Pilot Projects 2011
Description: Recent evidence suggests that noncoding DNA sequences (i.e. repetitive elements or retrotransposons) may actually be expressed, and if so can disrupt cellular functions. DNA methylation of these regions is an evolutionary response to inhibit their expression. Toxic metals, including lead, alter DNA methylation patterns and may induce hypomethylation of DNA. Methylation of retrotransposons can be lost in response to lead exposure. L1 sequences (also known as LINE-1) are the main group of viral-like retrotransposons that are still active in the human genome. L1 transcription during development might be reactivated by demethylation and thus elicit cell-wide inflammatory responses producing adverse health effects such as fetal growth restriction or preterm delivery. However, because <1% of the >500,000 L1 sequences are potentially active in the human genome, whether lead-induced L1 hypomethylation induces L1 retrotranscription, and whether such activation is responsible for lead toxic effects is undetermined. We propose to evaluate the role of L1 reactivation during pregnancy by measuring L1 mRNA in women selected from a large birth cohort in Mexico City. We will then explore the correlation between L1 methylation and L1 mRNA levels; the association of lead biomarkers with L1 encoded mRNAs; and possible mechanisms for demethylation.
Description: Prof. Racowsky and Dr. Machtinger conducted a study to evaluate whether exposure of immature human oocytes to BPA interferes with progression of the human oocyte through the normal stages of meiotic maturation. Immature oocytes (GV), otherwise discarded from patients undergoing IVF procedure, were used following patient signed informed consent for donation of their discarded oocytes for research. Previous documentation that BPA is present in human follicular fluid at a concentration of 1-2 ng/ml provided a guide for the work undertaken by Prof. Racowsky and Dr. Machtinger.
Two experiments were performed:
The first experiment involved exposure of human oocytes to high concentrations of BPA (20µg/ml) in order to determine whether BPA could adversely effect meiotic progression. The maturation rates were compared to those of sibling oocytes incubated in a medium without BPA. This experiment included pairs of oocytes from 21 patients. We showed that oocytes exposed to 20µg/ml BPA underwent meiotic maturation (to metaphase II; MII) at a significantly lower rate compared with controls (77.8% vs. 16.7%, p=0.003).
In the second experiment, lower concentrations of BPA (20ng/ml or 200 ng/ml) were tested. In cases of when there were only two GV oocytes available from a patient, one was incubated with 20ng/ml BPA and the other was incubated in control medium. In cases that three GV oocytes were available from the same patient, the third oocyte was incubated with higher concentration of BPA (200ng/ml).
This study is ongoing. Oocytes of 50 patients have been collected. In 20 of these cases, a third oocyte was available.
Generalized estimating equations were used to combine the results from the two experiments to assess whether there is a dose response effect of BPA on oocyte progression of the human oocyte to MII. It was discovered that as BPA dose increased, there was a significant decrease in the likelihood of an oocyte reaching MII (p=0.003). We also showed that as BPA dose increased, there was a significant increase in the likelihood of an oocyte becoming activated (p=0.04).
Description: This project investigates the feasibility of predicting cholera outbreaks on a global scale using a variety of newly available earth observing datasets. Cholera affects between 3 and 5 million people each year, and has been re-emerging over the last decade as a significant public health problem. In the late 1970’s it was discovered that the causative agent of cholera, the bacterium Vibrio cholerae, naturally inhabits coastal and estuarine waters around the world in association with copepod zooplankton hosts (Colwell et al., 1977, Huq et al., 1983). Strong correlations between cholera outbreaks and variables such as rainfall anomalies and productivity (Chl a) have been demonstrated for particular regions over short periods of time (Lobitz et al., 2000, deMagny et al., 2008, Mendelsohn & Dawson, 2007). Although salinity is known to be important for Vibrio growth and survival (Lipp et al., 2002), no other research team has used global salinity data in their modeling efforts or attempted to conduct a global scale analysis. We are using 40-year assimilated meteorological data from the new-generation NASA GEOS-MERRA system to develop a physically based model of the distribution of Vibrio cholerae in the environment, validating the model using data on cholera outbreaks.
