Pilot Projects 2014

2014 Round 1

  1. David Christiani et al, Genome-wide microRNAs expression profiles and birth weight in umbilical cord serum among women and infants exposed prenatally to inorganic arsenic. ($22,500) Abstract
  2. John Godlleski and Alex Carll, Does Inhalation of Traffic-Related Particulates Impair Cardiac Performance? ($22,500) Abstract
  3. Mi-Sun Lee et al, Cardiac Autonomic Effects of Secondhand Exposure to Electronic Cigarettes (ECigarettes). ($20,000) Abstract
  4. Alex Lu et al, The interplay of sub-lethal neonicotinoids exposure, mitochondrial epigenetics, and Parkinson’s disease. ($22,500) Abstract
  5. Ronit Machtinger et al, BPA and Phthalate exposure, FF exosomes, and IVF outcome. ($15,000) Abstract
  6. Marc Weisskopf et al, Assessment of a novel portable x-ray fluorescence device to measure bone lead. ($17,500) Abstract

2014 Round 2

  1. Gary Adamkiewicz: Pilot Development of a Dorchester Air Quality Surveillance System (DAQSS). ($22,000) Abstract
  2. Joe Allen: Evaluation of inhalation exposure to diacetyl and other flavoring compounds in e- cigarette. ($22,000) Abstract
  3. Jennifer Bobb: A statistical approach for estimating the health effects of air pollution mixtures on multiple outcomes simultaneously. ($22,000) Abstract
  4. Rama Krishnan: Assessment of Environmental Toxins: Bridging the Gap Between Cell Assays and Intact Animals/Humans. ($22,000) Abstract
  5. Jim Shine: Assessment of heavy metals levels in soil and among a human population living near a copper smelter in Chile. ($22,000) Abstract

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David Christiani et al, Genome-wide microRNAs expression profiles and birth weight in umbilical cord serum among women and infants exposed prenatally to inorganic arsenic. ($22,500)
About 130 million people world-wide are being poisoned by inorganic arsenic through drinking water with levels (>10 μg/L) higher than the guideline values defined by the World Health Organization [1]. Arsenic at a modest level (<100 μg/L in urine) is known to induce toxic effect on the developing fetus and has been found to be associated with decreased birth weight, head and chest circumference and increased risk of infection in infants [2,3]. Low birth weight is one of the major causes of perinatal morbidity and mortality and also associated with an increased risk for certain diseases later in life [4]. Both genetic and epigenetic mechanisms, including alteration of microRNA (miRNA) expression profiles are believed to play an important role in the pathogenesis of many arsenic associated disease [5]. The goal of this pilot study is to explore miRNA expression profiles in cord blood serum to elucidate the molecular basis that underlie in utero arsenic exposure with birth weight and generate preliminary data for a full proposal. Since exposure data in our study population has already been collected, we propose to use this archived resource to explore how well maternal blood, urine, hair and nail arsenic correlate with the miRNA expression profiles in cord blood with a view to understand in-utero fetal exposure. The results of this pilot study will be used as preliminary data to apply for a five-year RO1 grant.

John Godlleski and Alex Carll, Does Inhalation of Traffic-Related Particulates Impair Cardiac Performance? ($22,500)
Traffic-derived particulate matter (TPM) exposure is linked to heart failure morbidity and mortality. Prior research suggests TPM may impair left ventricular (LV) performance (contractility and lusitropy) by enhancing the autonomic nervous system’s (ANS) sympathetic influence. Yet, the evidence supporting this mechanism is limited by unrepresentative exposures and a crude index of LV contractility. This project will: 1) develop chronic LV pressure (LVP) measurements; 2) test whether repeat exposure to real-world TPM at environmentally relevant concentrations impairs LV performance; and 3) determine if increased sympathetic tone mediates these effects. Rats will be analyzed during and after a 4-wk exposure to TPM from our novel highway tunnel exposure system (vs. clean air) using telemetry-derived chronic LVP, electrocardiogram (ECG), blood pressure (BP), heart rate, and heart rate variability (HRV, a measure of ANS balance). We will subsequently compare air- or TPM-exposed rats treated with a sympathetic inhibitor (guanethidine) or saline to test for sympathetic mediation of TPM-induced cardiotoxicity. Stress tests and baroreflex challenges will be used to unmask latent effects of TPM on LV performance and ANS regulation during increased cardiac demand. Echocardiography (Echo) and molecular assays will test for LV performance decrements and their potential mediators.

Mi-Sun Lee et al, Cardiac Autonomic Effects of Secondhand Exposure to Electronic Cigarettes (ECigarettes). ($20,000)
Electronic cigarettes, e-cigarettes or electronic nicotine delivery systems, are battery-operated devices that vaporize chemical mixtures composed of nicotine, propylene glycol and other chemicals. As the use of ecigarettes is becoming popular, secondhand smoke exposure from e-cigarettes is increasing among nonsmokers and children, but limited data is available about their safety, raising significant public health concerns. Recently, a few studies have shown that increased airway resistance and decreased pulmonary function are linked to e-cigarettes exposure, but, to our knowledge, it is not yet to be explored whether secondhand exposure to e-cigarette is associated with cardiovascular disease, which remains the leading cause of death worldwide. Our pilot study employs a repeated measures design to assess whether secondhand exposure to e-cigarette is associated with changes in cardiac autonomic function. Specifically, we will examine the association between selected airborne markers and biomarkers of nicotine and tobaccorelated toxicants from e-cigarettes, and heart rate variability (HRV) extended in lifelong nonsmokers. Findings from this study will be used as preliminary data to apply for a five-year RO1 grant to elucidate the chronic effects of e-cigarettes exposure.

