Pilot Projects 2013
Pilot Grant Awardee: Konstantinos C. Makris
Project Title: Exposures to thyroid-disrupting chemicals and thyroid nodular disease: the case of Bisphenol A
Award Amount: $20,000
Description: There is an alarming increase in global incidence rates of thyroid nodules partially ascribed to the augmented use of ultrasonographs, while the effect of environmental chemicals, like bisphenol A (BPA) on the etiology of thyroid nodular disease remains poorly understood. Cyprus is topping the global list of countries with the highest thyroid cancer incidence rates. Our biomonitoring study showed very high BPA intake values for a Cypriot subpopulation during prolonged manifestation of adverse summer weather conditions (very high temperatures/UV index) that could enhance BPA leaching and thus, human exposures. Our aims are: (1) measuring urinary BPA and its chlorinated (mono-, and di-chloro BPA) and oxidative (4-methyl-2,4-bis(4- hydroxyphenyl)pent-1-ene, MBP) metabolite exposures in patients with thyroid nodular disease and perturbed or not thyroid hormonal status using a case-control design and an outcome-dependent sampling design in Cyprus, and (2) investigating relations between thyroid nodular disease cases, their dietary habits, and urinary BPA and its metabolite concentrations that show 10-1000x higher in-vitro estrogenic potency than that of BPA. The simultaneous urinary analyses for BPA and its derivatives could shed light on the importance of low-dose BPA health effects when parent compound partially transforms to more potent metabolites.
Pilot Grant Awardee: Stephanie Shore
Project Title: Impact of obesity and ozone on lung microbiota in mice
Award Amount: $24,000
Description: Obesity is a risk factor for asthma. Understanding the mechanistic basis for obesity-related asthma could lead to novel treatments. Gut microbiota are altered in obesity and these alterations appear to contribute to some obesity-related conditions. Microbiota also exist within the lungs and have been proposed to contribute to a variety of lung diseases. Hence, lung microbiota might also contribute to obesity-related asthma. Preliminary data indicate that both obesity and ozone (O3) exposure (a common asthma trigger) result in changes in lung concentrations of metabolites whose generation requires bacterial metabolism, suggesting that both obesity and O3 can impact lung microbiota. Such changes may result in lung metabolites that can affect airway function and trigger asthmatic symptoms. Hence, we propose to examine the hypothesis that both obesity and acute O3 exposure alter bacterial populations within the lungs. To do so, obese and lean mice will be exposed to room air or to O3. 24 h later, mice will be euthanized and a bronchoalveolar lavage (BAL) will be performed. Bacterial DNA will be extracted from BAL supernatant and 16-S pyrosequencing used to analyze taxa in the lungs. Both genetically obese db/db and genetically obese Cpefat mice will be examined to confirm that any observed changes are not specific to a particular genetic defect but a common result of obesity.
Pilot Grant Awardee: Akira Tsuda
Project Title: Rapid nanoparticle translocation across the neonatal alveolar air-blood barrier
Award Amount: $20,000
Description: The alveolar walls of infant lungs are likely more vulnerable than that of adults’ because the neonate lung undergoes significant morphogenetic and fluid balance changes. Thus, the ability of nano-size particles (NPs) to cross the alveolar air-blood barrier is also likely to be age-dependent during postnatal lung development. In the proposed project, we will perform systematic translocation experiments in neonate rats of different developmental stages to investigate, which physicochemical characteristics of the particles determine their ability to cross the alveolar air-blood barrier of infant lungs. Virtually nothing is known currently about NP translocation across the neonatal alveolar air-blood barrier. Therefore, the results of this project will provide us with fundamental knowledge on how NPs interact with the immature lungs of infants. This knowledge is essential for the assessment of nanotoxicology as well as for the optimal design of nanoparticles for systematic inhalation drug therapy for this vulnerable age group.
