OEFC Core Utilization Subsidy Program/ Voucher Awards

Large CUSP applications will be provided to subsidize already funded EHS research (for example NIEHS) by subsidizing up to 25% total OMICS costs capped at a $10,000 maximum.

Principal Investigator: Matt Cave, MD
Co-Investigator: Carolyn Klinge, PhD, Melissa Smith, PhD
Title: ISO SEQ Identification of Splicing Events in a Mouse Model of MASLD
Lay Description: The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) in the U.S. population is increasing with ~ 36-48% of the population affected. Our work examines the impact of environmental pollutants, including persistent organic pollutants called polychlorinated biphenyls (PCB), and diet on MASLD using experimental models including mice. The current study uses a special technique called IsoSeq from Pacific Biosciences to determine if a single oral exposure of mice to a PCB called Aroclor1260 affects the different forms of RNA transcribed and the association of those RNAs with pathways in human MASLD.

Medium CUSP applications support the expenses (up to $5,000) associated with critical exploratory research and proof-of-concept studies needed by CIEHS members for hypothesis generation and grant (re)submission.

Principal Investigator: Alex Carll, PhD
Collaborators: Petra Haberzettl, PhD, Melissa Smith, PhD and Juw Won Park, PhD
Title: Role of Pulmonary Oxidative Stress in the Cardiotoxicity of Inhaled Fine Particulate Matter
Lay Description: Inhalation of particulate matter air pollution evokes heart rhythm changes that may promote cardiac arrhythmias and sudden cardiac arrest. These effects are believed to result from altered nervous system regulation of the heart, involving enhanced ‘fight-or-flight’ stress activation through the sympathetic nervous system. We recently found in a mouse model that particulate matter exposure alters the expression and phosphorylation of cardiac proteins involved in electrical conduction and ion channel function. This work will use a common Beta-blocker drug that inhibits sympathetic receptors to elucidate beta-adrenergic receptor activation underlies the impacts of particulate air pollution on cardiac gene expression, thereby validating a molecular mechanism of particulate matter-induced cardiac toxicity.

Small CUSP applications support the costs (up to $1,500) associated with OMICs research needed to finish out a project or address questions arising in manuscript revisions or grant resubmissions.

Principal Investigator: J. Christopher States, PhD
Co-Investigators: Lu Cai, MD, PhD, Ted Smith, PhD, Charlie Zhang PhD, Rochelle Holm, PhD, D.J. Biddle, PhD
Title: Metals In Wastewater in Jefferson County
Lay Description: This award will allow us to follow up on two sites where we found elevated levels of lead (Pb) in the wastewater in spot samples. Elevated lead in wastewater could indicate leaching of lead from old lead water delivery pipes or industrial discharge into the sewers.

Supporting the Base (large) awards (up to 25% total OMICS costs capped at a $10,000 maximum) will be provided to subsidize CIEHS-member NIEHS-funded research.

Principal Investigator: John Wise, Jr., PhD
Collaborator: Lu Cai, MD, PhD and Jun Cai, MD, PhD
Title: Cr(VI)-Induced DNA Damage Contributes To Brain Aging
Lay Description: This research voucher supports Dr. Wise and his team to investigate the neurotoxicity of hexavalent chromium [Cr(VI)]. Cr(VI) is a known human carcinogen that made international news when Erin Brokovich challenged PG&E for contamination of drinking water in Hinkley, CA. Dr. Wise's study is the first to assess potential neurotoxic effects of Cr(VI) using a rat model exposed to drinking water levels that are currently considered safe by the World Health Organization (WHO) and the U.S. Environmental Protection Agency (EPA); 0.05 and 0.1 mg/L (or ppm), respectively. This research voucher will provide the necessary funds to assess accumulation of chromium in various brain regions using UofL's Metallomics Core facility, and results are expected to be disseminated next spring.

Medium research voucher applications support the expenses (up to $5,000) associated with critical exploratory research and proof-of-concept studies needed by CIEHS members for hypothesis generation and grant (re)submission.

