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Pilot Projects 2013

Systematic Lung Examination for Hemosiderin as a Marker of Exposure to Environmental Hazards

Principal investigator:  Ruth Etzel, MD, PhD, Director, Integrative Health Sciences Facility Core; Professor, UWM Zilber School of Public Health.

Pilot Amount:  $43,105

For hundreds of years, deaths that occur suddenly among infants have devastated parents, baffled physicians, and eluded scientists.  High rates of infant mortality are a major problem in Milwaukee.  Dr. Etzel is conducting a cross-sectional study of all infant deaths during the 3 year period from 2009 to 2011 in Milwaukee County, utilizing a multidisciplinary approach that includes a systematic review of all previously-performed autopsies and a review of death scene photos from the Medical Examiner's investigation for the evidence of possible sources of exposure to toxic household air pollutants, like mold, water damage, cigarettes, and other sources of chemicals.

Social Inequities and Toxic Air Pollution Exposures in Milwaukee, Wisconsin

Co-Investigators:  Amy Kalkbrenner, PhD, Assistant Professor, UWM Zilber School of Public Health and Lorraine Malcoe, PhD, Associate Professor, UWM Zilber School of Public Health.

Pilot Amount:  $59,990

Air toxics - hundreds of airborne metals and volatile organic compounds - cause oxidative stress and systemic immune responses, biologic effects which are likely to underlie suboptimal birth outcomes such as infant mortality or preterm birth.  Although air toxics exhibit the spatial gradients characteristic of environmental injustices, studies have not evaluated the extent to which these pollutants contribute to infant health disparities.  To address these important gaps in knowledge and to promote the public's health, this study endeavors to lay the foundation for a full exploration of the intersection of air toxics and social inequalities in contributing to infant mortality and preterm birth.  The investigators measured levels of 187 toxic air pollutants across the city of Milwaukee, examining variation in levels across the city, identifying social inequalities in levels of air toxics, and observing links between air pollution levels and birth outcomes.

Proximity to Toxic Sites and Congenital Heart Defects in Disadvantaged Minorities in the City of Milwaukee

Co-Investigators:  Pippa Simpson, PhD, Professor of Pediatrics; Chief of Quantitative Health Sciences, Medical College of Wisconsin, and Andrew Pelech, MD, Associate Professor of Pediatrics (Cardiology), Children's Hospital of Wisconsin.

Pilot Amount:  $58,643

Structural congenital heart defects (CHD) are the most common birth defects.  More children die from CHD in infancy than other types of disease except infection.  In spite of this significant impact, the etiology of most CHD is unknown.  The environmental determinants of CHD have had limited study.  Even less is known about the potential causes in minorities who are at greater risk due to residence in urban areas that are former industrial sites or toxic sites.  This study serves to document the prevalence of variant forms of CHD's using the Wisconsin Pediatric Cardiac Registry and to associate them with the proximity to brownfields within the City of Milwaukee.  It is the first study of minorities focusing on the environmental effects of toxic waste sites on CHD and whether brownfield clean-up can reduce the risk of CHD's in the minority population in Milwaukee.

Pilot Projects 2012

Computational Pipeline for Next Generation Sequencing Information from Zebrafish

Co-Investigators: Peter Tonellato, PhD, Director , Bioinformatics Unit; Professor, UWM Zilber School of Public Health, Michael Carvan, PhD, Associate Professor, UWM School of Freshwater Sciences, Warren Heideman, PhD, Associate Dean for Research; Professor, UW-Madison School of Pharmacy, and Richard Peterson, PhD, Professor, UW-Madison School of Pharmacy.

Pilot Amount: $89,000

Early in the development of model organism genome projects, the zebrafish was identified as a key organism to model human disease.  Danio rerio offers virtually all of the resources of a modern genetic model of complex human disease.  Its characteristics immediately facilitate research that investigates individual susceptibility to disease and the genome, epigenome, and regulation of gene expression in relation to environmental exposure from the earliest life stage into adulthood.  Taking advantage of this powerful model requires use of next generation sequencing (NGS) along with the traditional microarray and targeted sequencing technologies and access to stand-alone, efficient and low cost computational tools to analyze the large data sets that emerge from the experimentation envisioned above.  This project begins the process to build the bioinformatic infrastructure. 

