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["Title"," Principal Investigator"," Institution"," Grant Number"," RFA PA Number"," Program Officer"," Pubs"," Primary Science Code"," Secondary Science Code"," Abstract"]
["AFLATOXIN EXPOSURE, GROWTH FALTERING, AND THE GUT MICROBIOME AMONG CHILDREN IN RURAL GUATEMALA","Krajmalnik-Brown, Rosa ","Arizona State University-Tempe Campus","R01ES033999","PA20-185","Dzierlenga, Anika",0,"68 - Microbiome","03 - Carcinogenesis/Cell Transformation","Project Summary\nAflatoxin B1 (AFB1) is a carcinogen produced by Aspergillus flavus and A. parasiticus which grow on maize.\nGiven the high prevalence of stunting and other nutritional disorders in low- and middle-income countries where\nmaize is highly consumed, the role of aflatoxin exposure is worth investigating. Observational reports have\nshown associations between aflatoxin exposure and child growth. However, most have been cross-sectional and\nhave not assessed seasonal variations in aflatoxin, food preparation, and dynamic changes in growth. In\naddition, biological mechanistic data on how aflatoxin may exert impact on growth is missing. We will advance\nthe science of aflatoxin and child growth by assessing temporal changes in diet, aflatoxin exposure, and\ngrowth faltering in a prospective cohort of children from rural Guatemala, a country that has one of the\nhighest rates of child stunting and aflatoxin exposure in the world. In addition, we will use bioreactors to\ninvestigate possible biological mechanisms, specifically direct aflatoxin-gut microbiome interactions.\nWe hypothesize that aflatoxin exposure negatively impacts child growth by inducing inflammation and disrupting\nthe gut microbiome. In Aim 1, we will prospectively evaluate aflatoxin exposure and height-for-age difference\ntrajectories among 185 children between 6-9 and 24-27 months of age. We will assess aflatoxin exposure using\nserum AFB1-albumin adduct levels, and we will measure biomarkers of systemic and gut inflammation. In Aim\n2, we will evaluate the association between aflatoxin exposure, stunting status, and gut microbiome composition\nand function. We will evaluate the fecal microbiome of each child using 16S rRNA gene amplicon and whole\ngenome sequencing to identify key species and metabolic pathways for differing AFB1 exposure levels and\nstunting status. In parallel, we will use bioreactors inoculated with fecal samples to evaluate the response of the\ngut microbiome composition to varying levels of AFB1 exposure. In Aim 3, we will evaluate the impact of aflatoxin\nexposure on microbial nutrient metabolism and the impact of gut microbiota on aflatoxin\ndetoxification/metabolism by monitoring key nutrient metabolites (e.g., short-chain fatty acids) and AFB1\nbiotransformation products in bioreactors. We will also evaluate the effect of inflammation, aflatoxin, and\nmicrobiome composition on child stunting based on the results from the three aims using path analysis.\nSignificance and Innovation: Through a multidisciplinary approach that leverages access to an exposed\npopulation and expertise on epidemiology, toxicology, environmental engineering and human microbiome, we\nwill be able to evaluate the impact of aflatoxin exposure on growth and its possible mediation by the gut\nmicrobiome.\nImpact: Completion of this R01 proposal will advance understanding of the physiologic mechanism of aflatoxin-\nmediated growth restriction, pointing the way toward new public health strategies for mitigation of aflatoxin\nexposure and for microbiome-directed treatments."]
["CHARACTERIZATION OF NAPHTHALENE DNA ADDUCTS IN MICE AND FIREFIGHTERS","Hannon, Sarrah ","University Of Arizona","F31ES034268","PA21-052","Carlin, Danielle",0,"69 - Respiratory","03 - Carcinogenesis/Cell Transformation","Project Summary/Abstract\nNaphthalene (NA), a simple polycyclic aromatic hydrocarbon, is persistently present in the environment as a\nbyproduct of combustion of fossil fuels and burning of tobacco and other products. Its ubiquitous presence\nresults in widespread exposure to the general population. Certain occupational groups, such as firefighters,\nhave elevated levels of exposure. Firefighters also have increased incidences of certain types of cancer. NA is\ncurrently classified by the International Agency for Research on Cancer (IARC) as a Class 2B Carcinogen.\nThere is direct evidence of tumor formation in mice and rats but no direct evidence of carcinogenecity of NA in\nhumans at this time. The pathogenesis of tumor formation in mice and rats after exposure to NA is unclear;\ncytotoxic and genotoxic mechanisms are both proposed in the current literature. NA metabolism results in the\ngeneration of reactive intermediates such as 1,2-epoxide and reactive metabolites such as 1,4- and 1,2-\nnaphthoquinone (NAQ). Reactive quinone and epoxide metabolites of similar compounds, such as\nbenzo[a]pyrene, have been shown to enact their carcinogenecity through DNA adduct formation. Published ex\nvivo and in vitro data have demonstrated that NA metabolites can form adducts with DNA. The objective of this\nstudy is to identify and quantify NA-DNA adducts in mouse lung as well as mouse and human blood to enable\nassessment of potential genotoxicity in firefighters. Several hypotheses will be tested: 1) Circulating reactive\nNA metabolites, particularly NAQs, will form stable as well as depurinating adducts with DNA in both lung\ntissue and blood leukocytes in vivo; 2) the types and abundances of NA-DNA adducts in circulating leukocytes\nwill at least partly reflect adduct formation in the lung; 3) the types of NA-DNA adducts detected in circulating\nleukocytes from exposed mice and firefighters will be similar; and 4) exposure to fire smoke will increase NA-\nDNA adduct levels in firefighters. These hypotheses will be tested through the application of 3 Specific Aims. In\nAim 1, I will Identify and quantitate NA-DNA adducts formed in wild-type (WT) mice following NA inhalation\nexposure, with use of mass spectrometry methods. In Aim 2, I will dissect metabolic pathways responsible for\nNA-DNA adduct formation in the lung and circulating leukocytes of NA-exposed mice, with use of unique\ntransgenic mouse models (liver-Cpr-null, liver-Ephx1-null, and Cyp2abfgs-null). In Aim 3, I will characterize\nNA-DNA adducts in blood specimens from firefighters and control donors. This project will provide direct\nevidence for the formation of NA-DNA adducts in vivo, lay the foundation for future studies of the genotoxicity\nof NA, obtain evidence to support more extensive assessments of the carcinogenic risks of NA to firefighters,\nand could have direct implications for the general population. Through the execution of this project and the\nhelp of this fellowship, I will be fully trained in scientific and professional skills necessary for my career\nadvancement as an independent researcher in academia."]
