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