Pilot Projects Awarded 2019

Title of Project: Defining Integrated Environmental Exposure Measures in Adolescents

Principal Investigator (MPI): Yuri Levin-Schwartz, PhD; Robert Wright, MD, MPH

Co-Investigators: Elena Colicino, PhD; Donald R. Smith PhD

Project Period: July 1, 2019 – June 30, 2020

Pilot Award Amount: $25,000

 

Abstract: The measurement of a compound in a single biological sample is unlikely to fully represent the relative body burden of an environmental exposure, since no single tissue can encapsulate the overall toxicokinetics for most chemicals. Yet, this is the most commonly used surrogate of chemical exposure in environmental epidemiology research. Since each exposure biomarker provides complementary information about the level of exposure, we propose to develop and use methods that will take advantage of this information to create integrated exposure estimates, referred to as multi-media biomarkers (MMBs). As part of the Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) cohort, our group has collected samples of multiple biological media (blood, nails, urine, hair, bone and shed deciduous teeth) from mothers during pregnancy and after pregnancy. In this proposal, we will measure the concentrations of lead (Pb) in 100 women using stored urine from the second trimester of pregnancy and first month postpartum as well as nails from the same women from the first month postpartum to match similar measurements already done using the other media. Using exposure estimates from each medium, we will compare the utility of the individual media with that of the MMBs to assess to impact of Pb exposure, measured prenatally and postnatally, on neurodevelopment in the children as well as determine the existence of any window of susceptibility. This proposed work has the potential to transform environmental exposure quantification from the selection of one media over others to the joint use of multiple media to derive more accurate measures of exposure.


Title of Project: Environmental control of mitochondrial division as a signal to initiate skin cancer

Principal Investigator:  Jerry Chipuk, PhD

Project Period:   July 1, 2019 – June 30, 2020

Pilot Award Amount: $25,000

 

Abstract:  The skin is a fascinating and complex organ because it protects the body from the environment, microbes, and coordinates a multitude of homeostatic functions. Within the skin are neural crest derived melaninproducing cells known as melanocytes which offer protection from the sun’s damaging UV radiation. Melanocytes often develop an activating mutation in RAS (G12V) or BRAF (V600E) causing unwarranted proliferation that activates a tumor suppressor program referred to as oncogene-induced senescence (OIS). OIS initiates epigenetic, metabolic, and secretory reprogramming that arrests the targeted cell in a senescent state. Clusters of senescent melanocytes are clinically referred to as a nevus (i.e., mole), and they persist for decades. Over the decades, it is suggested that additional alterations from endogenous or environmental factors impact upon a few of these cells within a nevus to promote their escape from senescence leading to malignant transformation and melanomagenesis. In this application, we propose to establish that environmental factors such as heavy metals and ultraviolet radiation directly signal for mitochondrial division to promote OIS escape leading to melanoma. The premise for this application is our unpublished dataset using primary human melanocytes that we commit to RASG12V- or BRAFV600E-induced senescence and culture for months. These senescent melanocytes express all the normal markers and cytokines as patient nevi. When we induce senescence with lentivirus encoding for oncogenic RAS/BRAF, we also silently introduce a pharmacologically activated mitochondrial dynamin (dynamin related protein 1, DRP1) that can physiologically divide the mitochondrial network within a few minutes. Turning on DRP1 after a few months of senescence causes a subset of senescent melanocytes to escape from OIS and transform. Based on the literature, heavy metals and ultraviolet radiation alone cause mitochondrial stress and division, but no mechanistic links have been established to OIS or cancer. We wish to fill this knowledge gap with this pilot award and generate sufficient preliminary data for an R01 application.