["DISENTANGLING THE ROLE OF CULTURE, LIFE STAGE, AND INFORMATION DESIGN TO FACILITATE EQUITY IN DATA REPORT BACK","Ramirez-Andreotta, Monica D.","University Of Arizona","R01ES036236","ES23-006","Mcallister, Kimberly",0,"97 - Partnerships for Environmental Public Health/Community Research","03 - Carcinogenesis/Cell Transformation","Project Summary/Abstract\nThe environmental justice (EJ) framework highlights the social, political, and economic\nassumptions contributing to and producing unequal protection in EJ communities; highlighting\nthat understanding a community's perspectives is crucial to conducting impactful environmental\nhealth research and literacy initiatives. There remains a need for novel research that facilitates\nresponsible reporting back of research results (RBRR) in a manner that raises data and\nenvironmental health literacy (D/EHL) and supports communities striving for environmental health\nand structural change. Despite recent progress in addressing longstanding EJ issues, the\nbioethics literature focuses on: (a) harm, not beneficence or justice; (b) underestimates\nopportunities to raise D/EHL among communities; and (c) commonly employs risk communication\nstrategies that are technical, and not based in a cultural model. The project goal is to create and\npilot a national model of report back that engages diverse rural and urban EJ communities to\nensure that RBRR reaches all populations in a manner tailored to their individual needs, including\nculture, life stage, language, and design. Rooted in bioethics, the program focuses on how to\nreport back social determinants of health and soil and air quality data in rural and urban\ncommunities that are disproportionately impacted by pollution. Building upon trusted and\nestablished long-term partnerships and leveraging existing datasets, this project addresses cross-\ncutting research themes anchored in health equity, communication approaches, and the use of\ndata report back. Through partnerships with community-based organizations and local\ngovernment agencies, this project will address community concerns and social/EJ challenges in\nboth rural, predominately Hispanic mining communities and urban, Black/African American\ncommunities. The specific aims of this proposal include: (1) Using an equity-centered community\ndesign approach to develop different design types and identify what influences preferred report\nback strategies, (2) Within the context of specific populations (cultural identity) and groups (life\nstage), elucidate key D/EHL learning outcomes by design type, (3) Identify, evaluate, and mitigate\nthe unintentional consequences of environmental health report back by working with both rural\nand urban EJ communities, and (4) Develop capacity building tools for RBRR, train knowledge\nmediators/brokers and evaluate the efficacy of these tools to support the role of “environmental\ncounselors”."]
["EL TRABAJO NO TE DEBE DANAR: REDUCTION OF HAZARDOUS EXPOSURES IN SMALL BUSINESSES THROUGH A COMMUNITY HEALTH WORKER INTERVENTION","Beamer, Paloma I","University Of Arizona","R01ES028250","PA16-083","O'Fallon, Liam",0,"93 - Environmental Justice/Environmental Health Disparities"," - ","PROJECT SUMMARY\nThis project aims to reduce negative health outcomes in small businesses that primarily employ high-risk\nLatino workers by characterizing their exposures to hazardous chemicals and assessing if a community health\nworker (CHW) intervention is effective at decreasing these exposures. Although preventable by definition,\noccupational disease and injuries are leading causes of death in the United States, with a disproportionate\nburden faced by Latinos. Small businesses pose a particular risk. They are more likely to employ low-wage\nLatino workers, and often use hazardous solvents including volatile organic chemicals that can cause asthma,\ncancer, cardiovascular, and neurological disease; yet their workers lack access to culturally and linguistically\nappropriate occupational health and pollution prevention information due to economic, physical, and social\nbarriers. CHW-led interventions and outreach in Latino communities have documented increased access to\nhealth care and health education and reduced workplace exposures among farmworkers. CHWs are an\ninnovative method to bridge the gap between these small business communities and other stakeholders. The\nproposed project will capitalize on established partnerships between the University of Arizona, the Sonora\nEnvironmental Research Institute, Inc. and the El Rio Community Health Center. A community-engaged\nresearch framework will be used to complete the following specific aims: 1) quantify and identify exposures to\nhazardous chemicals in the two high risk small business sectors common in our target area (i.e., auto repair\nshops and beauty salons); 2) work collaboratively with business owners, trade groups, workers and CHWs to\ndesign an industrial hygiene – enhanced CHW intervention tailored for each small business sector; and 3)\nconduct a cluster randomized trial to evaluate the effectiveness of the CHW intervention at reducing workplace\nexposures to volatile organic compounds and assess which factors led to successful utilization of exposure\ncontrol strategies in both male and female-dominated businesses. Businesses will be randomized to either an\nintervention or delayed intervention group, both of which will receive incentives to participate including worksite\nhealth screenings. CHWs will work closely with business owners and employees to select and implement\nexposure-strategies appropriate for their worksite using a menu of complementary strategies of varying\ncomplexity and cost. This innovative project has the potential to directly reduce occupational health disparities\nthrough a CHW intervention that moves beyond providing occupational health education. The intervention will\novercome current barriers by helping marginalized Latino workers and small business owners who may have\nlimited education, literacy, and computer skills to understand the hazards associated with their work, and will\nempower them to have greater control over their occupational exposures, with the ultimate goal of preventing\noccupational disease and reducing health disparities."]