Principal Investigator: Carolyn Klinge, PhD
Collaborator: Melissa Smith, PhD and Eric Rouchka, PhD
Title: Determine If Palmitic Acid and Polychlorinated Biphenyl Exposures Alter m6A Marks in the Transcriptome of Aml12 Mouse Hepatocyte Cells
Lay Description: Environmental pollutants (polychlorinated biphenyls (PCBs)) increase progression of metabolic dysfunction associated steatotic liver disease (MASLD). We identified changes in a chemical modification of mRNA (m6A) in the livers of mice exposed to PCBs and a high fat diet that cause MASLD. The goal of this study is to determine if PCBs alter m6A in mRNAs in mouse liver cells to allow future specific mechanistic studies.

Medium research voucher applications support the expenses (up to $5,000) associated with critical exploratory research and proof-of-concept studies needed by CIEHS members for hypothesis generation and grant (re)submission.

Principal Investigator: LiQing He, PhD
Collaborator: Xiang Zhang, PhD
Title: RNA Modification Changes In CAA Treated Human Liver Cell Line
Lay Description: We will use chloroacetyaldehyde to treat the human liver cell line to mimic environmental pollution-related liver disease. A two-dimensional liquid chromatography-mass spectrometry will be used for identifying and quantifying RNA modifications at the epitranscriptome scale.

Principal Investigator: Andrew Mehring, PhD
Collaborator: Lu Cai, MD, PhD and Jason Xu
Title: The Use of Stormwater Biofilters as Long-Term Sensors Of Urban Heavy Metal Pollution
Lay Description:

• Stormwater biofilters (also known as raingardens or bioswales) are treatment systems designed to trap pollutants that flow over city streets during rainstorms, and if they are functioning properly, they should accumulate a long-term record of pollutants released in known areas of cities.
• Heavy metals (such as lead and mercury) in 40 biofilters in Louisville and neighboring cities will be measured to determine if metal pollution in biofilters is related to biofilter design, age, and layout of the city, or if it may also be related to household income or other demographic information.
• By monitoring pollutant accumulation in biofilters and other forms of urban treatment systems, we may improve our ability to detect pollution “problem areas”, effectively target our cleanup efforts, and address environmental health and justice issues within cities.

Large research voucher applications will be provided to subsidize already funded EHS research (for example NIEHS).

Principal Investigator: Matthew Cave, MD
Collaborator: Timothy O’Toole, PhD
Title: The Metabolic Effects Of Polystyrene Microplastics On The Liver Gene Expression
Lay Description: This voucher will help us to understand how exposure to microplastic pollutants reprograms liver gene expression contributing to obesity and diabetes.

Medium research voucher applications support the expenses (up to $5,000) associated with critical exploratory research and proof-of-concept studies needed by CIEHS members for hypothesis generation and grant (re)submission.

Principal Investigator: Kyung U. Hong, PhD
Co-Investigator: David W. Hein, PhD
Title: Transcriptomic Analysis Of Human Hepatocytes Exposed To Heterocyclic Amines
Lay Description: Cancer-causing compounds called heterocyclic amines are often formed during high temperature cooking of meat. Our study aims to explore, for the first time, a potential and important link between dietary consumption of heterocyclic amines and development of insulin resistance, a pre-diabetic condition that raises the risk of type 2 diabetes and cardiovascular disease. Studying how these toxic compounds contribute to insulin resistance (and potentially type 2 diabetes) will ultimately help us understand how environmental factors, such as eating cooked meat, contribute to metabolic disease resistance and also devise ways to protect individuals who are susceptible to this condition.

Medium research voucher applications support the expenses (up to $5,000) associated with critical exploratory research and proof-of-concept studies needed by CIEHS members for hypothesis generation and grant (re-) submission.

Principal Investigator: Carolyn Klinge, PhD
Collaborator: Michael Merchant, PhD
Title: Selenoprotein Analysis in a Murine Model of PCB-Induced TASH
Lay Description: Exposure to environmental pollutants including polychlorinated biphenyls (PCBs) are associated with progression of nonalcoholic fatty liver disease (NAFLD). We identified changes in a chemical modifications of RNA associated with translation of selenoproteins that protect the liver from injury in a mouse model of NAFLD after PCB exposure. The major goal of this study is to determine if PCBs alter selenoprotein levels in a mouse model of environmental exposure-associated NAFLD.

Large research voucher applications will be provided to subsidize already funded EHS research (for example NIEHS).

