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.