Role of B Cell Anergy in Dioxin-Induced Autoimmunity

Primary Investigator: Stephen Gauld, PhD, Assistant Professor, Medical College of Wisconsin, Department of Pediatrics (Immunology).

Pilot Amount:  $20,000

The mechanisms that result in the development of lupus, an autoimmune disease driven by autoantibodies, remain poorly understood.  While genetics undoubtedly play a role in the susceptibility to lupus, environmental factors are also implicated.  2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an environmental contaminant produced by the incineration of waste products, has been observed to cause lupus-like disease in the offspring of exposed mice.  The goal of this study is to define the role of TCDD in autoimmunity and specifically, autoantibody production.  An understanding of how TCDD drives autoantibody production is crucial for our understanding of how environmental chemicals promote immunomodulation and autoimmunity.

Characterization of Lipids, Polybrominated Diphenyl Ethers (PBDEs), and PBDE Metabolites in Wisconsin Mothers and Children with Hypoplastic Left Heart Syndrome (HLHS)

Co-Investigators: Joseph McGraw, PhD, Assistant Professor, Concordia University, Department of Pharmaceutical Sciences, and Andrew Pelech, MD, Associate Professor, Children's Hospital of Wisconsin, Department of Pediatrics (Neonatology).

Pilot Amount: $69,677

Congenital cardiovascular defects (CCVD's) are the most common non-infectious cause of death in infancy but the causes of CCVD remain largely unknown.  Genes cause a portion of CCVD cases, but one severe type of CCVD, known as hypoplastic left heart syndrome (HLHS), has been associated with environmental chemical exposures.  Polybrominated diphenyl ethers (PBDES) are an emergent class of environmental contaminants of concern.  PBDES are known to inhibit a receptor important for normal cardiac development, as well as to disrupt the thyroid hormone system, which is crucial to development of the brain and body.  This study will provide supportive information for the design of future studies to more clearly define the exposure-disease relationship.

Developmental Immunotoxicity of PAHs

Co-Investigators: Venkatesh Sampath, MD, MRCPCH, Associate Professor, Medical College of Wisconsin, Department of Pediatrics (Neonatology), and Ronald Hines, PhD, Associate Director, Children's Research Institute, Professor, Medical College of Wisconsin, Department of Pharmacology, Pharmacogenetics, and Teratology.

Pilot Amount: $70,000

Bronchopulmonary dysplasia (BPD), a chronic form of inflammatory lung disease that develops in 20-25% of very low birth weight (VLBW) infants (birth-weight <1500 grams), remains the major cause of pulmonary morbidity and mortality in infancy.  Recent data supports a substantial role for genetic and environmental risk-factors in the development of BPD in premature infants.  The overall hypothesis of this study is that gene-environment interactions between TLR/NLR genetic variants and fetal polycyclic aromatic hydrocarbon (PAH) exposure determine the susceptibility and/or severity of BPD in premature infants.  The study looks at 500 VLBW infants from across Wisconsin and Iowa.

Genetic Analysis of Degeneration of the Olfactory Epithelium

Primary Investigator: Katherine Shim, PhD, Assistant Professor, Medical College of Wisconsin Department of Pediatrics (Developmental Biology).

Pilot Amount: $20,000

The molecular mechanisms by which tissues regenerate in response to environmental damage are unclear.  In the olfactory epithelium, olfactory receptor neurons directly detect odor molecules from inhaled air, and thus are directly exposed to the environment.  Cells of the olfactory epithelium, including the olfactory receptor neurons, continually regenerate after birth and in adult life in response to environmental damage.  Research shows that mice mutant for the Sprouty2 (Spry2) gene have a progressive degeneration of their olfactory epithelia.  Primary data suggests that Spry2 antagonizes Fibroblast Growth Factor Receptor 1 (Fgfr1) signalling during maintenance of the olfactory epithelium.  Loss of one copy of Fgfr1 may rescue the degeneration seen in the mouse mutants.  This study investigates how Spry2 and Fgfr1 mouse mutants recover from exposure to a chemical toxin, which will improve our understanding of the mechanism by which the FGF/Spry pathway regulates regeneration of the olfactory epithelium.

