Pilot Projects Awarded 2019 (2)

Title of Project: Environmental Noise and Preadolescent Mental Health in Mexico City

Principal Investigator (MPI): Laura McGuinn, PhD; Itai Kloog, PhD

Co-Investigators: Robert Wright MD, MPH; Homero Harari, ScD; Avi Reichenberg, PhD; Mara Tellez-Rojo, PhD; Ivan Gutierrez, ScD

Project Period: January 31, 2020 – January 30, 2021

Pilot Award Amount: $25,000

 

Abstract: One in four people worldwide will be affected by a mental health disorder at some point in their life, making it a major global contributor to excess morbidity and disability. Depression and anxiety are two of the most common mental health conditions and are a particular issue for younger populations, as the prevalence of both in this age group has continued to increase. Mental health effects from the urban environment are of increasing concern, particularly in mega-cities such as Mexico City. The higher prevalence of mental health conditions in urban areas may be related to social and economic factors, but also factors such as noise pollution that serve as chronic environmental stressors. Noise pollution is of significant concern in Mexico City, as it is estimated to have among the top ten highest noise levels in the world; however, the health effects of noise pollution in this area are not well characterized. Further, while there is a growing body of research on the impact of noise on adult mental health, there is very little research in the younger populations in which chronic depression and anxiety often arises. We will address this novel research question by developing a spatially resolved noise prediction model in Mexico City, then use the resulting estimates to assess the relation between noise and mental health symptoms in preadolescents in the PROGRESS cohort, an ongoing longitudinal birth cohort. Anxiety and depression will be assessed using self-reported measures at age 10-11. The completion of this work will expand knowledge of the health effects of a ubiquitous, yet understudied, exposure and will result in one of the first noise prediction models for Mexico City. The predicted noise estimates developed from this work will be made available to all interested PROGRESS researchers, providing a rich resource for future grant applications.


Title of Project: Untargeted analysis of personal environmental exposures and respiratory outcomes in children

Principal Investigator: Douglas I. Walker, PhD; Maria José Rosa, DrPH

Co-Investigators: Marcela Tamayo y Ortiz, ScD

Project Period:  January 31, 2020 – January 30, 2021

Pilot Award Amount: $20,000

 

Abstract: Indoor and outdoor environmental risk factors for the development and exacerbation of childhood respiratory disease in Latin America remain understudied. Novel personal sampling methods, analytical techniques and big data approaches have been developed that can provide a comprehensive assessment of the external exposome. These new techniques can help researchers understand exposure within the actual microenvironments in which children live and potentially identify novel chemical exposures associated with respiratory disease that in turn may help drive public health interventions. In this proposal we will leverage an ongoing respiratory health study in Mexico City to comprehensively evaluate personal chemical exposures through untargeted analysis of silicone wristband passive samplers. These wristbands are noninvasive and have been validated in multiple populations as tools for environmental monitoring. While most studies have used targeted analysis of chemicals, by using untargeted methods, we can better discover novel exposures that may be driving respiratory outcomes. We will collect these measures in 100 children with lung function measures collected in the study and identify chemical exposures in personal samplers that are associated with lung function measures.


Title of Project: Identifying the role of early environmental toxicants in newborns with biliary atresia
Principal Investigator (MPI): Jaime Chu, MD; Lauren Petrick, PhD

Co-Investigators:  Elena Colicino, PhD; Syam Andra, PhD; Sanjiv Harpavat, MD, PhD

Project Period:   January 31, 2020 – January 30, 2021

Pilot Award Amount: $25,000

 

Abstract: Biliary atresia (BA) is the rapid and progressive destruction of bile ducts in neonates and results in 100% mortality by 1 year if misdiagnosed and left untreated. BA has long been the most common indication for pediatric liver transplantation, yet its etiology remains elusive and the field lacks any biomarkers to aid in early diagnosis. Research focused on GWAS and transcriptomic signatures at 6-8 weeks of age, the typical emergence of visible symptoms, have been unsuccessful at predicting cases of BA. The paradigm is shifting with recent data suggesting 1) a prenatal injury and the need for biomarkers at birth and 2) a role for persistent environmental toxins in BA. Therefore, we propose the first study to investigate toxicant exposure and endogenous biomarker levels in humans, prior to onset of clinical BA symptoms. We will interrogate archived newborn dried blood spots (DBS) collected from neonates that later developed BA and healthy controls. Using innovative methods developed by our team, we will 1) perform targeted quantification of flame retardants, organochlorine pesticides, polyaromatic hydrocarbons, and per- and polyfluoroalkyl substances to determine if infants with biliary atresia have increased prenatal exposure compared to healthy controls and 2) perform untargeted metabolomics analysis to identify differences in metabolite profiles at birth between neonates that later developed biliary atresia compared to healthy neonate controls and ascertain which combination(s) of DBS metabolites increase BA risk as potential pre-diagnosis biomarkers. This proposal addresses the critical unmet need for early and effective biomarkers in BA. We will leverage our diverse and complementary expertise in pediatric liver disease and innovative ability to extract small molecule data from DBS to establish a metabolic signature of infants with BA and introduce the novel prospect that analysis of newborn DBS can offer a window into etiology and earlier diagnosis, and potential transplant-sparing interventions.


