Previously Funded Pilot Projects

The SCEHSC promotes its scientific vision through integrative events such as seminar series, workshops and symposia, working groups, and retreats, bringing together Center investigators and invited experts to create an environment conducive to new interdisciplinary interactions and research directions.

Seminar Series 

The monthly seminar series brings distinguished guests from local, national, and international environmental health sciences communities. Visiting speakers share cutting-edge research and innovative methods and typically have expertise representing Research Program areas and new Center Initiatives.

Pilot Abstracts

2020
2019
2018
2017
2016
Three pilot projects were recently funded for a total of $148,909.

Metabolomic Insights of the Link between Prenatal Air Pollution Exposure and Autism

Principal Investigator
Zhanghua Chen, Ph.D.
Assistant Professor
Division of Environmental Health, Department of Preventive Medicine
Keck School of Medicine of USC
Abstract
Autism spectrum disorder (ASD) imposes large costs on our population. The prevalence of ASD has increased by 2.5-fold in the US since the year 2000. Causes of ASD are multi-factorial. Although genes and maternal malnutrition are well-known risk factors of ASD, increasing evidence suggests that early-life air pollution exposure has a critical role in causing ASD. Emerging evidence from human studies and animal models converges on neurotoxic effects of small particles. However, the mechanism linking prenatal fine particle exposure to ASD in children is unknown. We hypothesize that prenatal fine and ultrafine particle exposure may affect maternal and neonatal metabolism, which imposes the risk of ASD development in children. This study is built upon a large pregnancy cohort at Kaiser Permanente Southern California (KPSC) (400,000 mother-child pairs) and a novel resource of biospecimen stored in the California Biobank. We will select 50 children with doctor diagnosed ASD before age 5 (cases) and 50 typically developing controls who are matched with cases on birth year, sex, ethnicity and KPSC service area. Further, we will identify the mothers of these selected children and will retrieve both the mothers’ serum samples collected at mid-pregnancy and the newborn dry blood spots from the California Biobank. We will then perform high-resolution metabolomics on these samples and will examine key metabolic pathways in pregnant women and newborns that may be influenced by air pollution exposure and induce ASD risk. These targeted metabolic pathways are selected based on current literature. The pilot data will help build a foundation for our future R01 application to pursue the research in the entire KPSC cohort with ~4,400 ASD cases. Findings from this line of research will advance our knowledge about the biological responses to prenatal air pollution exposure and will help to detect early biomarkers (metabolomic signatures) for ASD.

Exploring the Use of Deciduous Teeth as Biomarkers of Exposure to Environmental Risk Factors for Childhood Leukemia

Principal Investigator
Adam de Smith, Ph.D.
Assistant Professor
Center for Genetic Epidemiology, Department of Preventive Medicine
Keck School of Medicine of USC
Abstract
Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, and one of the leading causes of cancer-related deaths in children. The etiology of ALL in most cases is unknown, although case control studies have reported associations between environmental exposures in early life, including pesticides, paint, and tobacco smoke, and leukemia risk. Such studies largely relied on parent questionnaire data, which are prone to bias and do not provide accurate measures or critical windows of exposure. Therefore, we propose the novel concept of using deciduous teeth (“milk teeth”) to capture accurate data on environmental exposures throughout the life course (i.e., “the exposome”) of childhood ALL patients. This approach has been used in studies of autism and other neurodevelopmental disorders, but not yet in childhood cancer; thus, this study has the potential to shift the paradigm of childhood cancer epidemiology research. Through existing collaboration with Dr. Philip Lupo, we have access to deciduous teeth and diagnostic bone marrow (tumor) material from childhood ALL patients. Reconstructing the early-life exposome of 20 ALL patients forms the basis of Aim 1. Exposome analysis will be performed in the laboratory of Dr. Manish Arora, who has pioneered methods to measure environmental components (e.g. metals, organic chemicals, nutrients) at tooth layers corresponding to specific life stages. In Aim 2, we will perform tumor whole genome sequencing to assess the somatic mutational landscape of each patient. We will then test for association between environmental exposures and patterns of somatic alterations, with a particular focus on gene deletions and mutational signatures. This study would demonstrate, for the first time, the use of teeth as biomarkers in epidemiologic studies of childhood cancer, and lay the groundwork for future funding efforts to pinpoint environmental risk factors and their critical windows of exposure that will be essential for prevention of childhood leukemia.

