Project Title: Gut Microbiome, Endogenous Estrogens and Endocrine Disrupting Chemicals: A Pilot Study in the LEGACY Girls Study
Principal Investigators: Heather Greenlee, ND, PhD, Assistant Professor of Epidemiology; Brent Williams, PhD, Assistant Professor of Pathology and Cell Biology; and Mary Beth Terry, PhD, Professor of Epidemiology
Co-Investigator: Lauren Houghton, PhD, Associate Research Scientist in Epidemiology
Award Amount: $35,000
Abstract: The hormonal milieu during adolescence may be important in determining breast development, morphology and breast cancer risk. The intestinal microbiome can have a profound impact on the bioavailability of estrogens and estrogen disrupting chemicals by contributing to the proportion of recirculated and excreted estrogens. The proposed pilot study maximizes the infrastructure and existing data of the LEGACY Girls Study. The LEGACY Girls Study is a multi-site NCI-funded cohort study of girls in the US and Canada. Half of the study participants are from high-risk breast cancer families, and half are from average breast cancer risk families. The proposed pilot study will add stool sample collection in girls and their mothers (n=10 evaluable pairs). All stool samples will be analyzed for fecal microbiota diversity and abundance using 16S rRNA sequencing at the Mailman School of Public Health’s Center for Infection and Immunity. A subset of the stool samples (n=2 pairs) will be assessed by shotgun metagenomic sequencing. Urinary estrogen will be measured via estrone-1-glucuronide (E1G), an estrogen metabolite that is an indicator of total circulating estrogens. Endocrine disruptors will be assessed by measuring urinary polycyclic aromatic hydrocarbon (PAH) metabolites. The primary aim is to assess the feasibility of collecting, processing and analyzing stool samples among mother-daughter pairs who consent for this ancillary study. Secondary aims are 1) To describe the fecal microbiota diversity and abundance in girls and their mothers, and to demonstrate our capacity for functional metagenomic analyses of the microbiome in this cohort, and 2) to measure i) total circulating endogenous estrogens (as assessed by E1G) and ii) endocrine disrupting chemicals (as assessed by PAHs) in girls and their mothers. Pilot study results will be used to inform the design of a planned R01 submission to NCI to investigate the association between endogenous estrogens, endocrine disrupting environmental chemicals, the fecal microbiome and breast development in girls participating in the LEGACY Girls Study. This pilot study represents a new collaboration among four faculty members of the Mailman School of Public Health.
Project Title: Unraveling Gene-Environment Interactions and Window(s) of Exposure in TDP43-Linked Amyotrophic Lateral Sclerosis
Principal Investigator: Diane B. Re (aka Gourion-Arsiquaud), PhD, Assistant Professor of Environmental Health Sciences
Award Amount: $35,000
Abstract: Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a rare adult-onset neurological disorder (incidence 1-2/100,000 persons) preferentially affecting the neurons which control muscles and voluntary movement, the “motor neurons”. It is characterized by progressive muscle weakness and muscle mass loss, and progresses aggressively to complete paralysis and death within 1-5 years after symptom onset. In ALS, the motor neurons are progressively dying, but the underlying pathogenic mechanisms remain elusive, and there is no treatment to slow or halt this process. Importantly, only 5-10% of ALS cases can clearly be explained by a genetic cause. Most patients have no familial history and are called “sporadic” cases. This indicates that patient exposure to unknown environmental factors may have a strong role in the development of the disease. Some studies have suggested that the number of ALS cases is constantly progressing, faster than the aging of industrialized population, while others have described strikingly high number of ALS cases in small geographical areas or among groups sharing the same occupation. Currently, 90% of the research effort against ALS is geared toward its rare genetic forms. More research on the potential implication of the environment in ALS is necessary today if we want to prevent and treat sporadic ALS tomorrow.
Several environmental/occupational neurotoxicants have been suggested to be associated with ALS (heavy metals, pesticides, cyanobacterial neurotoxins). However, none have been clearly demonstrated to cause ALS. This demonstration is indeed difficult to accomplish knowing that even sporadic ALS is rare and cannot be solely reduced to the exposure to an environmental toxin. The majority of persons in geographical areas or occupational groups where ALS is high still do not develop the disease, even though the probability to be affected is multiplied by 2-100. This means that only a combination of individual susceptibility factors (genetics) and exposure to a toxin can lead to the development of ALS. This phenomenon is called “gene-environment” interaction. Our long-term objective is to develop reliable and relevant cell and animal models to study these deleterious interactions and elucidate pathogenic mechanisms that could lead to a treatment for ALS. Although several genetic factors of susceptibility to ALS have been suggested, again, none has been confirmed and susceptibility models are lacking. In the present pilot study, we believe that we found an unprecedented opportunity to study gene-environment interaction in ALS. Recently, our collaborator at Columbia University, Dr. Neil Shneider, has developed a new generation of genetic animal models of ALS. In contrast with previous transgenic mice that were expressing mutant genes at non-physiological levels (~3-22 times higher), these new models express only one or two copies of the mutation, more similar to what is seen in ALS patients. Moreover, the mutant gene was introduced to replace the mouse gene at its exact original location, assuring it will be expressed where it should be in the body and at the right level. Dr. Shneider’s lab has generated such a mouse with a mutation in the protein TDP-43 which is thought to be implicated not only in some familial cases of ALS, but also in most of the sporadic cases of ALS and of frontotemporal dementia, where it has been shown to accumulate and aggregate in tissues. Unfortunately for geneticists such as our collaborator, this sophisticated near-perfectly designed genetic mouse model does not develop ALS over the short lifespan of the mouse (2 years vs. 50-60 years median age of the disease development in humans). However, this model of TDP-43 “silent ALS” mice represents a unique opportunity for environmental health scientists to unravel the potential origin and mechanisms of sporadic ALS.
