Pilot Projects 2012
Pilot Grant Awardee: Jonghan Kim
Project Title: Influence of FPN and HFE on clearance of manganese
Award Amount: $25,000
Description: Ferroportin (FPN) is an essential intestinal metal transporter and its expression is elevated in HFE-related hereditary hemochromatosis, one of the most common genetic disorders in humans. Hemochromatosis is caused by mutations in the HFE gene, resulting in hyperabsorption of intestinal iron. This promotes irreversible tissue damage including liver cirrhosis, cardiomyopathy, and premature death. In addition, we observed an increase in blood manganese clearance in HFE-deficient mice, suggesting a novel of role of FPN in manganese disposal. We postulate that FPN is responsible for Mn clearance by tissue deposition and/or by excretion from the liver into bile and these pathways are altered in HFE-associated hereditary hemochromatosis. This hypothesis will be tested by two specific aims: 1) To determine and compare the tissue distribution pharmacokinetics of 54Mn administered to FPN-mutant and wild-type “control” mice by intravenous and intraportal injection. 2) To characterize and compare the tissue distribution pharmacokinetics of 54Mn administered to HFE-deficient and wild-type mice by intravenous and intraportal injection. This work will enhance our knowledge of manganese homeostasis and the role of ferroportin in hemochromatosis and manganese neurotoxicity.
Pilot Grant Awardee: Chensheng (Alex) Lu
Project Title: Metabolomic Profiling for Dietary Pesticide Exposure in Children
Award Amount: $25,000
Description: “Environmental Metabolomics” is a newly emerging research focusing on the identification and quantification of the small molecule metabolites in biofluids. A key element in the environmental metabolomic research is to understanding what is “abnormal” in the targeted individuals under either well-defined or known exposure circumstances whose metabolic health can be interrogated using the metabolomic profiling approaches. The goal of this metabolomic analysis is to extract, identify, and quantify all of the metabolites, a global approach, in urine samples collected from the Children’s Pesticide Exposure Study (CPES). Since we will be looking into the non-targeted metabolomic profile changes in the same child who consumed organic and conventional foods during the study period, we should be able to minimize the potentially confounding influences, such as age, sex, race, and nutrition on interpretation of metabolomic results. Thus, this unbiased metabolomic analysis should provide robust insights into the influence of dietary pesticide intakes on the relative concentration of observed biochemicals. This proposed pilot study extends pesticide research to metabolomic analysis that links pesticide exposure to biochemistry-based health effects. Ultimately, we hope to identify biomarkers for pesticides with fingerprints on potential health effects through the metabolomic analysis.
Pilot Grant Awardee: Quan Lu
Project Title: Discovery of coding and non-coding RNA transcripts central to lead (Pb) neurotoxicity through Next-Gen deep sequencing
Award Amount: $25,000
Description: Lead (Pb) is a common environmental metal contaminant of great public health concern because it impairs neuronal function and adversely affects neurodevelopment in children. Despite overwhelming evidence from epidemiological as well as animal and cell-culture studies that show Pb is a neurotoxicant, the molecular mechanisms by which Pb impairs neuronal function remain poorly defined. Here we propose to use the powerful and now affordable Next-Gen deep sequencing technology to discover human gene transcripts, both coding and non-coding, that are critically involved in the neuronal response to Pb exposure. This proposal has two specific aims: 1) to identify messenger RNA (mRNA) and long non-coding RNA (lncRNA) expression changes through deep sequencing of polyadenylated RNAs from differentiated human neuronal cells exposed to Pb; and 2) to identify microRNAs (miRNAs) gene expression changes through deep sequencing of small RNAs from differentiated human neuronal cells exposed to Pb. Identification of these RNA transcripts will provide a comprehensive genetic framework critical for elucidating the mechanisms underlying Pb-induced neurotoxicity.