The Role of PFAS Exposures in NAFLD-Related Cirrhosis and Hepatocellular Carcinoma in the Multiethnic Cohort

Principal Investigator
V. Wendy Setiawan, Ph.D.
Associate Professor
Department of Preventive Medicine
Keck School of Medicine of USC
Abstract
Hepatocellular carcinoma (HCC) and cirrhosis rates have continued to increase over the past three decades. The health impact of the increasing incidence of HCC is compounded by its dismal prognosis, with overall 5- year survival of 18%. The major HCC and cirrhosis underlying etiology includes hepatitis C and B infections, alcohol-related liver disease, and non-alcoholic fatty liver disease (NAFLD). NAFLD is now recognized as a major contributor to cirrhosis and HCC development. Emerging evidence indicates that exposure to perfluorinated compounds (PFAS) disrupts lipid homeostasis in the liver and has an influence on the initiation and progression of a cascade of pathological conditions associated with NAFLD. Epidemiological evidence is scarce and there are no studies on the impact of PFAS exposure on NAFLD-related cirrhosis and HCC. Our objective is to examine the associations between plasma PFAS concentrations and NAFLD-related cirrhosis and HCC in the Multiethnic Cohort (MEC). We hypothesize that increased PFAS concentrations are associated with NAFLD-related cirrhosis and HCC and with alterations in key metabolic pathways implicated in NAFLD pathophysiology. We will conduct a nested case-control study of NAFLD-related cirrhosis and HCC (n=100) and matched controls (n=100). Plasma concentrations of PFAS and metabolomics profiling prior to disease onset will be determined using liquid chromatography with high resolution mass spectrometry. The proposed study is novel and cost efficient (leveraging existing data and samples from MEC), has the potential to advance our understanding of hepatotoxic effects of environmental pollutants, and may open new avenues for liver cirrhosis and HCC prevention. Findings from these pilot data will support a future R01 application to investigate the role of PFAS and metabolomics signatures in other liver diseases and cancers in the MEC.

The Role of PFAS Exposures in NAFLD-Related Cirrhosis and Hepatocellular Carcinoma in the Multiethnic Cohort

Principal Investigator
V. Wendy Setiawan, Ph.D.
Associate Professor
Department of Preventive Medicine
Keck School of Medicine of USC
Abstract
Hepatocellular carcinoma (HCC) and cirrhosis rates have continued to increase over the past three decades. The health impact of the increasing incidence of HCC is compounded by its dismal prognosis, with overall 5- year survival of 18%. The major HCC and cirrhosis underlying etiology includes hepatitis C and B infections, alcohol-related liver disease, and non-alcoholic fatty liver disease (NAFLD). NAFLD is now recognized as a major contributor to cirrhosis and HCC development. Emerging evidence indicates that exposure to perfluorinated compounds (PFAS) disrupts lipid homeostasis in the liver and has an influence on the initiation and progression of a cascade of pathological conditions associated with NAFLD. Epidemiological evidence is scarce and there are no studies on the impact of PFAS exposure on NAFLD-related cirrhosis and HCC. Our objective is to examine the associations between plasma PFAS concentrations and NAFLD-related cirrhosis and HCC in the Multiethnic Cohort (MEC). We hypothesize that increased PFAS concentrations are associated with NAFLD-related cirrhosis and HCC and with alterations in key metabolic pathways implicated in NAFLD pathophysiology. We will conduct a nested case-control study of NAFLD-related cirrhosis and HCC (n=100) and matched controls (n=100). Plasma concentrations of PFAS and metabolomics profiling prior to disease onset will be determined using liquid chromatography with high resolution mass spectrometry. The proposed study is novel and cost efficient (leveraging existing data and samples from MEC), has the potential to advance our understanding of hepatotoxic effects of environmental pollutants, and may open new avenues for liver cirrhosis and HCC prevention. Findings from these pilot data will support a future R01 application to investigate the role of PFAS and metabolomics signatures in other liver diseases and cancers in the MEC.
In 2019, three Pilot Projects were funded for a total of $124,993.

Single-Cell Molecular Dissection of the Role of Endocrine Disruptors in Metabolic Dysfunction

Principal Investigator
Xia Yang, Ph.D.
Associate Professor
Department of Integrative Biology and Physiology
University of California, Los Angeles
Abstract
Despite the fact that numerous human epidemiology and animal model studies have implicated a pathogenic role of developmental exposure to endocrine disrupting chemicals (EDCs) in promoting obesity, type 2 diabetes, and cardiovascular diseases, the underlying molecular mechanisms remain poorly understood. We have recently conducted a systems biology study in mice to comprehensively examine the multi-tissue transcriptome, epigenome, and gut microbiome alterations altered by developmental EDC exposure. As a result, we identified key genes, pathways, and tissue-specific regulatory networks that are perturbed in endocrine and metabolic tissues (hypothalamus, liver, and adipose tissues) and associated with metabolic dysfunctions. However, all previous molecular studies of EDCs, including ours, examined bulk tissues that represent mixtures of heterogeneous cell populations, thereby missing the opportunity to pinpoint the most sensitive and pathogenic cell types and cell-specific molecular pathways. Building on our recent success in implementing high-throughput single cell sequencing technology Drop-seq, here we propose to understand the multi-tissue, multi-cellular molecular perturbations induced by in utero exposure in mice to two common EDCs, namely, the model chemical Bisphenol A (BPA) and its much less well-understood substitute Bisphenol S (BPS) at single cell resolution. We will focus on the liver, adipose, and hypothalamic tissues due to their pivotal roles in obesity and metabolic dysfunction. Using Drop-seq, we will identify the most sensitive cell types and molecular pathways in individual cell types in each metabolic tissue that are affected by developmental exposure to BPA and BPS, and subsequently test the roles of the molecular changes in metabolic dysregulation. Our proposed pilot study will offer the first comprehensive map of the in vivo molecular activities of common EDCs in individual cell types of key metabolic tissues and will reveal key mechanistic commonalities and differences between BPA and BPS to facilitate precision medicine. The findings will help direct future therapeutic strategies to counteract EDC-induced cardiometabolic disorders.