Title of Project: Exposomics for agricultural workers in Costa Rica affected by chronic kidney disease of unknown etiology (CKDu)
Principal Investigator (MPI): Alison Sanders, PhD; Douglas Walker, PhD

Co-Investigators:  Jennifer Crowe, MPH, PhD; Andres Cardenas, PhD, MPH; Chris Gennings, PhD

Project Period:   July 1, 2019 – June 30, 2020

Pilot Award Amount: $69,608

 

Abstract: Chronic Kidney Disease of unknown etiology (CKDu) is a public health emergency in Central America and regions of Sri Lanka and India. CKDu affects agricultural workers and communities and it is not explained by traditional risk factors for kidney disease like age, hypertension or diabetes. Underlying factors contributing to the epidemic are unknown but likely multifactorial. Occupational exposure to agrochemicals, heat stress and metals are among the leading hypotheses; however, studies have focused on only a limited number of environmental exposures that are not representative of the complex exposures likely experienced by agricultural workers. Use and reuse of agricultural land and agrochemicals might transform, volatilize and degrade compounds, which would be missed by targeted chemical screenings. In this study, we will develop a framework to comprehensively characterize the exposome and complex mixture profiles of agricultural workers in a province of Costa Rica heavily affected by the CKDu epidemic. To achieve this goal, we will leverage an ongoing study of farmworkers in the region with well-characterized job history and baseline kidney function measures. We will deploy silicone wristbands as passive samplers for untargeted chemical screening during the workweek and will collect pre- and post-work urine samples to evaluate wristband profiles as a proxy for urinary exposure biomarkers. Our team includes experts in occupational health (co-I: Crowe), environmental/molecular epidemiology (co-I: Cardenas and co-PI: Sanders), exposomics and metabolomics (co-PI: Walker), biostatistics (co-I: Gennings) and renal epidemiology/toxicology (co-PI: Sanders). This work will advance our understanding of environmental exposures among CKDu affected farmworkers allowing us to compare and contrast exposure profiles within different job types. The proposed research will provide ample pilot data and samples for future R01 applications evaluating the exposome of populations at risk of CKDu for informing future interventions designed to prevent nephrotoxic occupational co-exposures.


Title of Project: Using deciduous teeth to assess children’s exposure to tobacco, marijuana, and other environmental toxins

Principal Investigator: Karen Wilson, MD, MPH

Co-Investigators: Manish Arora, BDS, MPH, PhD, FICD; Syam Andra, PhD

Project Period:  July 1, 2019 – June 30, 2020

Pilot Award Amount: $70,000

 

Abstract: With increasing marijuana legalization across the US, there are more opportunities for children to be exposed to secondhand marijuana smoke; however, we don’t have any research to explore the impact of marijuana smoke exposure on children’s health. We do not understand the prevalence of exposure among children, or whether there is coexposure with tobacco, or with pesticides used in the production of marijuana. Current research methods, especially in looking at long term exposure and outcomes, are significantly limited by ongoing fears of reporting children with exposure to children’s services. Analysis of shed deciduous teeth offers the opportunity to collect teeth and data anonymously, and yet still have a longitudinal picture of a child’s exposure, both prenatally and postnatally. Our project seeks to demonstrate this strategy and test the technology by recruiting 100 children from the Pediatric Associates Clinic, and obtain an anonymous parent report of exposures, health history, and current health. Parents will then return the child’s shed deciduous tooth to the study team, whether it will be analyzed in the lab for metabolites of marijuana and tobacco, electronic cigarette aerosol, and pesticides. This preliminary data will be critical for submission of an R01 to study the impact of marijuana smoke exposure on the health of children.


Title of Project: Innovating Data Visualization Strategies for Tooth-Based Lead Report-Back

Principal Investigator (MPI): Sarah Evans, PhD, MPH; Manish Arora, BDS, MPH, PhD, FICD; Maida Galvez, MD, MPH

Co-Investigators: Alison Mears, AIA

Project Period:  July 1, 2019 – June 30, 2020

Pilot Award Amount: $20,000

 