["ENVIRONMENTAL HEALTH SCIENCES RESEARCH FOR INDIGENOUS SCHOLAR ENGAGEMENT (EHS-RISE)","Zhang, Qing-Yu ","University Of Arizona","R25ES034923","PAR21-168","Humble, Michael",0,"87 - Institutional Training/Institutional Career Development Grants","03 - Carcinogenesis/Cell Transformation","PROJECT SUMMARY\nOverview\nEnvironmental Health Sciences Research for Indigenous Scholar Engagement (EHS-RISE) is a 5-year\nsummer research training program for Native American undergraduates at the University of Arizona\n(UArizona). It is housed within the Undergraduate Biology Research Program, the Department of\nPharmacology and Toxicology, and the Southwest Environmental Health Sciences Center. The long-term goal\nof this program is to increase the number of Native Americans in STEM fields. The short-term goal is to\ndevelop and retain a stable cadre of Native American students who graduate from University of Arizona with\nSTEM degrees. These goals will be realized through the intentional construction of a research training\nenvironment that supports and integrates Native values for Native students pursuing a science degree. The\nspecific objectives of this program are:\nObjective 1: Identify, recruit, and retain nine Native American undergraduate students annually for five years.\nObjective 2: Develop and expand trainees’ scientific skills and knowledge.\nObjective 3: Foster and sustain trainees’ level of engagement.\nObjective 4: Embed the program within a culturally relevant environment and learning community.\nThese objectives will be achieved by addressing each of the eight pillars of the American Indian Well Being\nModel in Higher Education within the context of a rigorous environmental health research training program.\nIntellectual Merit\nEHS-RISE approaches STEM diversity from a non-traditional mindset. Instead of recruiting Native students\ninto a program based on a Western scientific model, we have built a program that integrates Native values and\nbuilds bridges between Indigenous and Western science and knowledge. It is a model which equally values the\ncontribution of both epistemologies. In this way, we are advancing STEM workforce diversity and inclusion by\nhonoring and integrating the impact and influence of Native perspectives and values in science.\nBroader Impact\nA diverse workforce, in which the contributions of all members are valued, results in greater innovation,\ncreativity, engagement, and decision-making. Our model supports the development of culturally confident and\nscientifically competent Native American scientists who will bring their values and knowledge into the STEM\nworkforce, thus advancing science and innovation."]
["ENVIRONMENTAL HEALTH SCIENCES: TRANSFORMATIONAL RESEARCH UNDERGRADUATE EXPERIENCE (E-H-TRUE)","Chen, Yin ","University Of Arizona","R25ES025494","ES19-010","Humble, Michael",0,"87 - Institutional Training/Institutional Career Development Grants"," - ","PROJECT ABSTRACT\nEnvironmental Health: Transformative Research Undergraduate Experiences (E-H-TRUE) research\neducation program at the University of Arizona (UA) seeks to recruit, educate and retain 5 undergraduate\nstudents every year who are underrepresented in environmental health sciences over five-year period. UA\nhas a long record of accomplishment to train and retain under-representative students: more than 40% new\nfreshman students from under-representative groups, raking #1 in PhDs earned by Naïve American\nstudents and #8 in the number of PhDs earned by Hispanic/Latino students. UA has received status as\nan American Indian/Alaska Native and a Hispanic Serving Institution. In E-H-TRUE, we bring together two\npreeminent programs: the UA Center for Toxicology and the UA Undergraduate Research Program (UBRP)\nto provide the top-notch research training in environmental health sciences. On the research side, the UA\nCenter for Toxicology, one of leading toxicology research and training centers in the world, is home to the\nNIEHS-funded Southwest Environmental Health Sciences Center (SWEHSC) and the UA Superfund\nResearch Program. On the undergraduate education side, UBRP has served as a model for high-quality\nundergraduate research training for more than 30 years. Through established networks by UBRP, we will\ninitiate early contact with freshman/sophomore undergraduates to identify talented undergraduate\ncandidates from under-representative groups who are interested in environmental health science\nresearch. The well-designed educational component of E-H-TRUE will include a specifically designed\ncourse work in environmental health sciences to expose students to toxicology, immunology,\nepidemiology and government regulation. Program participants will receive hand-on training in research\nlaboratories. Students will work with their mentors and laboratory collaborators to learn how to review\nliterature, generate hypothesis, design step-by-step experimentation to test hypothesis, document\nresults, and deliver presentable data by due dates. The program will emphasize collaboration and near-\npeer mentoring by capitalizing on the recently renewed NIEHS T32 training program (continuously funded for\n40 years). The E-H-TRUE program will also facilitate community outreach activities in environmental health\nscience through the established outreach core in SWEHSC. Finally, we have implemented a\nrigorous evaluation plan to measure the success and impact of the program. The main goal of the program is\nto provide students with research experiences and encourage them pursuing Ph.D. or professional degrees\nto be active in environmental science research."]