Hepatotoxic Effects of Perfuorinated Compounds: A New Epidemiological Approach for Studying Environmental Fatty Liver Disease

Principal Investigator
Lida Chatzi, M.D., Ph.D.
Associate Professor
Division of Environmental Health, Department of Preventive Medicine
Keck School of Medicine of USC
Abstract
The prevalence of non-alcoholic fatty liver disease (NAFLD) in children has almost tripled over the past 20 years, currently affecting on average 8-12% of the general pediatric population and 34-40% of obese children in the US. Mounting evidence suggests that early life environmental exposures contribute to the etiology of NAFLD. Animal studies show hepatotoxic effects even at low levels of exposure to perfluorinated compounds (PFASs), persistent compounds widely used in water repellant textiles, nonstick coatings, and food packaging products. PFASs have long half-lives (up to a decade) in humans. Despite abundant evidence from experimental studies demonstrating liver toxicity by PFASs, epidemiologic evidence is limited to a few cross-sectional studies in adults. We therefore propose a novel study design for investigating PFASs hepatotoxic effects, based on clinical and liver histopathological data leveraged from the Follow-up of Adolescent Bariatric Surgery (FABS) study that offers a unique archive of liver tissue and blood samples collected at the time of surgery. We hypothesize that higher plasma and liver PFASs concentrations will be associated with more advance stages of NAFLD and with attenuated improvement in liver injury after bariatric surgery. We will use archived samples collected at the time of surgery to measure PFASs concentrations in plasma and liver. Existing liver gene expression data in the FABS cohort will allow characterization of PFASs associations with underlying mechanistic pathways of NAFLD, including lipid metabolism and inflammation pathways. Findings from these pilot data will support a planned R01 application to investigate further the role of the PFASs chemicals and multi-omics signatures in pediatric liver disease. Our new multidisciplinary collaboration will also be relevant to future directions planned for the upcoming renewal of the Southern California Children’s Environmental Health Center and other major ongoing research projects at USC [e.g., MADRES and ECHO projects].

Air Pollution and Breast Cancer Survival in California Teachers

Principal Investigator
Sandrah Eckel, Ph.D.
Assistant Professor
Division of Biostatistics, Department of Preventive Medicine
Keck School of Medicine of USC
Abstract
This pilot project aims to determine the relationship between ambient air pollution exposures and survival after diagnosis with breast cancer in the California Teachers Study (CTS). Using data from the California Cancer Registry (CCR), our group has previously shown that air pollution exposures after diagnosis are associated with shortened survival in lung and liver cancer patients. This work is based on the exposures occurring at the residential address at the date of diagnosis, the only address available in the CCR data. Despite biological plausibility for a role of air pollutants in breast cancer, we have not observed similar associations in breast cancer patients. We believe this is due to the longer survival of breast cancer patients, which requires access to longitudinal, individual-level data on address history (to produce more accurate exposure assignments) and data on other determinants of survival (potential confounders) which are not available in cancer registries. The CTS is a unique and rich data resource with extensive baseline and follow-up questionnaires, and addresses updated throughout follow-up. Data for those CTS participants residing in California at the time of breast cancer diagnosis are already included in the CCR. This pilot project will result in at least one publication and will lay the groundwork for subsequent NIH grant proposals: (a) an R01 to investigate the combined roles of air pollution and other risk factors on breast cancer survival with improved air pollution exposure modeling and (b) an R21 to investigate the impact of air pollution on lung cancer survival, accounting for smoking.

The Role of PFAS Exposures in NAFLD-Related Cirrhosis and Hepatocellular Carcinoma in the Multiethnic Cohort