Pilot Grant Awardee: Weisskopf, M
Project Title: An Economic Approach to Linking Adoption and Use of Improved Cookstoves to Reduced Indoor Air Pollution and its Effect on Cognitive Function
Award Amount: $20,000
Description: Biofuels burned on traditional cookstoves produce high concentrations of indoor air pollutants that are toxic to health and the environment. Recent studies have shown that lung and cardiovascular dysfunction are linked to indoor air pollution (IAP), but it has yet to be explored whether IAP is associated with any cognitive outcomes, despite evidence that aspects of outdoor air pollution—at much lower concentrations—cause cognitive deficits. The health effects that have been documented thus far have been shown to be reduced when traditional cookstoves are replaced with improved cookstoves. Problematically, programs that distribute improved stoves have found low levels of adoption and use. This pilot study aims to address these issues by first exploring whether indoor carbon monoxide and PM2.5 are associated with cognitive performance in a rural population in China that uses traditional cookstoves. We will then use this group to conduct a feasibility study where we randomly distribute improved cookstoves to assess reductions in CO and PM2.5, and improvements in cognitive outcomes. We will also measure stove usage and qualitatively explore barriers to stove use and adoption through surveys and focus groups. All of the data gathered from this study will be used to apply for grants to fund a randomized controlled trial that looks at stove adoption and use, IAP exposure and cognitive effects.
Description: Mercury is a globally distributed toxin found in fish and shellfish, and there is ample evidence that exposure to methymercury via seafood consumption can have adverse health effects. The aim of this project is to test whether the stable isotopic content of mercury in human biomarkers (hair) can be used to infer the source of the seafood products leading to exposures. This will be tested in two populations, one from the Faroe Islands and a second from the Gulf of Mexico, where we have prior information on seafood consumption patterns and levels of mercury in hair biomarker samples. The isotopic composition of mercury in a given fish is the result of the sum total of fractionation processes occurring upstream. If we can further link the isotopic composition of hair to the consumed fish, we will open up the doors to future studies that can link mercury processing in the environment to human health outcomes. A primary goal of this pilot study is to bring together biomedical and non-biomedical researchers to look at this type of data and discuss how to use tools such as this to better link human health to the environment.
Description: Esophageal adenocarcinoma (EA) is a lethal cancer with a mortality rate greater than 85%, and for the past four decades its incidence has been increasing by approximately 500% in the United States1-6. Major risk factors for EA include gastroesophageal reflux disease (GERD), obesity, and smoking. Conversely, infection of Helicobacter pylori (HP) is associated with a 50% risk reduction of EA. Better understanding of the mechanisms by which HP protect against EA could lead to new prevention approaches for EA. Recent works suggest that HP may affect GERD and obesity through inducing atrophic gastritis (AG) and adipokine production. However, there is insufficient direct evidence for determinant roles of these mechanisms in HP-EA relationship. We propose to utilize an existing EA cohort to evaluate whether HP-induced AG and adipokine dysregulation mediate the HP-EA relationship. The results of this pilot study will be used as preliminary data to apply for a five-year RO1 grant to elucidate the protective mechanisms of HP infection on EA risk.
Description: As engineered nanoparticles (ENPs) swiftly proliferate and enter consumer products, humans increasingly become exposed. Our body’s first line of defense against ENPs is the epithelium. Cultured epithelial cells therefore provide a relevant and efficient model system for assessing health impacts. Most nanotoxicological assessments use epithelial cells that are healthy and intact, but when injuries arise cells might become more vulnerable to ENPs. Further, there is a particular lack of understanding on the effect of particulate matter on the epithelium of the eye, which is a primary site of environmental exposure and resulting irritation. To address this gap in knowledge, we hypothesize that ENPs impede the healing of a wounded epithelium. We are working on developing a novel functional wound healing assay to test this hypothesis on human corneal epithelial cells using a panel of industrially relevant ENPs, including metals and metal oxides generated in-house using the recently developed Harvard Versatile Engineered Nanomaterial Generation System (VENGES). Our work will help in developing a physiologically relevant framework for evaluating nanomaterial safety for epithelial wounds.