["EXPOSURES, HEALTH IMPACTS, AND RISK FOR MINE WASTE CONTAMINATION","Ding, Xinxin ","University Of Arizona","P42ES004940","ES18-002","Carlin, Danielle",0,"35 - Superfund Research Program Centers"," - ","PROJECT SUMMARY (Overall Core: Maier and Zhang)\nThe University of Arizona Superfund Research program (UA SRP) addresses the unique human health risks\nencountered in the US Southwest, an area with a rich history and future of mining. The Southwest has distinct\ngeologic and climatic attributes that affect human health and exposures to pollution. Groundwater in Southwest\nregions with rich ore deposits often has elevated arsenic levels, leading to exposure from drinking water.\nExposure also occurs by inhalation and ingestion of arsenic-associated mining dusts transported from mining\nsites into the interior of homes and to exterior environments. Importantly, arsenic exposure has been linked to\nthe development of diabetes. Vulnerable populations residing near mining sites, including Native Americans and\nHispanic communities, exhibit increased incidence of diabetes. Our goal is to determine how chronic exposure\nto mine wastes that contain arsenic contributes to the development of diabetes. We will then use this information\nto help predict exposures and associated health outcomes as well as to inform public health prevention strategies\nin communities that neighbor mine waste sites. To achieve this goal, we have five research projects and four\ncores that will: 1) characterize how chronic mine waste arsenic exposure in mining impacted areas is linked to\ndiabetogenic outcomes through mediation of Nrf2 signaling; 2) determine how the gut microbiome and mining\nwaste mineral properties influence arsenic species transformation, bioavailability, and toxicity; 3) investigate the\ninfluence of capping material quality on success of mine waste revegetation to enhance cap and plant\nremediation technology; 4) model exposures to mining waste contaminants, accounting for socio-demographics,\nto understand risk factors that drive development of diabetes; 5) mitigate the human impacts of exposure to\nmining waste through effective interaction with stakeholders including regulators, the mining industry, and\naffected communities; 6) serve as a global resource for human and environmental health issues associated with\nmetal mining; and 7) train and graduate professionals who are equipped to address complex 21st century\nenvironmental hazardous waste problems (Aim 7). The expected outcome of this UA SRP effort is a measurable\nreduction in diabetes (and other diseases) in mining communities and perhaps beyond."]
["IMAGING BIOMARKERS OF NEUROTOXICITY IN WELDERS","Racette, Brad A","St. Joseph'S Hospital And Medical Center","R01ES021488","PA20-185","Hollander, Jonathan",0,"63 - Neurodegenerative"," - ","Abstract\nManganese (Mn) is an established neurotoxicant that affects the same motor and cognitive brain pathways\naffected in Parkinson disease (PD), notably the nigrostriatal system. A large body of research, largely from our\ncollaborative team, demonstrates that Mn-exposed workers have a clinical phenotype which overlaps\nsubstantially with PD, including Mn-dose-dependent progressive parkinsonism and nigrostriatal dysfunction on\npositron emission tomography (PET) brain imaging. In the first five years of the present PET imaging project,\nwe used PET biomarkers of the dopaminergic system in the brain to establish that Mn-exposed workers had\nlower caudate binding of the PET radioligand 6-[18F]fluoro-L-dopa (FDOPA), as compared to non-exposed\nworkers. These differences remained over five years of follow-up. We also found Mn-dose-dependent\nupregulation of dopamine type 2 receptor (D2R) binding, as measured by the radioligand [11C](N-\nmethyl)benperidol (NMB), in the substantia nigra, the same region of the brain most dramatically affected in\nPD. In addition, we found an inverse Mn-dose-response association with thalamic (i.e., extrastriatal)\n[11C]dihydrotetrabenazine (DTBZ) binding, as well as a decline in DTBZ binding in caudate, putamen, and\nsubstantia nigra over time. More recently, our lab found evidence of Mn-induced neuroinflammation (microglial\nactivation) in the brains of deceased Mn miners providing a potential mechanism for the in vivo findings in our\nwelder cohort. This renewal builds on our previous studies by exploring the role of neuroinflammation in Mn-\ninduced dopaminergic neurotoxicity. Our hypothesis is that Mn-induced progressive parkinsonism is a\nneurodegenerative disorder and is due to Mn-dose-dependent dopaminergic degeneration. We will perform\nrepeat DTBZ and NMB PET imaging in research participants from our longitudinal Mn-exposed worker cohort\nwho have already undergone baseline DTBZ and NMB scans to investigate the association between lifetime\ncumulative Mn exposure, informed by state-of-the-art neutron activated bone Mn quantication, and annual rate\nof change in DTBZ and NMB binding. We will also perform N-acetyl-N-(2-[(11)C]methoxybenzyl)-2-phenoxy-5-\npyridinamine [(11)C]PBR28 (PBR28) PET imaging in these workers to characterize patterns of microglial\nactivation in the same brain regions, and investigate the relationship between lifetime cumulative Mn exposure\nand PBR28 binding as a marker of neuroinflammation. We then will explore the role of neuroinflammation as a\nmediator of Mn-induced striatal degeneration. Finally, we enlarge our cohort to enrich for active workers and\nwill perform longitudinal PET imaging to characterize the relation between lifetime cumulative Mn exposure and\nthe annual rate of change in both striatal and extrastriatal binding/uptake of these radioligands between active\nand retired Mn-exposed workers. Successful completion of these aims will provide a unique opportunity to\nunderstand the mechanism of an important environmental nigrostriatal neurotoxicant and potentially inform the\nunderstanding of the environmental pathogenesis of PD."]