Principal Investigator
V. Wendy Setiawan, Ph.D.
Associate Professor
Department of Preventive Medicine
Keck School of Medicine of USC
Abstract
Hepatocellular carcinoma (HCC) and cirrhosis rates have continued to increase over the past three decades. The health impact of the increasing incidence of HCC is compounded by its dismal prognosis, with overall 5- year survival of 18%. The major HCC and cirrhosis underlying etiology includes hepatitis C and B infections, alcohol-related liver disease, and non-alcoholic fatty liver disease (NAFLD). NAFLD is now recognized as a major contributor to cirrhosis and HCC development. Emerging evidence indicates that exposure to perfluorinated compounds (PFAS) disrupts lipid homeostasis in the liver and has an influence on the initiation and progression of a cascade of pathological conditions associated with NAFLD. Epidemiological evidence is scarce and there are no studies on the impact of PFAS exposure on NAFLD-related cirrhosis and HCC. Our objective is to examine the associations between plasma PFAS concentrations and NAFLD-related cirrhosis and HCC in the Multiethnic Cohort (MEC). We hypothesize that increased PFAS concentrations are associated with NAFLD-related cirrhosis and HCC and with alterations in key metabolic pathways implicated in NAFLD pathophysiology. We will conduct a nested case-control study of NAFLD-related cirrhosis and HCC (n=100) and matched controls (n=100). Plasma concentrations of PFAS and metabolomics profiling prior to disease onset will be determined using liquid chromatography with high resolution mass spectrometry. The proposed study is novel and cost efficient (leveraging existing data and samples from MEC), has the potential to advance our understanding of hepatotoxic effects of environmental pollutants, and may open new avenues for liver cirrhosis and HCC prevention. Findings from these pilot data will support a future R01 application to investigate the role of PFAS and metabolomics signatures in other liver diseases and cancers in the MEC.
In 2016, four Pilot Projects were funded, for a total of $165,000.

Near-Roadway Air Pollution Exposure and the Gut Microbiome During Pregnancy and Early Life: Implications for Childhood Obesity

Principal Investigators
Claudia Toledo-Corral, M.P.H., Ph.D.
Assistant Professor
Department of Public Health, California State University, Los Angeles
Adjunct Assistant Professor of Research
Division of Environmental Health, Department of Preventive Medicine
Keck School of Medicine of USC
Tanya Alderete, Ph.D.
Postdoctoral Research Scholar
Division of Environmental Health, Department of Preventive Medicine
Keck School of Medicine of USC
Abstract
Prenatal and early life environmental exposures to air pollutants have been associated with low birth weight and increased risk for childhood obesity. Additionally, results from the Children’s Health Study have shown that in utero near-roadway air pollution (NRAP) exposure is associated with increased childhood body mass index. While the mechanisms underlying these associations remain uncertain, animal studies and our recent preliminary data suggest that NRAP exposure may alter the gut microbiota and modify risk for obesity. Despite this, no studies have examined the potential impact of NRAP exposure on the human microbiome during critical periods of development, including pregnancy and early life. Therefore, we propose a pilot study that will examine a subset of pregnant Hispanic women from the ongoing Maternal and Developmental Risks from Environmental Stressors (MADRES) cohort, a newly established pregnancy cohort with an end-target of 1,000 predominantly Hispanic mother-child pairs living in the greater Los Angeles region. This pilot study will support the collection and analysis of stool samples needed to perform detailed gut microbial profiling in 40 women during pregnancy and 40 infants at 1 and 12 months of age. To our knowledge, this will be the first study to examine the relationships between prenatal and early life air pollution exposure and the gut microbiome, providing novel preliminary data for future grant applications. We postulate that increased NRAP exposure will be associated with alterations in the gut microbiome, which will contribute to alterations in infant growth trajectories in the first year of life. Results from the proposed pilot study will test the feasibility of stool collection in MADRES and will generate preliminary data for external grant applications aimed to examine these relationships in a larger cohort of mother-infant pairs with repeated stool sampling.

Environmental Impacts on Cardiovascular Health Over the Lifecourse

Principal Investigator
Shohreh Farzan, Ph.D.
Assistant Professor
Division of Environmental Health, Department of Preventive Medicine
Keck School of Medicine of USC
Abstract
Cardiovascular disease (CVD) accounts for the largest proportion of mortality and morbidity worldwide. While a strong body of evidence supports a role for long-term air pollution exposure in CVD among adults, relatively little is known about how air pollution exposures during key developmental windows may affect subclinical markers of atherogenesis, and potential disease development, over the lifecourse. Early markers of these pathogenic processes, including measures of carotid artery intima-media thickness and arterial stiffening, can be measured in children and young adults and may provide insight into the beginnings of disease. The overall goal of this pilot is to generate key preliminary data for a competitive R01 submission to leverage existing cardiovascular health data from the Southern California Children’s Health Study (CHS) to inform the relationship between air pollution exposure and subclinical markers of CVD risk and begin to define how environmental air pollutants may relate to changes in cardiovascular risk from childhood and to early adulthood. We propose to recontact and reevaluate 20 CHS emerging adult participants, who provided carotid artery ultrasounds at age ~10. Using the childhood imaging data as a baseline measure of cardiovascular health, we will collect a second ultrasound scan from these participants to 1) calibrate newer instrumentation to enable longitudinal modeling of subclinical markers of CVD as measured by carotid ultrasound 2) explore calculation of echogenicity, a novel marker of arterial wall composition, from childhood ultrasound images and 3) begin to explore trajectories subclinical markers of atherosclerosis from childhood into adulthood and how these markers may relate to air pollution exposure over the lifecourse. These data will inform a larger study with a long-term goal to begin to characterize environmental contributions to early cardiovascular risk factors from childhood into early adulthood, which will be key to identifying those at risk to prevent later life disease.