Principal Investigator: J. Christopher States, PhD
Collaborator: Lu Cai, MD, PhD and Alexandra Nail, PhD
Title: Disruption of Human MRN Complex Signaling by Heavy Metal Exposure
Lay Description: Heavy metals are common toxic environmental contaminants and exposure is widespread. Many are known to induce cancer in humans. Several metals such as arsenic and cadmium are known to induce chromosomal instability which plays a role in carcinogenesis. However, the mechanism is unknown. DNA double strand breaks are potentially lethal DNA damage and contribute to chromosomal instability. Our NIEHS funded project revealed that DNA damage signaling mechanisms were dysregulated in skin cells chronically exposed to arsenic. This research voucher expands on our prior work and focuses on the ability of arsenic and cadmium to disrupt the mechanism signaling the presence of DNA double strand breaks to the DNA repair and cell cycle regulatory systems.

Medium research voucher applications support the expenses (up to $5,000) associated with critical exploratory research and proof-of-concept studies needed by CIEHS members for hypothesis generation and grant (re)submission. 

Principal Investigator:  Walter H. Watson, PhD
Collaborators: J. Christopher States, PhD, Ana Ferragut-Cardoso, PhD
Title: Comparative keratinocyte responses to environmental arsenic
Description:  Environmental arsenic is a world-wide health problem, and the skin is one of the major target organs of arsenic toxicity. Our OEFC Research Voucher Award from the CIEHS will help us answer the question of why some skin cells are resistant to arsenic toxicity while others are not. We will use ICP-MS to assess rates of arsenic import and export by different keratinocyte cells. The results should shed light on how differences in formation and export of glutathione-arsenic complexes translate into differences in sensitivity to cell death and transformation into cancer cells.

Medium research voucher applications support the expenses (up to $5,000) associated with critical exploratory research and proof-of-concept studies needed by CIEHS members for hypothesis generation and grant (re-) submission.

Principal Investigator: Venkatakrishna Jala, PhD
Collaborator: Matthew Cave, MD
Title: Combating environmental toxin, PCB-126 associated toxicities
Lay Description: Polychlorinated biphenyls (PCB) are environmental toxins and are associated with numerous cancers, skin lesions, thyroid disruption, and altered menstrual cycling, as well as damage to the nervous, immune, and cardiovascular systems. We found that exposure of one such PCB called ‘PCB-126’ caused significant damage to in intestinal epithelial barrier. We identified that co-treatment beneficial dietary microbial metabolite called ‘urolithin A (UroA)’ rescued PCB-126-mediated intestinal epithelial barrier damage. The goal of this project is to identify molecular mechanisms responsible for UroA-mediated protective activities against PCB-126-induced toxicities. We proposed to perform RNA-sequencing experiments to determine the regulation of differential gene expression in intestinal epithelial organoids that were exposed to PCB-126 in the presence or absence of UroA.

Principal Investigator: Carolyn Klinge, PhD
Collaborator: Matthew C. Cave, MD, Yan Li, MD, PhD, Xiang Zhang, PhD
Title: Epitranscriptome in a murine model of diet and PCB-induced HCC
Lay Description: This project will identify chemical modifications on transcribed RNA in the livers of male mice on a low-fat diet with or without a single exposure to a mix of polychlorinated biphenyls (PCBs). These chemical changes on RNA are the ‘epitranscriptome’. Some of the mice in this study developed hepatocellular carcinoma (HCC) and we will identify the transcriptome in the HCC tumors. We will use computational analysis to identify cellular pathways altered in these samples.

Principal Investigator: J. Christopher States, PhD
Collaborator: Juw Won Park, PhD
Title: Gene Fusions and In/del Mutations in Arsenic-induced Skin Cancer
Lay Description: Recent research has revealed that gene rearrangements resulting in formation of ‘hybrid genes’ (aka ‘gene fusions’) are driving carcinogenesis. Arsenic exposure is known to cause chromosomal instability and gene rearrangements. This research voucher will allow us to examine genomic DNA isolated from a few arsenic exposure induced skin tumors for evidence of deletions in genes and rearrangements of genes that may be causing the cancer formation.