["IN VITRO TO IN VIVO EXTRAPOLATION OF TOXICANT EFFECTS ON OVARIAN FUNCTION","Craig, Zelieann Rivera","University Of Arizona","R01ES034690","ES21-007","Schug, Thaddeus",0,"66 - Female Reproduction","03 - Carcinogenesis/Cell Transformation","PROJECT SUMMARY\nApproximately 7.5 million American women are unable to become pregnant or carry a baby to term (impaired\nfecundity). The ovary is considered a critical target organ in infertility cases based on the large number of\nwomen seeking infertility treatment who are unable to release a viable egg from their ovaries. Folliculogenesis\nis the process through which ovarian follicles, the functional units of the ovary, develop into a form capable of\nsustaining hormone production and ovulating a healthy egg for fertilization. Any environmental exposure that\ncauses damage to the ovarian follicle has the potential to impair fecundity in women. Most of what is known\nabout toxicity to ovarian follicles has been uncovered in laboratory rodents, but there is little available data on\ntoxicant exposure and related mechanistic toxicology studies in the nonhuman primate, the closest laboratory\nanimal model to humans. There is, therefore, a critical need to develop alternative approaches and tools that\nsynergize the accessibility and versatility of laboratory rodents with the physiological relevance of the\nnonhuman primate to deliver high quality ovarian follicle toxicity data. To meet this need, this proposal will\nsupport the formation of a virtual research consortium with expertise in mouse and nonhuman primate ovarian\nbiology, toxicology and computational modeling. The proposed consortium will generate lab-based data on the\nphysiological and toxicant-induced behavior of ovarian follicles in both species, using phthalate as a model\ntoxicant, to create computational models capable of effectively predicting ovarian follicle responses to chemical\ninsults in nonhuman primates. The experimental measures captured in the in vitro and in vivo model will be\nspecifically chosen to align with the needs of the modelers. To achieve this goal, the proposed consortium will\ncomplete three specific aims. Specifically, the ovarian biology/toxicology team will quantify the physiological\nand toxicant-induced behavior of computationally useful markers of in vivo and in vitro folliculogenesis in mice\n(Aim 1) and nonhuman primates (Aim 2), while the computational modeling team will construct in silico models\nthat match the physiological behavior of folliculogenesis in each species and predict follicular responses to\nphthalate insults in both species. Our virtual consortium includes researchers from five institutions and will\ncreate a transdisciplinary group that includes both experimental and computational expertise. The tight\ncoupling of these two domains will provide the needed communication pathways to develop translational\nmodels for IVIVE as well as cross-species extrapolations in reproductive toxicology."]
["MANGANESE-INDUCED NEUROTOXIC EFFECTS RESEARCH IN SOUTH AFRICA","Racette, Brad A","St. Joseph'S Hospital And Medical Center","R01ES026891","PA16-160","Gray, Kimberly",0,"63 - Neurodegenerative"," - ","Abstract\nManganese (Mn) is an established neurotoxicant that affects motor and cognitive brain pathways. This\nproposal builds on a growing body of Mn neurotoxicity research generated by our investigative team and\nothers. Despite these important contributions to studying the health effects of Mn exposure in vivo, defining\nthe associated neuropathology is essential to understand mechanisms of injury and to characterize dose-\nresponse relations that will inform regulatory policy. These types of studies are extremely challenging due to\nthe difficulty in acquiring human brain tissue and quantifying lifetime exposure to Mn in the same subjects.\nOver the last seven years, we have developed a collaboration with the University of the Witwatersrand in\nJohannesburg, South Africa using the only population-wide, occupational autopsy program in the world.\nThrough this collaboration we have conducted novel preliminary Mn neuropathology studies that support the\naims in this proposal. Our data suggest that chronic, low-level Mn exposure in these mines is associated with\nlower neuronal density and higher microglial/astrocyte ratios in the caudate and putamen, indicating that Mn\nexposure may cause astrocytic dysfunction which in turn induces a pro-inflammatory neurotoxic state in the\ncorpus striatum (caudate, putamen, globus pallidus), driven by the activation of microglia. Astrocytic\ndysfunction is likely attributable, in part, to dysregulation of several key mitochondrial proteins induced by Mn\nexposure. However, our preliminary studies also suggest that Mn mineworkers, with high MRI signal intensity\non T1 MRI, have similar corpus striatal tissue Mn concentrations, but possibly lower Fe concentrations, than\nnon-Mn mineworkers. In this proposal, we will follow-up on these preliminary data by collecting brains from\ndeceased Mn mineworkers with contemporaneous Mn exposures and appropriately matched non-Mn\nmineworkers. We will use unbiased stereologic methods to quantify neurons, astrocytes, and microglia in the\ncaudate, putamen, globus pallidus, substantia nigra pars compacta (SNpc), and olfactory bulbs in both groups\nof workers and investigate the overall and dose-response associations between these counts and cumulative\nMn exposure. We will also use immunofluorescence microscopy to quantify targeted astrocytic mitochondrial\nproteins and inductively coupled plasma-mass spectrometry to compare corpus striatal Mn and Fe\nconcentrations between groups. This highly innovative study will provide a rare opportunity to advance the\nfield of Mn neurotoxicity by investigating the neuropathologic effects of chronic Mn exposure."]