Exposomic and Metabolomic Approaches to Identifying Risk Factors for Pediatric Non-Alcoholic Fatty Liver Disease

Principal Investigator
Lida Chatzi, M.D., Ph.D.
Associate Professor
Division of Environmental Health, Department of Preventive Medicine
Keck School of Medicine of USC
Abstract
The prevalence of non-alcoholic fatty liver disease (NAFLD) in children has almost tripled over the past 20 years, currently affecting on average 8-12% of the general pediatric population and 34-40% of obese children in the US and in Europe. Mounting evidence suggests that early life environmental exposures contribute significantly to the genesis of metabolic diseases including NAFLD. Animal studies show hepatotoxic effects even at low levels of exposure to many endocrine disrupting chemicals (EDCs), and chronic exposures to ambient fine particulate matter have been shown to induce liver steatosis, inflammation and fibrosis in mice. Human evidence is limited to few cross-sectional studies in adults. We propose an innovative approach to evaluate the role of targeted environmental exposures measured prenatally in the subsequent development of childhood NAFLD. We will leverage the extraordinary existing resources of the “HELIX-The Human Early-Life Exposome” project, which includes harmonized prenatal geospatial data for air pollutants and targeted EDCs in 1200 pregnant mothers and children from 6 European countries. We propose to use archived blood samples collected during the childhood examination at ages 6-10 years to measure alanine aminotransferase (ALT), a validated surrogate biomarker for NAFLD in epidemiological studies of children, and cytokeratin-18 (CK-18), a marker of hepatocyte apoptosis. Existing omics signature data already measured in these samples will allow characterization of exposure associations with underlying mechanistic pathways of NAFLD, including metabolic, inflammatory and adipokine dysregulation pathways. Findings from this pilot project will be highly relevant to a planned R01 application to investigate further the role of the “human exposome” and multi-omics signatures in pediatric liver disease. Our new multidisciplinary collaboration will also be relevant to future directions planned for the upcoming renewal of the Southern California Children’s Environmental Health Center and other major ongoing research projects at USC [e.g., MADRES and ECHO pregnancy cohort projects].

Indoor Particulate Matter and the Nasal and Gut Microbiota: Implications for Acute Lower Respiratory Tract Infection in Infants from Rural Bangladesh

Principal Investigators
Talat Islam, Ph.D.
Assistant Professor
Division of Environmental Health, Department of Preventive Medicine
Keck School of Medicine of USC
Tanya Alderete, Ph.D.
Postdoctoral Research Scholar
Division of Environmental Health, Department of Preventive Medicine
Keck School of Medicine of USC
Abstract
In Bangladesh, acute lower respiratory infections (ALRI) have been estimated to cause 24% of deaths among children under five years of age. Increased exposure to particulate matter (PM) has been shown to contribute to ALRI. While the mechanisms underlying these associations remain uncertain, studies and our recently preliminary data suggest that PM exposure may alter the respiratory and gut microbiota, thereby modifying risk for ALRI. Despite this, no studies have examined the potential impact of PM exposure on the infant microbiota during critical periods of development, including the first year of life. Therefore, we propose a pilot study that will examine a subset of infants from the ongoing Bangladesh Pregnancy Cohort, which is evaluating the health effects of indoor PM exposure on ALRI in a large cohort (n=900) of women and their children. Through existing NIH funding (Fogarty), participants are already being extensively phenotyped for environmental exposures and infant health outcomes that include ALRI. This pilot study will support the analysis of respiratory and stool samples needed to perform detailed microbial profiling in 80 infants at 6 months of age. To our knowledge, this will be the first study to examine therelationships between the infant respiratory and gut microbiota and their associations with PM exposure and ALRI. Therefore, this pilot study will provide novel preliminary data for future grant applications. We hypothesize that increased PM exposure will be associated with alterations in the respiratory and gut microbiota, which will contribute to increased ALRI in the first year of life. Results from the proposed pilot study will test the feasibility of stool and nasal sample collection in the Bangladesh Pregnancy Cohort and will generate preliminary data for external funding applications that will examine these relationships in a larger cohort of participants with repeated microbiome sampling during the first year of life.
In 2017, four Pilot Projects were funded, for a total of $123,525.