Pilot Grant Awardee: Yongyue Wei
Project Title: Maternal Metal Exposure, Cord Blood Metabolomics Biomarker, and Birth Outcome
Award Amount: $20,000
Description: Metals such as lead, manganese, and arsenic are of increasing concern since recent data demonstrate their biological toxicity to birth outcomes. However, the mechanisms of such toxicity are not well understood. Metabolomics are the end products of cellular regulatory processes, and their levels can be regarded as the ultimate response of biological systems to environmental changes, e.g. metal exposures. Systemic changes in the metabolome relate to particular outcomes, e.g. birth outcomes. However, few studies have investigated the toxic effects of maternal metal exposure on birth outcomes that may be mediated by metabolites. Human development reflects dynamic processes mediated by a dynamic interplay among genetic, epigenetic, metabolic and environmental determinants. Toxic chemicals, interactive genes and metabolites may compose a functional network and, ultimately produce adverse birth outcomes. Few studies have explored such toxic effects using a network analysis. Taking advantage of the Superfund Program Project (Project #2, PI: D. Christiani), we conduct this study to identify metabolic biomarkers that mediate the effect of maternal metal exposure to low birth weight, which would have impact on the understanding of how metals induce toxicity and provide biological insight for potential treatment and prevention of adverse reproductive outcomes.
Pilot Grant Awardee: Andrea Baccarelli
Project Title: Flame retardants, plasma exosomal miRNAs in early pregnancy, and risk of gestational diabetes
Award Amount: $24,000
Description: Gestational Diabetes Mellitus (GDM) prevalence has increased up to 2.5 times in the past 20 years and is now diagnosed in 18% of all pregnancies. Polybrominated diphenyl ether (PBDE) flame retardants are endocrine disruptors that have been linked with insulin resistance and diabetes. This mechanistic project will build on a growing body of evidence suggesting that exosomes (extracellular vesicle) shed from placenta during gestation carry tissue-specific signals that reflect placental function and could be used to both predict pregnancy-related risks and characterize environmental exposures with placental toxicity. Exosomes are 30-100 nm vesicles encapsulated by a lipid bilayer and contain high concentrations of miRNAs. Our long term hypothesis is that PBDE exposures induce exosome-signaling from the placenta that mediates GMD development. We will isolate placenta-derived exosomes from maternal plasma in early pregnancy (8-21 weeks) in women at high GDM risk; measure their size and count; screen ~750 exosome-contained miRNAs; and prospectively determine their association with GDM [Aim 1]; evaluate the correlations of miRNAs in placental tissues with plasma exosomal miRNAs, as well as with GDM risk [Aim 2]; measure PBDEs in maternal plasma/placental samples and determine PBDE effects on exosomal/placental miRNAs and GDM risks [Aim 3].
Pilot Grant Awardee: Christopher Hug
Project Title: Does environmental arsenic exposure induce a novel form of cystic fibrosis?
Award Amount: $25,000
Description: The goal of this Harvard-NIEHS Center pilot program application is to conduct a cross-sectional study in Bangladesh to assess the relationship between environmental arsenic exposure, respiratory function and sweat chloride levels. Recent cell culture and biochemical studies have shown that arsenic promotes degradation of the cystic fibrosis transmembrane conductance regulator (CFTR), a chloride channel essential for normal function of the lungs, pancreas and intestines. Mutations in the CFTR gene cause cystic fibrosis, a rare autosomal recessive disease characterized by recurrent pneumonia and diagnosed by demonstrating an increased concentration of chloride in sweat. Our central hypothesis is that environmental arsenic exposure results in an induced cystic fibrosis phenotype in exposed individuals by causing degradation of CFTR. By demonstrating an association between arsenic exposure and abnormal sweat chloride levels, our project will establish a new molecular paradigm for the pathogenesis of arsenic-induced respiratory disease. The data from this pilot program will provide important preliminary data to support an R01 application in response to RFA HL-12-035, entitled “Early Cystic Fibrosis Lung Disease Studies in Humans.”
