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
depression
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
neurodevelopment

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.