Pilot Projects 2011

Growing Healthy Soil for Healthy Communities

Primary Investigator: Sheri Johnson, PhD, Associate Professor, Medical College of Wisconsin, Department of Pediatrics (Community).

Pilot Amount: $70,000

Cognitive and behavioral impairments due to elevated blood lead levels (>10 ug dL) in children are well documented.  The researchers hypothesize that it is feasible to integrate agronomy and environmental site assessment methods with principles of Community-Based Participatory Research (CBPR) to study the relationship between urban residential vegetable gardening and lead exposure in children and families.  The results of this pilot study will contribute to scientific knowledge regarding the types of residential vegetable gardening practices that contribute to lead exposure in children.  Additionally, the study will establish preliminary ranges for risk of lead concentration in "in-place" versus commercial replacement soils and home-grown compared to commercially available vegetables.  Finally, findings will reveal the challenges and benefits of incorporating principles of CBPR in environmental health research.

Intrauterine and Perinatal Bisphenol A Exposure and Neonatal Body Composition

Co-investigators: Ruth Rademacher, MD, Associate Professor, Medical College of Wisconsin, Department of Pediatrics (Neonatology) and Teresa Johnson, PhD, Associate Professor, UWM, College of Nursing.

Pilot Amount: $69,722

Animal studies demonstrate that bisphenol A (BPA) is associated with increased obesity and visceral fat.  This pilot study tests the hypothesis that BPA increases body fat and the risk of obesity.  BPA exposure in humans is widespread, yet impact on body fat has not been studied.  This study is designed to demonstrate feasibility, methods, validity, and effect size for optimal study design for larger studies.

Nicotine as a Modulator of Neural Crest Cell Migration and Differentiation

Co-investigators: Kurt Svoboda, PhD, Associate Professor, UWM Zilber School of Public Health and Vivian Lee, MBA, MD, PhD, Assistant Professor, Medical College of Wisconsin, Department of Cell Biology, Neurobiology and Anatomy.

Pilot Amount: $69,550

Nicotine is suspected of being responsible for birth defects caused by smoking during pregnancy.  In this study, the researchers test the hypothesis that nicotine exposure disrupts neural crest development in embryonic zebrafish.  Dr. Svoboda and Dr. Lee also investigate whether nicotine disrupts mammalian neural crest cell differentiation and migration in vitro.  Additionally, the researchers will determine if migrating neural crest cells express nicotinic acetylcholine receptors.

Establishing CABIN1's Role in Regulating Neural Crest Development to Model DiGeorge Syndrome

Co-Investigators: Ava Udvadia, PhD, Associate Professor, UWM School of Freshwater Sciences; Department of Biological Sciences and Vivian Lee, MBA, MD, PhD, Assistant Professor, Medical College of Wisconsin, Department of Cell Biology, Neurobiology, and Anatomy. 

Pilot Amount: $70,000

Craniofacial abnormalities are leading causes of infant morbidity and mortality, accounting for one third of all birth defects, and often occur as part of a cluster of congenital defects in syndromes such as 22q11.2 deletion syndrome, also known as DiGeorge syndrome, and the similar, but distinct 22q11.2 "distal deletion syndrome".  The cluster of congenital defects seen in many such syndromes are referred to as neurocristopathies.  Reduced expression of the CABIN1 gene in developing zebrafish leads to craniofacial abnormalities and other congenital defects similar to those observed in children with deletions within 22q11.2 band of chromosome 22.  This finding is significant because in the human genome CABIN1 resides within regions of 22q11.2 that are frequently deleted in 22q11.2 distal deletion syndrome.  This study examines neural crest development using transgenic zebrafish that express Green Fluorescent Protein in developing neural crest cells.  In animals lacking the CABIN1 gene, migration of neural crest cells was halted.  This is significant because neural crest cell differentiation occurs in response to environmental cues it finds along its migratory path and at its final destination in the periphery.  The researchers predict that the failure of these cells to be exposed to differentiative cues at the appropriate time leads to the developmental defects observed.

Linking Limnology to Cyanotoxins in Drinking Water Using Buoy Sensors and Auto-Sampling

Primary Investigator: Todd Miller, PhD, Assistant Professor, UWM Zilber School of Public Health.