Abstract: Reporting back biomonitoring data to study subjects has the potential to improve health literacy and promote exposure reduction behaviors. Technological advances in the field of exposure assessment allow for detection of biomarkers in novel matrices and measurement of multiple exposures across time, but resultant data is complex and clinical relevance is often uncertain. This poses unique challenges for communication of individual exposure data to study subjects in an understandable and meaningful way. Using methods pioneered in the Frank R. Lautenberg Laboratory for Environmental Health Sciences at Mount Sinai, we are able to reconstruct early life exposures to lead and other chemicals using deciduous teeth, contributing to our understanding of critical developmental periods during which organ systems are most susceptible to harm. This proposal seeks to develop effective strategies for reporting back individual child tooth lead data to families enrolled in birth cohort studies with the aim of promoting exposure-reduction behaviors. Given clinical uncertainty and the lack of normative data on tooth-lead levels, communicating results requires an innovative approach. To address these challenges, we will partner with students from the Parsons School of Design to create a novel, multi-modal strategy for reporting tooth lead levels to study subjects. This team science approach allows for cross-talk between environmental health scientists and data visualization and communication experts to create impactful public health messaging. Reports will include individual and aggregate tooth lead data, information about the health effects of lead exposure, and exposure reduction tips. Usability and efficacy of the developed materials will be tested in focus groups with English and Spanish speaking members of the East Harlem community. Feedback received will be used to modify the report-back strategy for future studies in which tooth lead data will be disseminated to participants in active birth cohort studies in the United States and Mexico.


Title of Project: Predicting response to immunotherapy in hepatocellular carcinoma by dissecting the gut microbiome: a pilot study

Principal Investigator (MPI): Amaia Lujambio, PhD; Celina Ang, MD; Jeremiah Faith, PhD

Co-Investigators:  Andrea Branch, PhD; Lauren Grinspan, MD; Tomi Jun, MD

Project Period:  July 1, 2019 – June 30, 2020

Pilot Award Amount: $50,000

 

Abstract: Background: Hepatocellular carcinoma (HCC) is a common and deadly cancer of the liver. Newlyapproved immune checkpoint inhibitors (ICIs) such as nivolumab can produce durable responses, but only 15-20% of patients respond to these treatments. Studies have suggested that the gut microbiome – – the microbial community of the digestive tract that forms a stable immunomodulatory component of our environment — may influence patients’ responses to immunotherapy. We propose a pilot study to determine whether the gut microbiome influences patients’ response to ICIs in HCC. Objectives: In this proposal, we study the fecal microbiome of 50 HCC patients before and after receiving an ICI (nivolumab or pembrolizumab) to test the following hypotheses: 1) Microbial taxa and diversity differ between ICI responders and non-responders in advanced HCC. 2) Changes in the gut microbiota that occur following ICI treatment differ between ICI responders and non-responders. 3) Gnotobiotic mice receiving fecal transplants from responders will exhibit greater response to ICIs compared to mice receiving fecal transplants from non-responders. Methods: We will collect pre- and 8 week-post-treatment stool and blood samples from patients with advanced HCC who receive an ICI. Stool microbial composition will be determined using 16S rRNA sequencing. Mouse studies will make use of a novel CRISPR-Cas9 based model of HCC carcinogenesis optimized to study immunotherapies. Significance/innovation: This proposal takes advantage of the large HCC patient population at Mount Sinai and the combined effort of investigators across the institution with expertise in oncology, in vivo liver cancer models, and the gut microbiome, to understand the role of the gut microbiome as an environmental factor that modulates the efficacy of ICIs in HCC. This pilot award will enable us to generate preliminary data necessary to be competitive for a recently announced RFA from the NIH that is devoted to microbiota-manipulation strategies for cancer therapy.