Alex Lu et al, The interplay of sub-lethal neonicotinoids exposure, mitochondrial epigenetics, and Parkinson’s disease. ($22,500)
Parkinson’s disease (PD) is the most prevalent neurodegenerative movement disorder. Higher incidence of PD has been associated with farmers, and therefore agricultural pesticides have been implicated as the agents for PD progression. However the exact mechanisms on how pesticides affect PD are largely unknown. Data from our current study in honeybees have suggested a significant link of sub-lethal neonicotinoid exposure and the increase of mitochondrial DNA copy number (mtDNAcn) over generations. Here we aim to demonstrate how imidacloprid, the most persistent and commonly used neonicotinoid insecticide, affects PD using human neuroblastoma SH-SY5Y cell lines. The differentiated SH-SY5Y cell lines with Parkin- knockdown and overexpressing, provide a unique opportunity to examine the changes of mtDNAcn and the mtDNA methylation. This proposed study will expand our understanding on how neonicotinoids affect neurodegenerative disease such as PD, establish a cell line based protocol to examine the causal relationship, and pave the way to develop health-based biomarkers such as mtDNAcn and mtDNA methylation for future epidemiological research.

Ronit Machtinger et al, BPA and Phthalate exposure, FF exosomes, and IVF outcome. ($15,000)
Concerns are increasing that endocrine disrupting chemicals (EDCs) may have adverse effects on animal and human fertility. We have shown that in vitro exposure of immature human oocytes to bisphenol-A (BPA) impaired oocyte maturation and spindle formation. However, the mechanism by which bisphenol A and EDCs affect oocyte quality is unclear. The human oocyte is surrounded by and in bi-directional communication with cumulus granulosa cells which, in turn, are bathed in follicular fluid (FF) within the ovarian follicle. Innovative studies have proposed that intercellular transmission within the follicle might involve secretion and uptake of microRNAs (miRNAs) carried in membrane-bound extracellular vesicles such as exosomes. Our hypothesis is that EDCs such as BPA and phthalates in the FF might alter FF exosome profile and secretion of miRNAs and thus impair oocyte maturation, fertilization and day 3 embryo quality. We propose to isolate exosomes from the FF among women undergoing IVF. The goals of this pilot grant are to investigate whether there is a correlation between FF levels of BPA and phthalate metabolites with miRNA profiles of FF exosomes (Aim 1) and to determine the association of miRNA profiles of FF exosomes with oocyte maturation and day 3 embryo quality (Aim 2).


Marc Weisskopf et al, Assessment of a novel portable x-ray fluorescence device to measure bone lead. ($17,500)
The development of X-Ray Fluorescence (XRF) techniques to measure lead in bone led to a windfall of critical scientific research implicating cumulative exposure to lead in hypertension, heart disease, renal dysfunction, cognitive decline, Parkinson disease, cataracts, and psychiatric symptoms to name a few. However, the Kshell XRF (KXRF) using a 109Cd energy source which has been the principle method used for bone lead analysis has severe limitations such that all of this work has been essentially limited to only two research groups. Furthermore, the limitations make it impossible to use in many epidemiological studies, thereby limiting what questions can be asked. The KXRF approach requires a dedicated room; it requires at least one half hour of measurement time; and it uses a radioactive isotope in limited production as an energy source, which currently severely restricts the use of the technique because of regulatory demands. To address these limitations, we propose to conduct a pilot study to assess a portable XRF (pXRF) device to non-invasively measure lead in vivo in bone. We aim to compare results with this new approach against existing serial blood lead measurements and KXRF measurements in the Normative Aging Study, and an occupationally exposed population seen at the Cambridge Health Alliance. Demonstrating comparable results with the use of the pXRF could result in tremendous new research opportunities in settings among children or patients of diseases that affect their ability to come to a central research site(e.g. Alzheimer’s disease or ALS), as well as in field settings where exposures are often highest.

 

2014 Round 2

Gary Adamkiewicz: Pilot Development of a Dorchester Air Quality Surveillance System (DAQSS). ($22,000)
We propose to build a partnership between HSPH, MIT and Dorchester-based community groups to establish a prototype real-time community-based and community-scale air quality sensor network. This model is based on the web-based CLAIRITY monitoring network which is currently operational on the MIT campus. The proposed network will utilize low-cost and web-connected sensors, data storage and data visualization to allow for community and researcher engagement with quantitative air quality data collected across exposure-relevant spatial and temporal scales. Via the collaborative, we will work closely with community partners to design a real-time interface for dissemination of the data acquired with the network. Our aim is to provide the community with interactive tools that promote exploration and understanding of the factors controlling their air quality. Our expectation is the network will result in data-driven strategies to mitigate community-specific exposures, addressing topics that are central to the scientific and societal mission of the NIEHS center. We are confident that such a platform will have significant application to other studies and grant opportunities in the coming year, as evidenced by specific EPA and NIH RFPs.