["METABOLIC MECHANISMS OF NAPHTHALENE TOXICITY IN LUNG","Ding, Xinxin ","University Of Arizona","R01ES020867","PA18-484","Carlin, Danielle",0,"69 - Respiratory"," - ","Naphthalene (NA) is a ubiquitous pollutant to which humans are widely exposed. NA causes nasal and lung\ntoxicities, including tumors, in adult rats and mice and has been classified as a possible human carcinogen.\nThe mechanism of NA carcinogenicity, which may involve both genotoxic and non-genotoxic events, is not\nclear. A prerequisite for NA cytotoxicity is bioactivation by cytochrome P450 (CYP) enzymes. The reactive\nmetabolites formed, which derive from the NA-epoxide (NAO), can deplete cellular glutathione and bind\ncovalently to proteins. Research in the current funding cycle, which was focused on NA bioactivation and\nacute lung toxicity, provided compelling evidence for the ability of human CYP2A13 and 2F1 to mediate NA’s\nlung toxicity in vivo in a humanized mouse model, and insights on the interplay between systemic disposition\nand target tissue bioactivation of inhaled NA and its impact on NA’s airway toxicity. Initial novel evidence was\nalso obtained for the ability of NA to produce stable DNA adducts ex vivo, and for a possible role of\nsystemically generated NA metabolites in lung toxicity in vivo. In the proposed studies for the next funding\ncycle, we will continue to study the metabolic mechanisms of NA lung toxicity by: identifying liver-generated\nNA metabolites that contribute to lung toxicity in vivo (Aim 1), determining the ability of human CYP2A6\nexpressed in the mouse liver to mediate airway toxicity of inhaled NA (Aim 2), and identifying the stable NA-\nDNA adducts in the lung and dissecting metabolic mechanisms of their formation (Aim 3). The central\nhypothesis is that NA has the potential to cause both cytotoxicity and genotoxicity in human lung, and that the\nmetabolism of NA in both lung and liver influences the toxic outcome on an individual basis. We will employ a\ncombination of in vivo, ex vivo, and in vitro approaches, and utilize novel genetically modified or humanized\nmouse models, as well as human lung cells and liver microsomes, to address the specific aims. The long-\nterm goal of these studies is to define the metabolic mechanisms that influence NA-mediated lung toxicity in\nexperimental animals and humans. The outcome is expected to improve assessment of human lung disease\nrisks from exposures to NA and other related chemicals."]
["NEUROLOGICAL EFFECTS OF TOXIC METAL EXPOSURE IN MODEL RODENTS COLLECTED IN ZONES OF INDUSTRIAL AGRICULTURE ON THE U.S.-MEXICO BORDER","Credo, Jonathan M","University Of Arizona","F31ES032299","PA21-052","Hollander, Jonathan",0,"60 - Nervous System Research","03 - Carcinogenesis/Cell Transformation","ABSTRACT\nYuma County is a large agricultural hub of the United States and provides over 90% of the winter leafy greens\nconsumed in the U.S. To maintain high agricultural output, more than 2.6 million kilograms of agrichemicals are\nused in Yuma County each year. These agrichemicals represent a significant exposure source of toxic\nchemicals for residents, especially the migrant and seasonal farmworkers and those living near agricultural\nlands. Previous research focused on organic based pesticides and lead exposure sources, but inorganic\nmetals-based pesticides have not been examined in this area. I performed quantitative metal(loid) analysis of\nhuman (n = 323) and rodent (Peromyscus eremicus, n = 300) hair samples and found concentrations of\nneurotoxic metals (especially Cu and Mn) at levels known to be associated with adverse health outcomes.\nFollowing these findings, preliminary transcriptomic analyses demonstrated disrupted genetic pathways,\nincluding those associated with lipid metabolism and muscle contraction, in the brains of rodents that I\ncaptured from agricultural sites, compared to non-agricultural sites, from Yuma County. Cu and Mn are\nnaturally occurring elements and are essential micronutrients in enzymatic reactions, but both are toxic at high\nconcentrations. Cu causes non-specific oxidative damage in tissues, while Mn accumulates in the basal\nganglia and dopaminergic neurons and is linked with behavioral issues in children and motor dysfunction in\nadults. Farmworkers and communities near agricultural areas with high agrichemical application are an\nunderstudied population regarding excessive Cu and Mn exposure. This proposal expands upon my\npreliminary work that identified elevated concentrations of Cu and Mn in human and rodent hair collected in\nYuma County by using the P. eremicus rodent model to investigate transcriptomic and lipidomic responses to\nexposure. Additionally, I am developing a similar approach in collaboration with the Cocopah Tribe in Yuma\nCounty to assess the risk of contaminant exposure in their people. Under the guidance of a multidisciplinary\nteam, I aim to: Aim 1) assess effects of mixed metals exposure on brain gene expression in rodents collected\nfrom agricultural vs. non-agricultural regions of Yuma County, using both non-targeted Nanostring and targeted\nqRT-PCR approaches; Aim 2) assess effects of mixed metals exposure on brain metabolic profiles in rodents\nfrom these two exposure regions, using liquid chromatography-ion mobility spectrometry-mass spectrometry;\nand Aim 3) gather P. eremicus samples on Cocopah Tribal Lands to conduct preliminary exposure risk\nassessment. This project will provide information on the neurological effects of exposure to metals used in\nagriculture and aid in developing models that assess health impacts in the underserved population of\nfarmworkers and tribal members in Yuma County."]