Principal Investigator: Banrida Wahlang, PhD
Collaborator: Carolyn Klinge, PhD, Matthew C. Cave, MD
Title: Alterations in gut microbiome caused by long-term exposure to PCBs
Lay Description: Polychlorinated biphenyls (PCBs) are environmental chemicals that have been linked to numerous health effects in people who are exposed to them. These health effects include liver disease, reproductive defects, and cardiovascular diseases. Our gut bacteria play an important role in influencing liver health with higher amounts of "good bacteria" known to be beneficial to the liver. PCBs are known to cause changes to gut bacteria composition, and this may potentially promote liver diseases. Using experimental models in the laboratory, extensive research has been performed on how PCB exposures, over shorter periods of time, can cause toxicity to organs such as the liver and gut. However, little is known on how PCB exposures over longer periods of time can impact these organs. The proposed project seeks to understand how long-term exposures to PCBs can affect the composition of gut bacteria in the body, and how these changes can, in turn, impact liver health and/or worsen liver disease. Importantly, people are exposed to "forever chemicals" such as PCBs over their life span, therefore these long-term exposure studies are relevant because they better reflect human exposure patterns.

Principal Investigator: Kupper Wintergerst, MD
Collaborator: Lu Cai, MD, PhD, Yi Tan, PhD, Sara Watson, MD
Title: Serum nonessential and essential metals in children with type 1 & type 2 diabetes
Lay Description: Our study will investigate the connection between diabetes and the presence or absence of essential and toxic metals in children and adolescents with type 1 or type 2 diabetes. Essential metals, such as zinc or calcium, are important to normal body function. Toxic metals, such as lead or arsenic, can be dangerous. Our goal will be to determine if there is an association between having high or low quantities of these metals and the diagnosis of diabetes.

Medium research voucher applications support the expenses (up to $5,000) associated with critical exploratory research and proof-of-concept studies needed by CIEHS members for hypothesis generation and grant (re)submission. 

Principal Investigator: Barbara J. Clark, PhD
Collaborator: Carolyn M. Klinge, PhD
Title: STARD5 and lipid dysregulation with ER stress
Description: Environmental exposure to persistent pollutants is recognized as a risk factor for development of metabolic diseases. The risk is greater when combined with underlying genetic and dietary factors. Chronic endoplasmic reticulum (ER) stress from over nutrition and environmental toxicants can lead to inflammatory responses that promote development of toxicant-associated steatohepatitis (TASH), yet the mechanisms that promote disease progression are complex and not well defined. Using a novel Stard5 knock-out mouse model this project will test whether the loss of STARD5 is risk factor for development of steatohepatitis under ER stress conditions. STARD5 is a member of the steroidogenic acute regulatory protein (StAR)-related lipid-transfer (START) domain family of lipid transport proteins, and is highly expressed in key cell types that promote steatohepatitis. We have identified changes in select target genes that support Stard5-/- mice are more sensitive to tunicamycin-induced changes in liver lipid metabolism. The work proposed will define the liver transcriptome for wild type vs Stard5-/- mice after tunicamycin-induced ER stress. Using this unbiased approach our understanding of the impact of Stard5 knockout on mouse liver mRNA transcriptomes under normal and stress conditions will be expanded. The novelty is there are no transcriptomics reports using the Stard5-/- mice. The work will provide proof-of-concept support to expand investigations on loss of STARD5 in contributing to diet-environmental pollutant-induced TASH.

Principal Investigator: Anna Gumpert, PhD
Collaborator: Daniel Conklin, PhD
Title: Combined Effects of Air Pollution and Hypertension on Cardiovascular Remodeling
Description: Human population studies indicate that 60-70% of the premature deaths attributed to air pollution are cardiovascular deaths. High blood pressure and cardiac fibrosis are important contributors to detrimental structural and functional changes and progressive worsening of heart disease. Our studies aim to investigate how environmental factors (i.e. air pollution) contribute to worsening outcomes and decreased quality of life.

Small research voucher applications support the costs (up to $1,500) associated with OMICs research needed to finish out a project or address questions arising in manuscript revisions or grant resubmissions.