Title of Project: Examination of Potential Substances Related to CKD in children (EXPOSURE-CKD Study)

Principal Investigator: Smita Goodman, DO

Co-Investigators: Manish Arora, BDS, MPH, PhD, FICD; Jeffrey Saland, MD; Chris Gennings; PhD

Project Period:  January 31, 2020 – January 30, 2021

Pilot Award Amount: $25,000

 

Abstract: Chronic Kidney Disease (CKD) affects children of all ages and is a major risk for progression to renal failure which is in turn associated with significant morbidity and reduced life expectancy. Environmental exposure studies remain challenging in pediatric populations with CKD. Importantly, tooth-matrix can provide a quantifiable and time-sequenced record of elemental uptake from the second trimester to childhood.  The analytical protocol for the identification of the neonatal zones in enamel and dentine of deciduous teeth and the measurement of metal concentrations in these regions using laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) has been validated extensively. In this improved and innovative model of exposure analysis, our reconstruction seeks to yield a biomarker indicative of a potential early life determinant of CKD in children. We hypothesize there is a prenatal and early life exposure to essential and toxic elements during critical development windows that is associated with pediatric CKD. We propose an IRB-approved case-control pilot study using validated tooth-matrix biomarkers to obtain time-sequenced quantifiable elemental exposure profiles in children with a diagnosis of CKD. We are recruiting subjects from the clinical practice of the Division of Pediatric Nephrology and patients meet criteria as a case if they are a patient 0-21 years old with a diagnosis of CKD and shed tooth for collection. The focus of our study population is patients with renal anomalies (e.g. structural anomaly of the genitourinary tract, nephrotic syndrome with urine protein loss) that have renal damage but maintain normal or mild decline in renal filtration function. This is not a study population focused on patients with end stage renal disease.  Controls are age and gender matched healthy subjects without CKD enrolled from an ongoing study at the Seaver Center at Mount Sinai.  Exposure metrics focus on known metal nephrotoxins (arsenic, cadmium, lead, mercury) with an additional exploratory analysis of zinc, copper, manganese, and magnesium. Outcome metrics are an established diagnosis of pediatric CKD.  As tooth development begins in the second trimester, all shed teeth have a record of exposure that predates the diagnosis of CKD. Our two aims are as follows: (1): Identify quantifiable differences in environmental exposure profiles of individual essential and toxic elements present in the tooth record of the pediatric CKD population as compared to controls without CKD (that is, associations of single elements with CKD).  (2) Identify the joint association of exposure of essential and toxic elements as a mixture occurring in the pediatric CKD population. As this type of detailed multiple-analyte tooth investigation has never been performed in this population, this proposed study will allow us to make preliminary determinations about time-sequenced patterns of element exposure expressed in the tooth record of children with renal disease that will enable future research in this population. Our goal is to use novel biomarkers of early life exposure to increase understanding of potential modifiable environmental exposures in the childhood CKD population and lay the foundation for larger studies that explore the early life determinants of CKD. The results of this pilot project will serve as the foundation of the applicant’s K grant application.


Title of Project: The Relationship between Neonatal Intensive Care Unit (NICU) Stress, Telomere Length, and Neurodevelopment in Preterm Infant

Principal Investigator (MPI): Xueying Zhang, PhD; Annemarie Stroustrup, MD, MPH

Co-Investigators: Andrea Baccarelli, PhD

Project Period:  January 31, 2020 – January 30, 2021

Pilot Award Amount: $20,000

 

Abstract: Moderately preterm infants are at elevated risk of adverse neurobehavioral outcomes. Emerging data has linked exposure to environmental stress and chemicals in the neonatal intensive care unit (NICU) to alterations in neurodevelopment. Recent studies indicate that telomere length may be a useful indicator of environmental exposures, and also associated with neurologic outcomes in non-NICU populations. Leukocyte telomere length change has been shown to be meaningful during the NICU hospitalization. The proposed research will investigate the association between established biomarkers of NICU stress response and chemical exposure with the change rate of telomere length for hospitalized preterm infants enrolled in the NICU Hospital Exposures and Long-Term Health (NICU-HEALTH) cohort. Additionally, we will investigate the association between the change rate of telomere length and early neurobehavioral performance. Findings of this study will provide critical preliminary data for a definitive study of the role of telomere length on the pathway between NICU-based environmental exposures and preterm infant neurobehavioral disorders.