["NOVEL MARKERS OF EXPOSURE AND PATHWAYS OF RESPONSE TO CHROMIUM","Lemos, Bernardo ","University Of Arizona","R01ES027981","PA21-268","Shaughnessy, Daniel",0,"09 - Genome Integrity"," - ","Abstract\nCr(VI) is a human carcinogen of significant public health concern, and a substantial exposure in a number of\noccupational settings. Cr(VI) induces mutations, changes in gene copy number, and exposure has been\nassociated with humans cancers in exposed populations and animal models. Our novel preliminary data\ndemonstrate that Cr(VI) exposure causes amplification in ribosomal DNA (rDNA) copy number and changes in\nthe nucleolus (the crudely understood nuclear organelle that is the site of ribosomal RNA (rRNA) transcription,\nand integration of myriad cellular functions). A crucial element of nucleolar function is rDNA copy number\n(rDNA CN). rDNA CN modulates (i) epigenetic states across the genome, (ii) DNA damage responses, (iii) cell\ncycle progression, (iv) chromosome segregation, and (v) global genetic stability. Furthermore, disruption of\nrDNA arrays, ribosome biogenesis, and the nucleolus are central to carcinogenesis. Our central medical\nhypothesis is that Cr-induced changes in rDNA CN are responsible for Cr-induced carcinogenesis. Our central\nbasic hypothesis is that rDNA arrays are not fixed, but rather a genetically dynamic component of the nuclear\ngenome with copy number that is modulated by Cr exposure. Our proposal examines rDNA changes upon\nCr(VI) exposure to reveal a novel pathway of Cr toxicity with medical and basic relevance. Key elements are a\ncareful investigation of the toxicology of Cr-induced-rDNA-amplification (Cr-i-rDNA-a), hypotheses-driven\nfunctional genomic analysis the rDNA and the nucleolus upon Cr(VI) exposure, and extensive genetic analyses\nof Cr-i-rDNA-a using a powerful model organism. Our first aim will investigate the toxicology of Chromium-\ninduced-rDNA-amplification (Cr-i-rDNA-a) in a human lung epithelial cell model. We will determine dose-\nresponses of Cr-i-rDNA-a, map amplification boundaries in Cr-i-rDNA-a, examine temporal profiles and\nrecovery from Cr(VI) exposure, and examine whether Chromium-induced CN changes are responsible for Cr-\ninduced carcinogenesis. Our second aim investigates the functional genomics of Cr-induced nucleolar stress\nand Cr induced transformation in a human lung epithelial cell model. Examining genome-wide responses to Cr\nexposure is critical to understand how Cr induces rDNA amplification, nuclelar stress, and carcinogenesis. Our\nthird aim addresses the genetic determinants of Chromium-rDNA interactions. We will examine Cr-i-rDNA-a in\nspecific cells, quantify the extent of copy number change, isolate the affected tissues, and use high-throughput\ntechniques to characterize the changes. Our efforts will shed light on Cr-rDNA interactions, with research that\nis directly relevant to the human health mission of the NIH. The manifold effects of rDNA CN indicate that\nperturbing this central regulator with Cr will have profound consequences to cellular function. We anticipate\nthat determinants of complex human diseases with strong environmental components such as cancer will\nultimately be traced to environmentally triggered variation in rDNA segments of the genome."]
["NOVEL PET MARKERS OF COGNITIVE IMPAIRMENT IN MANGANESENEUROTOXICITY","Criswell, Susan ","St. Joseph'S Hospital And Medical Center","R01ES029524","PA18-484","Hollander, Jonathan",0,"76 - Imaging"," - ","Manganese (Mn) is an established neurotoxicant that causes parkinsonism and cognitive impairment with\nfeatures overlapping with Parkinson disease (PD), PD dementia (PDD), and mild cognitive impairment (MCI).\nThe causes of PD and related dementias are mostly unknown although growing evidence suggests that\nexposure to environmental toxicants such as Mn may induce alterations in gene expression that can be linked\nto disease susceptibility. Our team has conducted key studies using positron emission tomography (PET) that\ndemonstrate Mn dose-dependent dopaminergic dysfunction in the midbrain and striatum contribute to clinical\nparkinsonism. However, the role of the dopaminergic system in the cognitive dysfunction that is associated\nwith clinical Mn neurotoxicity is unknown. Recent pre-clinical data also implicate dysfunction of the cholinergic\nsystem in Mn neurotoxicity. The extensive degeneration of the cholinergic system is a well-known hallmark of\nage-related dementias, and recent molecular imaging innovations have led to a re-emerging interest in the\ncholinergic system as an important mechanism of cognitive dysfunction in PDD. Within the striatum, cholinergic\nand dopaminergic systems are highly integrated with extensive reciprocal innervations. Current models of\ncognitive decline in PD and PDD propose a “two-hit” effect in which the combined dopaminergic and\ncholinergic deficits lead to early cognitive impairment and eventual dementia. Similarly, dysfunction in these\ntwo vital striatal systems has been proposed as a core mechanism for Mn neurotoxicity. Given the dose-\nresponse relationship between Mn-exposure, dopaminergic dysfunction, and parkinsonism this occupationally\nexposed cohort provides an invaluable opportunity to study the in-vivo pathophysiology of parkinsonism and\ncognitive impairment in humans. In this proposal of 60 Mn-exposed workers, we will use a targeted\nneuropsychiatric battery of validated cognitive tasks with the dopaminergic ligand [11C](N-methyl)benperidol\n(NMB) to measure D2 receptor (D2R) function and the novel cholinergic PET radioligand (-)-(1-(8-(2-\n[(18)F]fluoroethoxy)-3-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-piperidin-4-yl)(4-fluorophenyl)methanone\n(VAT) to measure in-vivo vesicular acetylcholine transporter (VAChT) concurrently. The specific aims of this\nproject are 1) to use NMB PET to evaluate the relationships between Mn exposure, dopaminergic dysfunction,\nand cognitive impairment; 2) to use VAT PET to evaluate the relationships between Mn exposure, cholinergic\ndysfunction, and cognitive impairment; and 3) to use mediation analysis to quantify the amount of cognitive\ndysfunction due to Mn exposure that is attributable to dopaminergic and cholinergic dysfunction respectively.\nWe will use state-of-the-art imaging methods combined with an innovative statistical approach to understand\nthe dual roles of the cholinergic and dopaminergic systems in Mn-induced cognitive dysfunction. Ultimately, our\ngoal is to understand the role of environmental neurotoxicants and the combined effect of these key\nneurotransmitters in the pathophysiology of age-related neurodegenerative dementias such as PDD."]