Accordingly, our first objective in this pilot study is to use cells produced from these mice that are relevant to ALS pathology (motor neurons and supporting cells called astrocytes) to screen for environmental toxins suggested to be involved in ALS (lead, manganese, arsenic, organophosphorous pesticides, and cyanobacterial beta-methylamino-Lalanine) and identify which one(s) can spark a TDP-43-related ALS pathology in a dish. Once such a toxin is identified, our second objective will be to expose TDP-43 silent ALS mice to this toxin following different temporal exposure paradigms (perinatal, adult, continuous …) to study if they develop symptoms of ALS (motor weakness, TDP-43 accumulation and aggregates in tissues) and which window(s) of exposure is (are) critical in doing so. The data generated in this pilot study could represent an unprecedented breakthrough in the ALS field as well as in the neurotoxicity of neurodegenerative disease field. Indeed, this work could validate for the first time an ALS-inducing toxin and provide some insights into the timing of exposure necessary across the life course to trigger adult-onset neurodegeneration.
Project Title: E-cigarettes and circulating microRNAs in extracellular vesicles
Principal Investigator: Elizabeth C. Oelsner, MD, MPH, Assistant Professor, Division of General Medicine
Co-Investigators/Mentors: Andrea Baccarelli, MD, PhD, Professor and Chair of Environmental Health Sciences; R. Graham Barr, MD, DrPH, Professor and Chief, Division of General Medicine
Award Amount: $35,000
Abstract: E-cigarettes are increasingly popular, including among youth and young adults. E-cigarettes are also relatively new, so the long-term health effects of e-cigarettes are currently unknowable. E-cigarette vapor is known to contain chemicals that can have potentially toxic effects on the lungs and other organs. So, in order to inform public health and relevant regulation of e-cigarettes, it is important to understand whether e-cigarette use has short-term effects that might allow us to predict long-term risks. In this pilot study, we propose to test for the first time whether e-cigarette use is associated with changes in circulating extracellular vesicles and the microRNAs they contain—often described as “messages in a bottle”—which together serve important roles in cell-to-cell signaling. These can be measured by a simple blood draw, and provide enormous amounts of information on how exposures are affecting cells throughout the body. We propose two related studies to assess the feasibility of our protocol and to obtain preliminary pilot data. First, to assess the chronic effects of e-cigarette use, we will compare the amount and size of extracellular vesicles in the blood, and which microRNAs they tend to contain, in 10 young adults who have never used e-cigarettes, 10 intermittent e-cigarette users, and 10 daily e-cigarette users. Second, to assess the acute effects of e-cigarette use, we will test how quickly and in what ways “vaping” a standardized e-cigarette alters circulating extracellular vesicles and microRNA profiles in 10 intermittent e-cigarette users. If we discover that there are substantial differences in extracellular vesicles and microRNAs between e-cigarette users and non-users, and before and after “vaping,” this will suggest that e-cigarettes may have important health effects, warranting larger-scale studies using these innovative measures.
Project Title: Prenatal exposure to organophosphates and PD-like symptoms in adolescence
Principal Investigator: Virginia A. Rauh, ScD, Professor of Population and Family Health
Award Amount: $35,000
Abstract: Findings to date suggest that prenatal exposure to chlorpyrifos (CPF), a widely used organophosphate (OP) insecticide, is associated with persistent brain, behavioral and motor effects in different populations of children, using different biomarkers of exposure (Rauh et al., 2011; Engel et al., 2011; Bouchard et al, 2011). Specifically, in the urban CCCEH cohort, there is recent evidence of persistent motor deficits/movement disorders, including poor finger dexterity and tremor among 11-12 year old children who were highly exposed during the prenatal period (Rauh et al., 2015). In adult populations, there is growing evidence from other studies that OP insecticide exposures may be associated with Parkinson’s Disease (PD), a progressive disorder of the nervous system that affects movement (Pessoli and Cereda, 2013). As part of a new P50 (NIEHS, M-PIs, Peterson and Perera; PI of Neurodevelopmental Study, Rauh), we are now funded to conduct neuropsychological testing and repeated structural MRI at 16-18 years of age on the CCCEH cohort of children (N=350 will receive the full assessment under P50 funding), who have been followed since the prenatal period. In light of the evidence that OP pesticide exposures may be associated with PD in adults, and evidence of measureable motor problems throughout childhood in the CCCEH cohort among those children who were highly exposed during the prenatal period (Rauh et al., 2006; Rauh et al., 2015), we now propose to leverage the existing P50 center grant, in a subset of 75 children, to investigate the novel hypothesis that prenatal CPF exposure in an urban cohort may have long-term motor consequences, as measured by early preclinical and non-motor indicators for PD-like problems.