Title of Project: Exposure to Perfluoroalkyl Substances, Metabolomic Profiling, and Type 2 Diabetes Risk: A Prospective Investigation in an Ethnically Diverse U.S. Population.

Principal Investigator (MPI): Damaskini Valvi, MD, MPH, PhD

Co-Investigators:  Ruth Loos, PhD; Douglas Walker, PhD

Project Period:  January 31, 2020 – January 30, 2021

Pilot Award Amount: $70,000

 

Abstract: The prevalence of type 2 diabetes (T2D) has almost tripled over the past 40 years in the U.S., currently affecting more than 20 million people. Mounting evidence from studies in vivo and in vitro shows that exposures to environmental chemicals, such as perfluoroalkyl substances (PFAS), can alter insulin secretion and promote impaired glucose tolerance, and may therefore contribute to the T2D epidemic. PFAS constitute a major public health issue, as current exposure is widespread in the general population through contaminated drinking water and food along other possible exposure sources, and potentially associated health risks are not fully understood. Despite abundant experimental data, population-based evidence on the association of PFAS with T2D risk is limited, almost exclusively comprised by cross-sectional studies, and underlying mechanisms are underexplored. Therefore, we propose to investigate the prospective associations of PFAS exposures with incidence of T2D, and potential underlying mechanisms using state-of-the-art untargeted high-resolution metabolomics (HRM) technologies. We will conduct a prospective nested case-control study by selecting 180 incident T2D cases and 180 controls matched by age, sex, ancestry and calendar year at blood draw, from Mount Sinai’s BioMe. BioMe is an ongoing electronic health record-linked biobank that comprises >50,000 adult participants enrolled since 2007, with a broad spectrum of longitudinal data on health outcomes and clinical markers already recorded, and genome-wide array data available. We will utilize the unique archive of plasma samples collected from all BioMe participants at study entry (i.e. prior to T2D diagnosis), representing an ethnically diverse population residing in New York, to characterize exposure to PFAS and untargeted metabolomic pathways. Findings will support a planned R01 application to conduct the largest prospective study of well-phenotyped incident T2D cases to date, on the associations of PFAS exposures with the metabolome and T2D risk, as well as gene-environment interactions.


Title of Project: Phthalates and the developing brain: a multidisciplinary investigation of the effects of prenatal phthalate exposure on early markers of ADHD

Principal Investigator (MPI): Anna Rommel, PhD; Avi Reichenberg, PhD

Co-Investigators:  Shanna Swan, PhD; Muhammad Parvaz, PhD

Project Period:  January 31, 2020 – January 30, 2021

Pilot Award Amount: $20,000

 

Abstract: Phthalate plasticizers are ubiquitous in consumer products and can be detected in almost all pregnant women. Phthalates cross the placental and blood–brain barriers, affecting fetal brain development and subsequent functioning. Prenatal exposure to phthalates has been associated with adverse cognition and behaviour in areas central to attention deficit hyperactivity disorder (ADHD), including inattention and externalizing behaviours, and with increased risk for ADHD diagnosis. ADHD is the most prevalent neurodevelopmental disorder with enormous personal, medical and societal costs. Thus, early detection and intervention are crucial. Research has documented robust behavioural, cognitive and neurophysiological differences between individuals with ADHD and typically developing controls, which emerge in infancy and predict ADHD symptomatology later in life. These include activity levels, negative temperament, inattention, and alterations in event-related potentials (ERPs) indexing attention (i.e. P2 and P3). ERPs are electrical potentials generated by the brain in response to stimuli, which permit direct examinations of brain processes with millisecond temporal resolution. Here, we seek to obtain feasibility data to understand the biological basis via which phthalates alter brain and behavioral functioning to increase risk for ADHD. To do so, we propose to investigate the effects of 11 phthalates (MCPP, MEP, MIBP, MBP, MECPP, MEHHP, MEOHP, MBZP, MEHP, MCiOP, MCiNP) on neurophysiological development using ERPs indexing attention (P2 and P3) elicited by an auditory oddball task, and on behavioural and cognitive development using the Infant Behavior Questionnaire and the Ages and Stages Questionnaire. The significance of this study lies in the ability to provide a novel, objective method for assessing neural processes underlying the impact of intrauterine phthalate exposure on neurodevelopment and the earliest markers of ADHD. Identifying risk early is crucial for timely interventions to minimize the potential adverse effects of intrauterine phthalate exposure.