Effects of Particulate Matter on Neural Stem Cell-Mediated Proliferation and Response to Hypoxic Injury

Principal Investigator
Frank Attenello, M.D.
Assistant Professor 
Department of Neurosurgery
Keck School of Medicine of USC
Abstract
Exposure to air pollution and nano-sized particulate matter (nPM) has been associated with effects in neurologic pathologies due to generation of inflammation and oxidative stress. Specifically, nPM exposure exacerbates stroke cortical damage and neurological injury in mouse models. Neural stem cells (NSC) represent a critical population of renewing neural cells, with migration towards cortical lesions. The effect of nPM exposure on NSC proliferation and migratory capacity in stroke has not been studied. We hypothesize that exposure to nPM decreases the population of NSCs in the subventricular zone (SVZ) and capable of responding and migrating to cortical injury sites (in stroke), and increases apoptotic and cell stress markers in NSCs. nPM obtained with a high-volume ultrafine particle sampler is administered through whole-body exposure chamber to transgenic mice. A model of cortical ischemic injury, via middle cerebral artery (MCA) occlusion, will then be evaluated for SVZ and stroke site neurosphere formation. We will subsequently evaluate SVZ activated and quiescent NSC density and gene expression. Following exposure to either filtered air or aerosolized nPM, we will follow neurosphereforming capacity of SVZ and ischemia sites, as well density of quiescent and activated NSCs following stroke. We will also evaluate NSC expression profiles. This study utilizes common NSC genetic profiling and phenotype studies to evaluate NSC SVZ and cortical behavior to a novel nPM exposure. We hypothesize that exposure to nPM will result in decreased neurosphere production at both SVZ and stroke sites, as well as a decreased population of SVZ NSCs (with a proportionally increased effect on activated NSCs) with expression of genetic upregulation of apoptosis and cell stress.

Role of Butyrate Producing Gut Microbiome in Immune-Regulation of TRAP Related Airway Inflammation

Principal Investigator
Omid Akbari, Ph.D.
Professor
Department of Immunology
Keck School of Medicine of USC
Abstract
The consequences of reduced lung function contribute to significant but preventable clinical and public health issues, such as COPD and asthma. Two important components in the pathophysiology of reduced lung function are dysregulated lung inflammation and exposure to environmental pollutants, such as traffic-related air pollution (TRAP). Using a variety of experimental approaches, we identified an important role in new subset of immune cells, Group 2 innate lymphoid cells (ILC2s). ILC2s constitute a recently identified cell population that produces type 2 cytokines such as IL-5 and IL-13 in response to a growing number of environmental signals and epithelial cell-derived cytokines. Initially described as a key source of IL-13 in anti-helminth innate in models of asthma, ILC2s are sufficient to provoke lung inflammation accompanied by airway hyperreactivity (AHR) independent of adaptive immunity. Based on these findings, identifying agents capable of modulating ILC2 function is an important step towards advancing treatment of air pollutant induced asthma. Moreover, we found that sodium butyrate, a short chain fatty acid (SCFA) naturally present in our body’s tissues and fluids, significantly suppresses the production of type 2 cytokines by ILC2s and relieves ILC2-dependent AHR. We additionally found that pulmonary ILC2s highly express a receptor for sodium butyrate, GPR109a. Further transcriptome analyses revealed GATA-3, a key transcription factor in ILC2 development and function, was significantly down-regulated after treatment with sodium butyrate. Given that intestinal bacteria are the predominant source of butyrate in mammals, we now propose to characterize the mechanisms by which microbial-derived sodium butyrate potentially modulates ILC2 effector function and reduces air pollutant ILC2-dependent AHR in vivo. The overall goal of this research project is to discover a comprehensive set of molecular signatures and markers that can be used as therapeutic targets to treat lung inflammation associated with TRAP. In order to achieve this objective, we will first fully characterize the phenotype, function, and mechanisms of action of sodium butyrate in animal models of AHR. Next, we will assess the capacity for therapeutic intervention in translational animal models deficient for GPR109a receptor. Finally, we will aim to prevent development of air pollutant AHR via altering microbiome of mice with high butyrate producing strains of bacteria and compare the results to the recipients of microbiome without capacity to produce butyrate. Because of the novelty of animal models, translational approaches and clinical relevance nature of this project, great progress is expected.

Toxic Metals Exposure and Metabolomic Perturbation: Impacts on Children Living Near Battery Recycling Industry

Principal Investigators
Jill Johnston, Ph.D.
Assistant Professor
Division of Environmental Health, Department of Preventive Medicine
Keck School of Medicine of USC
Shohreh Farzan, Ph.D.
Assistant Professor
Division of Environmental Health, Department of Preventive Medicine
Keck School of Medicine of USC
Abstract
Neighbors of a local active lead-acid battery recycler that processes millions of spent automotive batteries per year have raised concerns about residential exposure pathways and the resulting public health threat. Battery recycling operations (i.e. secondary lead smelters) are notoriously associated with airborne and suspended dust releases of toxins, including lead (Pb), arsenic (As), cadmium (Cd), and antimony (Sb). The Quemetco Inc. secondary lead smelter in City of Industry, CA is no exception and has drawn recent attention for violations of air quality standards and excessive emissions of toxic metals. The extent to which these emissions may be impacting the surrounding low-income community of color are, as yet unknown, but initial screening of soil samples found concentrations of Pb, Cd, and As 30, 400, and 500 times higher, respectively, than California health screen ‘safety’ standards for residential soil. We propose a community-engaged research study in the vicinity surrounding the battery recycling operations in the San Gabriel Valley of Los Angeles County to characterize individual biomarkers of toxic metal exposures in the communities adjacent to the smelter. It is critical to understand the body burden of multiple metals in the community in order to evaluate the impact of metal mixtures on human health. We will enroll 100 children and assess potential smelter-related exposures, by measuring concentrations of metals, including Pb, As, Cd, and Sb, in samples of blood and toenails. Lead by two junior investigators, this research will produce key data on the internal dose of metal mixtures to support the development of a long-term study to relate biomarkers of toxic metal exposures to child health outcomes.