Joe Allen: Evaluation of inhalation exposure to diacetyl and other flavoring compounds in e- cigarette. ($22,000)
The World Health Organization reports that $13 billion was spent on e-cigarettes in 2013, with sales expected to increase 17-fold in 15 years. A staggering number of children have begun to experiment with this product; CDC estimates that 1.75 million children tried e-cigarettes as of 2012, with 160,000 of them reporting that they had not used tobacco cigarettes. There has been very little research on the health implications from the constituents of e-cigarettes. Of that research, there is none that examines the flavoring chemicals used in e-cigarettes, despite over 7,000 flavors currently being marketed. Chemicals used in flavorings gained notoriety in the early 2000’s after workers at microwave popcorn were diagnosed with bronchiolitis obliterans, which was attributed to diacetyl exposure from inhalation of vapors off heated mixing vats. Diacetyl, a flavoring compound, and its replacements, 2,3-pentanedione and acetoin, are used in the manufacture of many foods for a wide range of flavors beyond butter (e.g., caramel, cream, pina colada, strawberry). Many of these flavors are common in e-cigarette flavor cartridges, and, similar to popcorn workers, users of e-cigarettes are directly inhaling heated flavoring compounds. We propose to quantify the concentrations of these flavoring compounds in e-cigarettes, estimate exposures for users of e-cigarettes, and compare these to health-based guidelines.


Jennifer Bobb: A statistical approach for estimating the health effects of air pollution mixtures on multiple outcomes simultaneously. ($22,000)
In environmental epidemiology, the most common approach is to select a few health outcomes hypothesized a priori to be affected by the exposure and then estimate the exposure-response function and associated risks. However, a key limitation of this approach is that other adverse outcomes that are clinically important but less expected or less common could be missed. In this study, we will develop a new scientific paradigm for analyzing a massive number of health outcomes simultaneously. We will apply this framework to identify the complete spectrum of health conditions that are most likely to occur during air pollution events, defined as days with high levels of several pollutants concurrently. This project will enable us to study, for the first time, the short-term effects of exposure to air pollution mixtures on more than 15,000 ICD-9 codes simultaneously, rather than on pre-specified individual conditions. Knowledge of the range of health responses that are affected by air pollution mixtures will provide insight into the physiological pathways by which pollution affects health, thereby informing public health approaches to prevention. Moreover, the statistical approach will enable future studies to estimate the impacts of exposures to mixtures of metals, organic chemicals, particulate matter, and other toxins on large constellations of human health outcomes.


Rama Krishnan: Assessment of Environmental Toxins: Bridging the Gap Between Cell Assays and Intact Animals/Humans. ($22,000)
Science and technology produce abundant new chemicals and particles. The NIEHS, NTP, and other government agencies are faced with identifying ones that have potential health and ecological threats. Currently, our NIEHS Center has a number of cell-based assays that emphasize high throughput screening. At the other end of the spectrum, we have lifetime animal studies in rodents, as exemplified by the classical NTP approach. There is even a smaller number of toxins with data from epidemiologic studies in humans. Between these oversimplified assays and the complexity and expense of studying intact animals and humans, there is an important gap. This pilot project intends to fill that gap with an assay that is capable of testing large numbers of environmental toxins, and yet better represents the complexity of intact animals and humans. We propose to improve and calibrate an assay, Precision Cut Lung Slices (PCLS), to investigate chemicals that are likely to be toxic. We take advantage of our experience with zinc chloride (ZnCl2) chemical exposures. Zinc (Zn) will serve as a model toxin to determine the predictive power of the proposed platform. We see this array of assays and especially the PCLS system as the foundation for multiple grants relating to novel uncharacterized materials, such as families of nanomaterials or organic chemicals.

Jim Shine: Assessment of heavy metals levels in soil and among a human population living near a copper smelter in Chile. ($22,000)
Chile is the largest copper producer in the world, and mining activities are conducted all over the country. In the area of Ventanas-Puchuncaví a copper smelter was established in 1962. Preliminary data show a mixture of different heavy metals (mainly lead, copper, arsenic, cadmium, mercury and manganese) in soils around the smelter and in surrounding residential areas. The goal of this project is to gather and analyze environmental and biological samples for generation of preliminary data assessing an association between the presence of a mixture of metals in soil with heavy metals in toenails and hair in 280 permanent residents for further epidemiologic studies. The next stages of this project will be an examination of metal related human toxicity, geoavailability and bioavailability, depending on variables related to different biological, chemical and geological processes (such as chemical state of metals, type and proportion of each metal, presence of other compounds, type of soil, proximity to slag piles, and biologic characteristics of exposed individuals). DNA samples are already available through a previous project funded in Chile, so we intend to study associations between metal levels and some biomarkers of epigenetic alterations and oxidative stress.