Pilot Amount: $10,000

Cyanotoxins are produced by cyanobacteria.  These bacteria, also known as blue-green algae, are nearly ubiquitous and often harmless.  When conditions are especially favorable for cyanobacteria, rapid growth in their population can result in harmful concentrations of cyanotoxins.  This study uses high-resolution sensors on buoys and a new automated sampling device to investigate relationships between the physical and chemical characteristics of lakes and the presence of cyanotoxins in lakes and drinking water.

Supported through Director's Fund.

Pilot Projects 2010

High Throughput Screening of Zebrafish Mutants: Identification of Genes with Environmental Health Relevance

Principal Investigator: Michael Carvan, PhD, Associate Professor, UWM School of Fresh Water Sciences.

Pilot Amount:  $20,000

The community of researchers who work with zebrafish has announced the creation of the Zebrafish Phenome Project, whose objective is to knockout every gene in the zebrafish genome and provide phenotypic information on the resultant changes in phenotype.  The UWM lab is part of a collaborative team that has set out to phenotypically characterize 300-400 zebrafish knockouts.  The study includes phenotypic screens involving exposure to toxicants and assessment of changes in responsiveness.

Zebrafish (Danio Rerio) Sediment Contact Assay as a Novel Tool for Integrating Human Health and Ecological Risk Assessment

Co-investigators: Tim Ehlinger, PhD, Associate Professor, UWM Department of Biological Sciences and Michael Carvan, PhD, Associate Professor, UWM School of Fresh Water Sciences.

Pilot Amount: $69,869

Congenital heart disease (CHD) is a leading cause of infant mortality, as well as the most common form of birth defect.  Its etiologies are largely unknown.  In this study, sediments were collected from Lake Michigan tributary watersheds.  Sediment contact assay responses from zebrafish embryos were compared to the prevalence of congenital heart disease and vital statistic birth indicators aggregated from civil divisions associated with the watersheds. Significant risk relationships were detected between variation in early life-stage endpoints of zebrafish embryos 72 hours post-fertilization and the birth prevalence of human congenital heart disease and infant mortality.  This supports the hypothesis that bioassays normally used for ecological screening can be useful as indicators of environmental stress to humans. This has the potential to expand our understanding of environmental-human health linkages.

Effects of Metal Oxide Nanoparticles on Eukaryotic Cell Structure and Metabolism

Principal Investigator:  Krassimira Hristova, PhD, Assistant Professor, Marquette University, Department of Environmental Microbiology and Biotechnology.

Pilot Amount: $20,000

Metal oxide nanoparticles are known to be toxic to the yeast Saccharomyces cerevisiae, but the mechanism of the toxic effect is unknown.  The findings of the study support the conclusion that yeast mitochondria are prone to reactive oxygen species production when exposed to Cu2+/ CuO nanoparticles.

Effect of Early Life AHR Activation on T-Cell Tolerance

Co-investigators:  Michael Laiosa, PhD, Assistant Professor, UWM Zilber School of Public Health and Calvin Williams, MD, PhD, Interim Director, Children's Research Institute; Professor, Medical College of Wisconsin, Department of Pediatrics (Rheumatology).

Pilot Amount: $69,700

Disease of the immune system are chronic, costly, and on the rise worldwide.  Early life environmental factors appear to contribute to diseases later in life, including pediatric autoimmune and inflammatory diseases.  Halogenated aromatic hydrocarbons related to 2,3,7,8-Tetrachlordibenzo-p-dioxin (TCDD) may predispose individuals who are exposed to it in utero to immune diseases later in life.  Human exposure to very low levels of TCDD and related compounds occurs on a daily basis through pollutants in food.  TCDD mediates all of its biological activity via the Aryl hydrocarbon receptor (AHR).  The authors of this study test the hypothesis that AHR activation in hematopoietic stem cells (HSC) during critical periods of early development reprograms the immune regulatory progenitor cells required for enforcement of immune regulation later in life.

Mechanisms of Action of SSRI's at Environmental and Low Therapeutic Doses

Principal Investigator: Rebecca Klaper, PhD, Associate Professor, UWM School of Freshwater Sciences.