Principal Investigator: Banrida Wahlang, PhD
Collaborator: Matthew Cave, MD
Title: Sex-dependent effects on gut microbiome associated with PCB exposures
Description: Polychlorinated biphenyls (PCBs) are environmental chemicals or toxicants that have been associated with numerous health effects in people who are exposed to them. These health effects include liver disease, reproductive defects, and cardiovascular diseases. While extensive research has been performed on how PCBs can induce organ damage and toxicity using experimental models, little is known about how PCBs behave with regards to their toxic actions, in the context of sex and gender.  The proposed project seeks to understand how exposures to chemicals such as PCBs can cause changes in the composition of gut bacteria in the body, how these changes can impact liver health, and if these changes are different in males vs. females. Such studies will help to better understand the relationship between these environmental contaminants with sex and gender, and if men or women are more at risk to such PCB-associated health effects.

Medium research voucher applications support the expenses (up to $5,000) associated with critical exploratory research and proof-of-concept studies needed by CIEHS members for hypothesis generation and grant (re)submission. 

Principal Investigator: Madhavi Rane, PhD
Collaborator: Lu Cai, MD, PhD, Michael Merchant, PhD, Shesh Rai, PhD
Title: Effects of whole life exposure to low-dose cadmium on post weaning high fat diet-induced pathogenesis in the kidney
Description: Obesity and cadmium (Cd) exposure are both independent risk factors for chronic kidney disease (CKD) and end stage renal disease (ESRD) necessitating dialysis or kidney transplantation. Since no current effective therapies exist to prevent progression to CKD, understanding how environmental exposure to Cd and diet-induced obesity simultaneously contribute to the pathogenesis of CKD is urgently needed. The current study, examining the dual effects of obesity (high-fat-diet) and cadmium exposure on kidney damage, is novel and will lead to generation of molecular target-based therapies to slow down progression to ESRD. 

Medium research voucher applications support the expenses (up to $5,000) associated with critical exploratory research and proof-of-concept studies needed by CIEHS members for hypothesis generation and grant (re-)submission.

Principal Investigator: Carolyn Klinge, PhD
Collaborator: Matt Cave, MD; Xiang Zhang, PhD, Shesh Rai, PhD
Title: Epitranscriptome in a murine model of TASH
Description: Chronic environmental exposures to polychlorinated biphenyls (PCBs) contribute to metabolic diseases including toxicant-associated steatohepatitis (TASH). Mice co-exposed to high fat diet and PCBs develop TASH, but the precise mechanisms involved in disease progression remain to be identified. There are over 160 chemical modifications of transcribed RNA that regulate transcript fate and the contribution of these modifications to the mouse liver proteome with HFD +/- PCB exposure is unknown. The objective of the proposed research is to identify global RNA modifications in C57Bl/6J male mouse liver mRNA, lncRNA, and pri-miRNA after exposure to PCB (Aroclor1260 or PCB 126) + HFD versus HFD alone (control) using mass spectrometry. Once differences in epitranscriptomic marks are identified, we will evaluate the expression of the readers, writers, and erasers of these marks to determine how environmental exposures result in different RNA epitranscriptomic modifications in liver.

CLICK HERE to view the publication that was funded in part by a CIEHS OEFC RESEARCH VOUCHER to Carolyn M. Klinge for the analysis performed in the CREAM core (headed by Dr. Xiang Zhang) to identify the global post-transcriptional chemical modification (PTM) of RNA in male mouse liver samples in a study performed in Dr. Matt Cave’s lab in which the mice were fed a HFD for 12 weeks with a single PCB exposure at the 2-week time point.

Principal Investigator: Alex Carll, PhD, MSPH
Collaborator: Michael Merchant, PhD, Petra Haberzettl, PhD, Daniel Conklin, PhD
Title: Neural and Neuroendocrine Pathways of Airborne Toxin-Induced Cardiac Dysfunction
Description: The inhalation of airborne irritants is known to alter neural and neurohormonal regulation of the heart via the autonomic nervous system and the hypothalamic pituitary adrenal axis. These effects may in turn impair cardiac conduction, contraction, and relaxation, by impairing cardiac ion homeostasis through phosphorylation and/or de-phosphorylation of transmembrane ion channels and intracellular ion-handling proteins. This project will examine the impacts on the global cardiac phosphoproteome of inhalation exposures to three different airborne toxins with irritant properties (formaldehyde, e-cigarette aerosol, and ambient particulate matter). The data generated from this study will complement electrocardiographic data to elucidate the role of intracellular signaling and neural and neurohomormonal dysregulation in cardiac dysfunction induced by independent exposures to a diverse set of inhaled irritants.