Pilot Grant Awardee: Nancy Krieger
Project Title: Air pollution, racial discrimination, and blood pressure: an exploratory study
Award Amount: $22,000
Description: We will conduct a repeat cross-sectional exploratory and novel study that efficiently links 3 Boston-based data sets: 2 health studies (My Body My Story (N=1005) and United for Health (N = 1201)) and a unique spatiotemporal data set that enables precise estimation, to the latitude and longitude of a person’s residential address, of time-specific exposure to traffic-related air pollution, reflected by black carbon concentrations in PM2.5 (particulate matter with an aerodynamic diameter ≤ 2.5 μm). Our specific aims are:
- Aim 1: map and assess the social-spatial distribution of black carbon exposure, in relation to census tract sociodemographic characteristics and individual-level data on age, gender, race/ethnicity, exposure to racial discrimination, lifetime socioeconomic position, smoking, nativity, and body mass index; and
- Aim 2: test our hypotheses that: (1) higher exposure to black carbon is associated with increased risk of blood pressure (measured at the time of the exam, with analyses controlling for body mass index, based on measured weight and height, plus age, gender, nativity, smoking, and lifetime socioeconomic position), and (2) the effect of black carbon on blood pressure is modified by exposure to racial discrimination
Description: Vehicle exhaust is a mixture of toxicologically important chemicals, but there has not been a systematic effort to develop exposure biomarkers. “Exposome” technologies provide an opportunity for a data-driven approach to biomarker development. In particular, metabolomics techniques can identify chemical features of all small molecules in a blood sample, providing an opportunity to identify novel exposure and early effect markers by comparing samples from exposed and less exposed groups (1,2). The proposed study will demonstrate application of metabolomics technology to biomarker development for traffic exhaust using samples collected from workers in the trucking industry. We will identify chemical features that are associated with previously collected exposure measures, including job title, and area exposure levels of PM2.5, EC, OC, particle-bound PAH, and ultrafine particle surface area and urinary nitro-PAH metabolites. Additionally, we will determine if these features are associated with the following early effect markers: blood markers of inflammation (CRP, IL- 6), endothelial dysfunction and activation (ICAM-1, VCAM-1), and oxidative stress (8OHdG). If we successfully identify a novel biomarker of traffic exposure from the metabolome, the results from this pilot can be directly applied to future studies of chronic disease.
Pilot Grant Awardee: Jessica LaRocca
Project Title: Elucidating the effects of prenatal exposure to multiple endocrine disrupting chemicals on microRNA and mRNA expression in the human placenta
Award Amount: $25,000
Description: Recent evidence has suggested that early life exposure to environmental compounds, including endocrine disrupting chemicals (EDCs), may alter risk of disease development. A number of EDCs are found in many everyday products, such as plastic containers, canned goods and receipt paper. EDC exposure to developing children is of particular concern because early life chemical exposure to a hormonal sensitive organ can result in phenotypic organizational changes that are persistant throughout life. Several animal studies have demonstrated that prenatal exposure to EDCs can alter postnatal development, and may be linked to risk of developing adult disease. The health of the placenta, the hormonally active organ responsible for nutrient exchange between the fetus and the mother, is critical to the health of the developing child. Various environmental toxicants, including EDCs, have been shown to cross the placental barrier and alter gene expression. We hypothesize that prenatal exposure to EDCs will alter mRNA and miRNA expression in human placenta, which could potentially affect the health of the child. Using two Boston birth cohorts, we propose to examine if exposure to a number of EDCs during pregnancy alters mRNA and miRNA expression levels of the human placenta, and how this correlates with maternal complications and birth outcomes.
Description: The scientific goal of this Harvard NIEHS Center pilot program application is to conduct a case-control study in Bangladesh to assess the relationship between environmental arsenic exposure and neural tube defects, which are common, serious birth defects that result in life-long disabilities. Secondary analyses will investigate genetic and nutritional factors that may account for individual differences in sensitivity to arsenic exposure. By combining investigations of toxic exposure with examination of genetic polymorphisms related to nutrition and metabolism, this proposal has the potential not only to demonstrate an association between environmental arsenic exposure and neurological defects in children but also to suggest means by which individual resistance to such exposure may be enhanced. The data from this pilot program project will provide important preliminary data to support an application in response to NIH RFA PAR-11-031 entitled “Brain Disorders in the Developing World (R21).” This RFA is soliciting applications for projects in developing countries that study disorders “that result from abnormal prenatal development or influences during the prenatal and perinatal period…including genetic and nutritional factors…and environmental toxins.” This future, prospective, active surveillance study will allow us to extend our evaluation of the gene-environment interactions explored here.
Description: Obesity increases pulmonary responses to ozone, a common air pollutant and asthma trigger. We have established that ozone causes greater airway hyper-responsiveness (AHR), a characteristic feature of asthma in obese compared to lean mice. Our preliminary data indicate that IL-17A may be involved in obesity-related augmentation of ozone-induced AHR. Among its other activities, IL-17A has been shown to affect metabolism within adipocytes. Metabolomics is an emerging technology that simultaneously quantifies hundreds to thousands of small molecules generated from cellular metabolism. In mice, metabolomics has been successfully employed to identify strain related differences in lung cellular metabolism that may explain strain related differences in sensitivity to another environmental pollutant, acrolein. We propose to use a metabolomics platform developed by Metabolon, to 1) determine whether there are obesity-related differences in the effect of ozone on lung cell metabolism; and 2) determine whether IL-17A contributes to differences in metabolism. Understanding the metabolic “signatures” of ozone exposed mice and how they vary with a common risk factor (obesity) may ultimately lead to the development of biomarkers that can be used to assess human responses to ozone and identify other susceptibility factors.