Pilot Amount: $20,000

The release of pharmaceuticals and personal care products from sewage systems into surface waters and related drinking water systems has been demonstrated several times in the United States, Canada, and Europe.  This is a public health concern as sensitive subgroups have the potential of receiving a chronic low-dose exposure with unknown impacts.  An important example is selective serotonin reuptake inhibitors (SSRIs).  The effect of chronic, low-dose exposure to SSRIs remains unknown.  Lower doses are known to have a stimulatory effect and higher doses may impair the performance of the nervous system.  Duration of exposure is also important.  Using fathead minnows as models of human exposure, preliminary data shows that fish exposed to the SSRI fluoxetine initially became aggressive, but behavior changed with chronic exposure.  The response to stimuli such as food and mates diminishes, while obsessive behavior increases.  This study tests the hypothesis that chronic low-dose exposures to SSRI's cause alterations in neurogenesis pathways in specific regions of the brain that differ from those at therapeutic levels and these alterations differ from early exposure to late exposure.

Supported through Director's Fund.

Beach Microbial cCmmunities as Sentinels for Oil Impacts on Gulf Coast Beaches

Principal Investigator:  Sandra McLellan, PhD, Associate Professor, UWM School of Freshwater Sciences.

Pilot Amount: $30,000

The Deepwater Horizon oil spill illustrated the difficulty of assessing the nearshore impacts of oil spills.  Microbes are considered sentinels, meaning that they are the first to respond to environmental changes.  Changes in microbial communities may provide a way to gauge the impact of ecosystem perturbation.  The purpose of this study is to learn about using microbial communities as a reflection of impacts from ecosystem disturbances or pollution events.  The researchers are in the initial stages of testing the sensitivity and connection of these community changes to increased human health risks.

Supported through Director's Fund.

Pilot Projects 2009

Sewage Contamination within a Municipal Drinking Water System Following Heavy Rainfall: Pilot and Feasibility Study

Co-investigators:  Marc Gorelick, MD, CEO, Children's Specialty Group, Professor, Medical College of Wisconsin, Department of Pediatrics (Emergency Medicine) and Sandra McLellan, PhD, Associate Professor, UWM School of Freshwater Sciences.

Pilot Amount: $69,647

Up to 12% of gastroenteritis in the US may be attributable to contaminated drinking water.  Prior research found an increase in cases after heavy rainfall, but the underlying mechanisms are unclear.  The authors hypothesize that cross-contamination may occur between sewer and drinking water pipes.  The goal of this study is to gather data about the proportion of the drinking water sample with human fecal contamination and pathogens during wet and dry weather, as well as to demonstrate the feasibility of enrolling households for prospective disease monitoring.

Effects of Gold Nanoparticles on Ovarian Steroidogenesis and Gene Expression

Principal Investigator:  Reinhold Hutz, PhD, Co-director, Career Development, Professor, UWM Department of Biological Sciences.

Pilot Amount: $25,000

While gold nanoparticles (GNPs) have received considerable attention for potential consumer, medical, and industrial applications, concerns have arisen about the possible toxicological consequences of GNPs within biological systems and the environment.  The wide distribution and likely increased usage in the future highlight the potential risk for environmental and occupational exposures to GNPs; and these might ultimately cause reproductive health deficits in adolescent girls and women.  This study looks at the influence of GNPs on the production of ovarian steroids, like progesterone and estradiol, and gene expression in rats.  This information will improve our understanding of the genomic responses to GNPs by providing insight into the subcellular effects elicited by GNPs on ovarian function, will serve as a foundation for future in vivo studies of GNP-induced ovotoxicity in rats, and will aid in determining the molecular basis for potential female reproductive pathologies from exposure to GNPs.

Offspring Meconium: The Optimal Biospecimen Matrix for Intrauterine Toluene and Trichloroethylene Biomonitoring

Co-investigators: Raj Narayan, MD, FRCOG, FACOG, Associate Professor, Medical College of Wisconsin, Department of Obstetrics and Gynecology and D. Gail McCarver, MD, Professor, Medical College of Wisconsin, Department of Pediatrics.