Lipophilic Environmental Pollutants and Adipose Tissue Metabolic Profile at the Time of Bariatric Surgery: A Novel Approach for Exploring Mechanisms

Principal Investigator
Lida Chatzi, M.D., Ph.D.
Associate Professor
Division of Environmental Health, Department of Preventive Medicine
Keck School of Medicine of USC
Abstract
The prevalence of obesity is rising worldwide, and excess food consumption and lack of physical activity do not fully explain the current obesity epidemic. The “environmental obesogen hypothesis” proposes that early life exposure to environmental pollutants that can interfere with endocrine and metabolic systems can alter metabolic programming and growth patterns, thereby increasing the risk for obesity and related diseases, such as type 2 diabetes and cardiovascular disease. Although the mechanisms remain uncertain, the impact of lipophilic environmental obesogens (including persistent and non-persistent organic pollutants) on adipose tissue (AT) development and expansion is thought to be mainly through the direct modulation of adipogenesis, lipogenesis and lipolysis. Indirect effects in AT are also possible through pollutant-induced alterations in the functions of other metabolically relevant tissues, including the liver and the central nervous system. We propose a new approach to investigating the environmental obesogen hypothesis by studying human AT. We hypothesize that environmental pollutant concentrations accumulated in AT will be associated with alterations in AT metabolic pathways related to fatty acid metabolism, inflammation and steroid hormone biosynthesis and metabolism. To evaluate this hypothesis, we will collect AT samples at the time of bariatric surgery from 15 obese adolescents at Cincinnati Children’s Hospital. We will use high-resolution mass spectrometry techniques pioneered by investigators at the Emory HERCULES Exposome Research Center and Children’s Health Exposure Analysis Resource (CHEAR) laboratory to measure the environmental pollutant burden and associated targeted and untargeted biological responses in AT. Metabolic pathways will be characterized using novel metabolomics approaches. This is the first study, to our knowledge, aiming to apply highresolution mass spectrometry techniques to identify known and potentially unknown obesogenic environmental pollutants, and to evaluate the associations of environmental pollutant mixtures with the metabolome directly in human AT.
In 2016, four Pilot Projects were funded, for a total of $165,000.

Neuronal Control of the Oxidative Stress Response: Genetic Analysis of SKN-1/Nrf2 Activation by Neuroendocrine Signaling

Principal Investigator
Derek Sieburth, Ph.D.
Associate Professor 
Department of Cell & Neurobiology, Zilkha Neurogenetic Institute
Keck School of Medicine of USC
Abstract
Exposure to atmospheric pollutants causes toxic cellular effects largely through the promotion of oxidative stress. The Nrf2 transcription factor plays a critical role in mediating adaptive responses to cellular stress by directing the expression of cytoprotective genes that function to detoxify reactive oxygen species produced by these pollutants. However the mechanisms underlying the regulation of Nrf2 activity by environmental toxins in multicellular organisms are not well understood. My laboratory investigates cellular and molecular pathways that regulate the activity of the Nrf2 homolog SKN-1 in vivo using the genetic model system C. elegans. We recently identified a role for the nervous system in promoting resistance to oxidative stress by activating SKN-1 in distal tissues through the release of neuropeptides from specific neurons. Our findings suggest that neuroendocrine regulation of the oxidative stress response may have evolved as a survival mechanism to protect organisms from environmental toxicants. This proposal describes a set of genetic, molecular, and behavioral experiments, designed to uncover the cellular and molecular mechanisms by which neuroendocrine signaling promotes the activation of SKN-1/Nrf2. In Aim 1 we will determine how neuropeptide signaling activates SKN-1/Nrf2 in distal tissues. In Aim 2 we will determine whether neuropeptide release is regulated by oxidative stress. In Aim 3 we will examine whether neuroendocrine signaling regulates stress responses to atmospheric pollutants known to activate Nrf2. Pilot grant funding will allow generation of preliminary data to support NIH funding aimed at understanding how Nrf2 is regulated by the nervous system and for developing therapeutics that target the pathway for prevention of respiratory, cardiovascular, and neurological diseases caused by pollution.