Pilot Grant Awardee: Peggy Lai
Project Title: Endotoxin, the airway transcriptome, and asthma
Award Amount: $25,000
Description: Asthma is a chronic inflammatory lung disease that affects an estimated 25 million Americans. The contribution of indoor endotoxin exposure to asthma morbidity has been extensively studied in the home environment, but little attention has been paid to indoor endotoxin exposure in schools. Studies show that gene expression changes due to environmental exposures in the lower airways (bronchial epithelium) are also mirrored in the upper airways (nasal epithelium), with the advantage that the latter is easily accessible. Endotoxin is a consistent predictor of acute changes in gene expression of the airway epithelium. Airway gene expression studies in tobacco-related lung disease have been used to identify mechanisms of disease and provide useful biomarkers for diagnosis, prognosis, and treatment. However, the transcriptional changes induced by chronic environmental endotoxin have not been defined, particularly in the field setting.
The purpose of this pilot proposal is to identify longitudinal changes in the airway transcriptome in asthmatic children in response to school endotoxin exposure, and to identify a gene signature at baseline that predicts future asthma exacerbations in response to school endotoxin exposure.
Pilot Grant Awardee: Young-Ah Seo
Project Title: Manganese-induced neuronal cell apoptosis through ER stress
Award Amount: $18,000
Description: Chronic exposure to manganese (Mn) results in neurobehavioral deficits similar to Parkinson disease. Despite growing awareness of the problems associated with Mn neurotoxicity, particularly in children, little is known about the molecular mechanisms underlying Mn-induced neurotoxicity. We found that Mn induces cell injury and ultimately apoptosis both in vitro and in vivo. This apoptotic effect is synergized by iron deficiency. However, it is not clear how these two metals interact. This is particularly important because iron deficiency is the most prevalent nutritional deficiency in children, and Mn intoxication may produce greater effects during development. Accumulating evidence suggest that ER stress plays a significant role in neurodegenerative diseases because the unfolded protein response (UPR) leads to cell apoptosis. Thus, we postulate that Mn induces neuronal cell apoptosis through ER stress and this pathway is potentiated by iron deficiency. This hypothesis will be tested by two specific aims: 1) To determine whether Mn-induced ER stress initiates neuronal apoptosis in vitro. 2) To determine whether iron deficiency enhances Mn-induced neuronal apoptosis and/or ER stress in vitro and in vivo. These studies will provide insight into mechanisms of Mn-induced neurotoxicity and the environmental health risks from Mn exposures in iron-deficient children.
Pilot Grant Awardee: Vishal Vaidya
Project Title: Quantitative High-Throughput Screening Platform for Predictive Kidney Toxicology
Award Amount: $25,000
Description: Drugs and environmental chemicals play an important role in the high incidence and prevalence of kidney injury, which in many circumstances can be prevented or at least minimized by predictive toxicity screening. We propose to transform the traditional in vivo, dose-response based toxicity assessment by developing in vitro, high throughput, multi-dimensional signatures that map early biological perturbations of a damaged cell. This involves developing a ‘grid’ using quantitative dynamical systems analysis to integrate the chemical structure with dose and time dependent hemeoxygenase-1 (HO-1) response with high content imaging for perturbations in nucleus, endoplasmic reticulum and mitochondria following toxicant exposure. In Aim 1 we will develop and optimize homogenous time resolved fluorescence (HTRF) assay to allow high throughput measurement of HO-1 as a biomarker of toxicity. In Aim 2 the Library of pharmacologically active compounds will be screened and a multidimensional predictive toxico-response signature will be created by linking HO-1 response with structure, pharmacological activity and high content cell perturbation markers along dose-time axis by combining statistical, reverse engineering/inference and kinetic approaches. The ultimate goal is to develop a predictive kidney toxicity test to speed safety screening and risk assessment.