 


Title of Project: Using eye-tracking to Identify associations between metal exposure and children’s social cognition: A pilot study in Mexico City

Principal Investigator (MPI): Elza Rechtman, PhD; Megan Horton, PhD

Co-Investigators:  Roberto Lucchini, MD; Paul Curtin, PhD; Manish Arora, BDS, MPH, PhD, FICD; Christine Austin, PhD

Project Period:  July 1, 2019 – June 30, 2020

Pilot Award Amount: $25,000

 

Abstract: Social cognition refers to the cognitive process by which humans infer the state of mind of others and anticipate their reactions. This complex skill relies on integrated information processing, including the perception of social cues gathered from faces, eyes, hands and body of others. Growing research indicates that early life exposure to neurotoxicant metals including lead and manganese is associated with maladaptive social behavior. Although promising, these findings have been based on self- and parent-reports of social behavior which suffer from response biases. While the value of collecting objective phenotyping measures along with surveys has long been recognized, the majority of large-scale community and population studies rely on survey reports of social behavior. In this costeffective and innovative proposal, we propose to use eye-tracking as an objective phenotyping tool for detecting environmentally-associated changes in social cognition. Eye-tracking is a simple, rapid, non-invasive, sensitive and quantitative method enabling of recording spontaneous, unconscious gaze behavior towards socially relevant cues that provides insight into neural processing. We hypothesize that early life metal exposure adversely impacts social perception and that eye-tracking is a more sensitive assessment of environmentally-induced changes in neural connectivity. To test this, we leverage the PROGRESS study with existing longitudinal exposure and behavioral measurements and ongoing follow-up including high-resolution neuroimaging. We propose to add a recognized naturalistic eye-tracking paradigm of clips displaying peer-to-peer social interactions, and measure viewing time and number of fixations at the eyes, mouth, and faces of characters. We will examine associations between early life Pb and Mn exposure (in blood and teeth) and social cognition using eye tracking and parent-reported scale of social behavior. We will then investigate associations between early life metal exposure and intrinsic functional connectivity of the social brain. To our knowledge, no other study has attempted to investigate associations between similar aspects of social cognition, longitudinal assessment of early life metal exposure and high-resolution brain imaging.

 


Title of Project: Secondhand smoke in Central and East Harlem: Understating cancer survivors’ and family caregivers’ perceptions of the health consequences of involuntary and voluntary exposure to tobacco smoke

Principal Investigator (MPI): Nihal E. Mohamed, PhD; Lina Jandorf, MA

Co-Investigators:  Karen Wilson, MD, MPH

Project Period:  July 1, 2019 – June 30, 2020

Pilot Award Amount: $50,000

 

Abstract: Prior research showed that approximately half (46.8%) of African Americans (AA) and a quarter (23.9%) of Hispanic nonsmokers are exposed to secondhand smoke (SHS) in the US. This exposure is high in individuals with low socioeconomic levels, and in particular among those living in multiunit and subsidized housing conditions. The impact of SHS might be more detrimental for AA and Hispanic cancer survivors who live in multiunit and subsidized housing. Reported challenges in physician-patient communication about smoking cessation also indicate that a discussion about SHS exposure and risk might be insufficient because of the fear of damaging therapeutic relationships, concerns about exacerbating patients’ guilt, and lack of physician’s good understanding about SHS risks and prevention. Unfortunately, studies on SHS in at-risk AA and Hispanic cancer survivors and their family caregivers are limited. Guided by an established theoretical framework, literature reviews, and our prior studies, we will (Aim 1-a/b) explore cancer survivors’ and caregivers’ perceptions about their exposure, (i.e., both voluntary and involuntary) and how it affects their health; and (Aim 1-c) how SHS exposure affects the health of children living in their communities. We will recruit 30 survivors living in public housing in East and Central Harlem and their family caregivers (N = 30) to examine the study aims. Participants will be invited to participate in 12 focus groups. Focus groups will be stratified by race, role (survivors/caregiver) and smoking status (nonsmoker vs. smoker) to examine: 1) knowledge, impact on health, and salient beliefs about exposure to SHS; and 2) input on successful strategies to prevent SHS. All focus groups will be qualitatively analyzed using Atlas.ti software. The study outcomes will inform the design of a biobehavioral study to assess actual exposure (Cotinine levels), risk perceptions, health beliefs, and health outcomes in AA and Hispanic cancer survivors and their caregivers.