Pilot Amount: $69,499

More than 90% of people are exposed to volatile organic compounds, like toluene, and halogenated hydrocarbons, like trichloroethylene.  Exposure during pregnancy has been associated with poorer neurodevelopmental outcomes and decreased growth.  Meconium is the earliest stool of an infant and is composed of material ingested while in the uterus.  The aim of this study is to evaluate meconium biomonitoring as an alternative to maternal biomonitoring throughout pregnancy to facilitate large studies of offspring outcomes.

TLRs - Modulators of Environmental Lung Injury in Premature Infants

Co-investigators:  Venkatesh Sampath, MD, MRCPCH, Associate Professor, Medical College of Wisconsin, Department of Pediatrics (Neonatology) and Ronald Hines, PhD, Associate Director, Children's Research Institute, Professor, Medical College of Wisconsin, Department of Pediatrics.

Pilot Amount: $70,000

Bronchopulmonary dysplasia (BPD), a lung disease that develops in 20-25% of very low birth-weight (VLBW) infants, remains a major cause of pulmonary morbidity and mortality in infancy.  While the exact mechanisms that cause the disease are unclear, intrauterine exposure to environmental toxicants, postnatal exposures to invasive bacteria and hyperoxia interact with unknown genetic risk-factors to modulate susceptibility and severity of BPD in infants.  Because the Toll-Like Receptor (TLR) signalling pathway plays critical roles in regulating protective pulmonary responses against environmental toxicants, oxidative stress and bacterial-derived toxins, the authors hypothesize that functional genetic variation in the TLR signaling pathway genes would modulate susceptibility or severity of BPD in premature infants.  Data from this study support the hypothesis that TLR pathway genetic variants act as susceptibility loci for the BPD phenotype in VLBW infants and modulate vulnerability to environmental lung injury in premature infants.

The Role of ERR-Gamma in Mediating Bisphenol A Neurotoxicity

Co-investigators:  Robert L. Tanguay, PhD, Oregon State University, Department of Environmental and Molecular Toxicology and Daniel Weber, PhD, Senior Scientist, Aquatic Animal Models Facility Core, UWM Great Lakes Research Facility.

Pilot Amount: $16,435

Developmental bisphenol A (BPA) exposure has been implicated in adverse behavior and learning deficits, but the mode of action is unclear.  The objective of this study is to determine whether low-dose, developmental BPA exposure affects larval zebrafish locomotor behavior and whether learning deficits occur in adults exposed to BPA during development.  This study demonstrates the efficacy of using the zebrafish model for studying the neurobehavioral effects of low-dose developmental BPA exposure.

Development of Zebrafish as a Natural Model System for Studying Scoliosis

Co-investigators:  Xue-Cheng Liu, MD, PhD, Professor, Medical College of Wisconsin, Department of Orthopedic Surgery, and Henry Tomasiewicz, PhD, Director, Aquatic Animal Models Facility Core; Associate Director, Exposure and Biological Analysis Core, UWM Great Lakes Research Facility.

Pilot Amount: $25,000

A lack of good animal models has hindered investigation into the origins of idiopathic scoliosis.  Recently, spinal curvatures have been observe in several fish species, including several of the zebrafish in the researchers' colony.  The authors suspect that the "scoliosis" in their zebrafish is the result of one or more mutations in the zebrafish genome.  Data shows that the curved spines were due to a recessive mutation and that an underlying environmental factor influenced the severity of the condition.

Pilot Projects 2008

The Influence of Developmental Methylmercury Exposure on Cardiac Function

Co-investigators:  Michael Carvan, PhD, Associate Professor, UWM School of Freshwater Sciences and Janette Strasburger, MD, Medical College of Wisconsin, Department of Pediatrics (Cardiology).

Pilot Amount: $50,000

Developmental exposure to methylmercury has been demonstrated to result in abnormalities in cardiac function that persist into adulthood.  The association between heart rate variability and mercury exposure has been demonstrated in individuals with occupational exposure to mercury and in patients with Fetal Minamata Disease.  Recent evidence from the Faroe Islands suggests that lower methylmercury exposures during development will also lead to reduction in heart rate variability via impairment of its autonomic regulation.  Reduction of heart rate variability is associated with an increased risk for cardiovascular morbidity and mortality.  This study will develop a zebrafish model to study the relationship between developmental methylmercury exposure and cardiac functional deficits.