Use of Novel Analytical Techniques and Biomarkers to Determine Toxic Metals Exposure from a Southeast Los Angeles Battery Recycling Plant

Principal Investigator
Jill Johnston, Ph.D.
Assistant Professor
Division of Environmental Health, Department of Preventive Medicine
Keck School of Medicine of USC
Abstract
Neighbors of a lead-acid battery recycler (or secondary lead smelter) that processed ~11 million batteries per year and operated for nearly two decades without proper environmental review are concerned about the resulting public health threat and residential exposures. Secondary battery recycling operations are associated with airborne and suspended dust releases of lead (Pb) in addition to toxins such as arsenic (As), cadmium (Cd), manganese (Mn). The extent of elevated soil contamination, the co-exposure to multiple pollutants, and process to identify residential remediation needs in this environmental justice community are, as yet, unknown. We propose a community-driven research study in the vicinity surrounding the battery recycling operation in southeast Los Angeles, to conduct in-situ soil measurements for multiple metals using a rapid assessment technique to evaluate areas of high risk and to assess historical exposure using baby teeth as biomarkers. In both cases, we will measure concentration of Pb, As, Cd, Mn and antimony (Sb). We will recruit parents/ guardians willing to provide baby teeth of their children through community workshops and organizations. Multivariate linear regression will be used to assess whether soil concentrations are positively associated with early childhood heavy metal biomarkers in teeth of exposure children. This pilot project will estimate community risks from exposure to multiple metals associated with the nearby battery recycling operation, test the ability to use teeth as biomarkers to reconstruct exposures retrospectively, and advance the community capacity to participate in and to use scientific research to help guide mitigation efforts in support of public health.

Farm Exposures, Immunology and Microbiome: A Feasibility Study in Twins

Principal Investigator
Wendy Cozen, M.P.H., D.O.
Professor
Departments of Preventive Medicine and Pathology
Keck School of Medicine of USC
Abstract
Evidence that the fecal microbiome plays an important role in immune system regulation is accumulating. Although diet has a profound effect on the fecal microbiome, little is known about other environmental influences. Agricultural exposures include both organic (animals, crops) and inorganic (pesticides) exposures and are known to be associated with risk of chronic diseases, in particular, lymphoma. B-cell activation, inflammation and immune suppression are the pathways thought to lead to lymphoma development and it is not known whether agricultural exposures influence these pathways. Moreover, the association between farm exposures and fecal microbiota has not been extensively studied. The goal of this proposal is to conduct a feasibility study for a future R01 with the goal of understanding the effect of agricultural exposures on the immune system and microbiome. We will compare the fecal microbiome from stool samples and serum molecules associated with systemic immune activation, in 30 twin pairs discordant for occupational and residential farm exposures. Validated questionnaires from the Iowa/Mayo NHL study (Cerhan) will be used to document current and past exposures to farms, crops, animals and pesticides. Laboratory methods include multiplex cytokine/chemokine assays and 16S rRNA sequencing of microbiome samples. A matched-twin design will be used to compare microbiome and immune response markers in the identical, exposure discordant twins. We will choose twins with extreme exposure differences to enhance the likelihood that we will observe an effect. The chief advantage of identical twins is that the commonality of their genetic, early life and cultural identity simplifies the interpretation of biological associations, approximating an experiment of nature. This proposal will provide feasibility and preliminary data for an R01 to more comprehensively examine the interaction between farm exposures, the microbiome and the immune response to provide critical information for understanding the underlying biological mechanisms, which could lead to new prevention strategies.

In-Utero Exposure to Air Pollution and Birth Weight

Principal Investigator
Rima Habre, Sc.D.
Assistant Professor
Division of Environmental Health, Department of Preventive Medicine
Keck School of Medicine of USC
Abstract
In the United States, the burden of obesity disproportionally affects the Hispanic population, with prevalence in excess of 21% nationally compared to 14% in non-Hispanic whites. This obesity disparity is already present by preschool age, suggesting that it may have its origins in the earliest stages of life. In California, the Hispanic population also carries the highest cumulative burden of multiple harmful environmental exposures 1, and air pollution is a pervasive exposure of concern. In-utero exposure to particulate matter air pollution is associated with decreased birth weight in full term births, with many studies pointing to the 3rd trimester as the exposure window with highest impact. Low birth weight as a result of environmentally-induced intrauterine growth restriction (IUGR) is associated with higher risk of metabolic syndrome and obesity later in life. This proposal aims to investigate whether in-utero, third trimester exposure to fine particulate matter (PM2.5) air pollution, measured using cutting-edge, personal exposure monitoring, is associated with infant birth weight in 100 pregnant, Hispanic women enrolled in the ongoing MADRES pregnancy cohort and living in the Los Angeles, CA, area. We hypothesize that third-trimester PM2.5 exposure will be inversely related to infant birth weight in this Hispanic population experiencing a disproportionate burden of environmental exposure and obesity risk.
Southern California Environmental Health Sciences Center
Keck School of Medicine, University of Southern California
2001 North Soto Street, MC 9237
Los Angeles, CA 90089-9013
scehsc@usc.edu
Supported by NIEHS grant P30ES007048
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