chemicals and psychological stress both impact sex hormone physiology and differential exposure to sex steroids during prenatal development (e.g. altered testosterone, estradiol, progesterone levels) may represent a pathway to sex differences in neurodevelopment. Research in this area to date has been limited by a reliance on sex steroid assessment in single sample of saliva or amniotic fluid which can only represent sex steroid level over short periods of time. The proposed pilot analyses will take advantage of banked maternal saliva and hair samples from a subset (n=140) of mother-infant dyads participating in the PRogramming of Intergenerational Stress Mechanisms (PRISM) study to assess both diurnal fluctuations in sex steroids (representing daily rhythms of salivary testosterone, progesterone, and estradiol) and longer-term trait-like sex steroid levels measured in mothers’ hair collected shortly following delivery (representing integrated average levels over trimesters). The joint distribution of hair and salivary sex steroids will be assessed using advanced statistical approaches; combinations of sex steroid measures that are best associated with prenatal maternal stress and/or chemical exposures (metals, endocrine disrupting chemicals) will be determined. Associations between identified composite sex steroid indices and infant temperament, an early marker of infant neurodevelopment, will also be explored. We will compare the relative effectiveness of these derived prenatal sex steroid indices with respect to early neurobehavioral outcomes compared with conventional methods (single salivary measure or hair measure alone). This is the first study to assess the combined contributions of sex steroids measured in repeated saliva samples providing diurnal variation and in hair recreating exposure over the course of pregnancy in a longitudinal study examining infant neurodevelopment.

Pilots Awarded in 2014

The newly funded Mount Sinai NIEHS Core Center announced its first call for Pilot Grant proposal in December 2014. The Center’s mission is to increase the Environmental Health (EH) research portfolio at Mount Sinai and to bring non-EH researchers into the field through new transdisciplinary collaborations.

Title: Novel Tissue Elemental bio-Imaging to Study the Role of Environmental Pollutants in Type I Diabetes

PI: Dr. Manish Arora

There is a well-documented rise in the incidence of type 1 diabetes (T1D) in children from industrialized countries suggesting a role for environmental chemical exposures. Alarmingly, the increased incidence is seen mostly in children under age 5. However, research on environmental chemical exposures and T1D is very limited and there is an urgent need for research to fill this gap in our knowledge. Therefore, the goal of this proposal is to identify environmental pollutants that play a role in the increased incidence of T1D in children. Identifying the causes of the increasing incidence of T1D in children will enable us to develop prevention strategies based on the mechanisms causing the disease.

Title: Autism Spectrum Disorders and Prenatal Persistent Organic Pollutants (ASD-POP)

PI: Dr. Avi Reichenberg

There is an urgent need to understand the role of environmental factors in the risk for Autism Spectrum Disorders (ASD). Prenatal exposure to several classes of chemicals, including pharmaceuticals, has been examined in relation to ASD risk. Increased risk of ASD was recently reported for prescribed mood stabilizers (SSRIs and Valproate). However, pregnant women and fetuses are exposed to many pollutants in addition to pharmaceuticals, and for most of these the risk of ASD has scarcely been characterized. To address this, population-based investigations are required that can adequately examine the role of prenatal exposure to environmental chemicals in ASD etiology. This project will help establish the necessary preliminary work to accurately and precisely estimate the contribution of prenatal POPs exposure to the etiology of ASD.

Title: Air Pollution Exposure During Pregnancy and Respiratory Health in Childhood

PI: Dr. Rosalind Wright

In utero exposure to ambient pollution may adversely affect the developing respiratory system. Despite the long history of research on this issue, very little is known regarding which life stages are most susceptible. The identification of windows of susceptibility in pregnancy or in childhood would direct the appropriate timing of public health efforts and could direct researchers to more efficiently elucidate the mechanisms through which ambient air pollution is associated with respiratory morbidity, as the timing for assessments would be evidence based. We predict that children with higher exposure during this window will have lower lung function measures and higher levels of airway inflammation. We will also explore a potential interaction between ambient air pollution and psychosocial stressors.

Title: Neuroimaging Phenotypes of Prenatal and Early Childhood Exposure to Manganese

PI: Dr. Megan Horton

Modern neuroimaging tools such as magnetic resonance imaging have been used to characterize the development of normal brain processes and to understand the neuropathological and neurofunctional correlates of developmental disorders such as autism spectrum disorder and attention deficit hyperactivity disorder. Only recently, these neuroimaging tools have been applied to epidemiologic studies of children’s environmental health to begin to explore the neuropathological and neurofunctional mechanisms by which exposure to environmental toxicants derail normal neurodevelopment. In this study, we propose to examine the neuroimaging phenotypes associated with prenatal and childhood exposure to manganese (Mn). Several recent environmental epidemiologic studies extend these findings to children revealing inverse associations between early life exposure and childhood cognition, behavior and motor skills. To date, no studies have investigated the neural correlates of Mn-induced neurodevelopmental toxicity in children.

Title: Leveraging Big Data and Machine Learning to Assess the Effects of Multiple Air Toxics on Cognitive Outcomes in Children

PI: Dr. Gaurav Pandey

Epidemiologic studies have shown that prenatal exposures to ambient air pollutants are associated with neurodevelopment and behavior in infants and children. Although ambient air is a complex mixture of multiple pollutants, most previous research has focused on the effects of individual pollutants on children’s cognitive health. Machine learning techniques present a new opportunity to examine the joint effects of multiple air pollutants on cognitive outcomes, but there has been limited implementation of these techniques in air pollution epidemiology. Overall, this pilot will establish the feasibility of applying machine learning techniques to pediatric environmental health data, provide preliminary findings of epidemiologic risk estimates, and facilitate the development of future collaborative work strategies for our interdisciplinary research team.

Title: Hospital-Based Chemical Exposure and Neurodevelopmental Outcomes in Preterm Infants

PI: Dr. Annemarie Stroustrup

Each year in the United States, over 300,000 neonates require admission to a neonatal intensive care unit (NICU) where they are exposed to a chemical-intensive hospital environment. Preterm infants spend a particularly vulnerable developmental period corresponding to the third trimester in the NICU. It is known that chemical exposure at this point in development can permanently alter neurobehavioral outcomes in healthy fetuses, and that phthalates and phenols are common constituents of medical products used in neonatology. We also know that NICU graduates experience neurodevelopmental abnormalities at higher rates than the general population and may represent a highly vulnerable subpopulation for toxic chemical exposure. Neurodevelopmental disorders among NICU graduates are incompletely predicted by degree of prematurity or neonatal illness.