Project Title: Low-level arsenic exposure and markers of chronic lung disease among aging US adults: A pilot study in the Multi-Ethnic Study of Atherosclerosis-Lung (MESA-Lung)
Principal Investigators: Ana Navas-Acien, MD, PhD, Professor of Environmental Health Sciences and Tiffany Sanchez, PhD, Postdoctoral Research Scientist, EHS
Co-Investigators: Miranda Jones, John Hopkins School Public Health; Maria Grau, MS, EHS; Matt Perzanowski, PhD, EHS; Elizabeth Oelsner, MD, General Medicine; R. Graham Barr, MD, General Medicine; Joseph Graziano, PhD, EHS
Award Amount: $30,000
Abstract: Environmental exposures affecting chronic respiratory disease are frequently ascribed to air toxicants and bio-aerosols, meaning research on the environmental sources of respiratory disease tends to focus on inhaled exposures. Interestingly, the ingestion of inorganic arsenic from naturally contaminated groundwater can cause lung cancer and is also associated with non-malignant respiratory disease. Existing research shows that moderate (10-50 µg/L) and high (>50 µg/L) levels of exposure to arsenic through drinking water are associated with poorer lung function in children, adolescents, and adults. Chronic high water arsenic exposure is markedly associated with increased bronchiectasis mortality, a rare lung disease associated with repeated respiratory infections. The existing epidemiologic research comes from Bangladesh, India, Pakistan, Chile, and Mexico. However, few studies have focused on the relation between arsenic and chronic lung disease in the United States, where water arsenic exposure is much lower (<10 µg/L) and populations are exposed to arsenic mostly through food. Computed tomography (CT) markers can further distinguish among different forms of lung disease and detect early changes in structure which are precursors to clinically apparent lung disease. Studying these novel markers in combination with lung function tests will significantly improve the pathophysiologic understanding of arsenic-associated lung disease. The goal of this pilot study is to determine whether chronic low-level arsenic exposure (measured in two urine samples over 10-years of follow-up) is associated with clinically meaningful and mechanistically relevant markers of chronic lung disease in a US-based cohort of older adults. This pilot will draw upon a random sample of 300 participants of the Multi-Ethnic Study of Atherosclerosis-Lung Study (MESA-Lung). Half of the proposed participants already have had Exam 1 (2000-2002) arsenic measured as part of a previous study, in this pilot we will measure arsenic from Exam 1 urine for the other half of the participants (a chest CT scan was first obtained at Exam 1) in addition to measuring arsenic from Exam 5 (2010-2012), when a lung function and a full-lung CT scan were also obtained for all 300 participants. This pilot study addresses several of the Center for Environmental Health in Northern Manhattan’s thematic goals. Our proposed research focuses on better understanding the impact low-level environmental arsenic exposure has on the respiratory system among an ageing population for whom lung disease development and progression is easiest to detect. We plan to use the data generated from this pilot study to develop and submit a K99/R00 and an R01 proposal in the following year. The proposed research uses the Trace Metals and Integrative Health Sciences Cores to achieve its goals.
Project Title: Relocation of the ‘Fresh Direct’ online food distribution facility from Queens to the South Bronx: Impacts on a community already subjected to significant levels of air pollution
Principal Investigator: Markus Hilpert, PhD, Associate Professor of Environmental Health Sciences
Co-Investigators: Steve Chillrud, LDEO; David Evans, COEC; Diana Hernandez, SMS and COEC Director; Upmanu Lall, Earth & Environmental Engineering; Mychal Johnson, South Bronx Unite (Community Partner)
Award Amount: $27K + $4K Supplement (Dean’s Funds)
Abstract: Fresh Direct, an online grocery store in NYC, is planning to relocate its distribution center from Queens to the Harlem River Yards in the South Bronx. This area is already heavily impacted by environmental pollution due to waste management facilities, hydrocarbon storage facilities, and vehicle exhaust from major traffic arteries. All school and public playgrounds are in close proximity to these arteries. The elevated levels of air pollution are linked to the exceedingly high prevalence of asthma and cardiovascular disease within the community. The goal of this pilot study is to gather scientific evidence, which will enable the community to advocate for (1) access to high-quality green space and (2) interventions that mitigate the adverse health impacts of the already substantial air pollution, which can be expected to increase due to the relocation. To achieve these goals, we propose to measure, document and analyze current air pollution [Black Carbon (BC) and fine particulate matter (PM2.5)], noise levels, and traffic counts for a 3-month period. We also propose to conduct horizontally and vertically resolved short-term measurements of BC to (1) quantify the exposure of playing children, (2) explore whether exposure would be lower on alternative playground locations on the waterfront, and (3) understand better how emissions from the major traffic arteries cause air pollution in the playgrounds.