["PRENATAL EXPOSURE TO PESTICIDE MIXTURES AND CHILDHOOD ADHD","Furlong, Melissa ","University Of Arizona","R00ES028743","PA16-193","Gray, Kimberly",0,"61 - Neurodevelopmental"," - ","Prenatal levels of organophosphorus pesticide (OPs) biomarkers have been associated with hallmark\nsymptoms of Attention Deficit Hyperactivity Disorder (ADHD), including deficits in working memory, social\nresponsiveness, and ADHD indices. Cross-sectional studies have also linked concurrent pyrethroid pesticide\nmetabolites with ADHD and ADHD behaviors in children. Toxicology studies report mixture effects for these\npesticides on health outcomes. Three major gaps exist in this literature: 1) No studies have evaluated\nprenatal and childhood exposures to these pesticides and clinical ADHD diagnoses. 2) Prenatal\nepidemiological studies of OPs/pyrethroids typically rely on urinary DAP biomarkers, which reflect ingestion of\nboth non-toxic metabolites and toxic parent pesticides. Urinary biomarkers from spot urine samples also do\nnot characterize pregnancy-wide exposures, since OPs and pyrethroids are rapidly metabolized. 3)\nStudies of pesticide mixtures in epidemiology are scarce, and use of biomarkers for such mixtures analysis is\nproblematic. For instance, administration of chlorpyrifos (an OP) results in increased tissue concentrations of\ncypermethrin while reducing urinary excretion of the pyrethroid metabolite 3-phenoxbenzoic acid. Thus, the\nmixture itself may affect biomarker levels and increase exposure misclassification. A geospatial framework for\npesticide exposure can address some of the limitations of urinary biomarkers: exposures from agricultural\npesticide applications can be estimated for an entire pregnancy rather than a few days; estimates reflect the\ntoxic parent pesticide rather than non-toxic OP metabolites; and estimates reflect actual exposures rather than\na post-metabolism level. However, geospatial (GIS) methods of pesticide exposure assessment for\nepidemiology in the US have only been done in California, and usually rely on distance-to-field measures.\nGIS exposure may be enhanced with drift models that incorporate heat, humidity, inversions, atmospheric\nstability, and wind, while external validity may be increased by studying a population outside of California.\nWe propose to assess the relationship between OPs, pyrethroids, and ADHD in an Arizona population. To\nidentify a study population, we will apply a validated phenotyping algorithm with exceptional diagnostics to\nArizona Medicaid records to identify 4,000 childhood ADHD cases and 16,000 controls. In the mentored phase,\nthe Candidate will develop geospatial, phenotyping, exposure assessment, mixture modeling (Bayesian Kernel\nMachine regression [BKMR]), and machine learning skills while constructing the case-control study. In the R00\nphase, the Candidate will compare the drift model against traditional distance-to-field measures in a frequentist\nframework (Aim 2), and model associations between prenatal OP and pyrethroid pesticide mixtures and ADHD\nwith BKMR (Aim 3). These results will expand GIS studies beyond California, contribute to sparse but critical\nliterature on pesticide mixtures and neurodevelopment, and be among the first to report associations between\nGIS estimates of prenatal pesticide exposures and ADHD case status."]
["RENAL DISPOSITION IN NASH","Cherrington, Nathan J","University Of Arizona","R01ES028668","PA18-484","Shreffler, Carol",0,"55 - Liver"," - ","PROJECT SUMMARY\nThe interrelation between liver disease and kidney function is becoming increasingly researched, as hepatic-\nderived systemic inflammation can have a profound effect on the physiology of the kidney. This is a vital factor\nto consider with respect to precision medicine, as these changes can disrupt the proper metabolism and\nelimination of the 32% of marketed therapeutics that rely upon renal function for excretion. Among the liver\ndiseases that affect renal physiology is nonalcoholic fatty liver disease (NAFLD), characterized by a series of\nmechanistic events that mediate the transition from simple steatosis to nonalcoholic steatohepatitis (NASH),\nwhich include inflammatory events. Our lab has identified NASH-induced phenotypic conversions of several drug\nmetabolizing enzyme and transport proteins that significantly alter the pharmacokinetic profiles of certain drugs\nand xenobiotics. Interestingly, in a profiling study of various rodent models of NASH, we have also identified\nNASH-induced phenoconversion of renal transport proteins, a phenomenon that also contributes to altered\npharmacokinetics of xenobiotic substrates in vivo. To date, no studies have been published examining human\nNASH-related phenoconversion of renal drug transporters, and that will be the first item we address in this\napplication. Our central hypothesis is that NASH alters the expression and function of major renal drug\ntransporters, thereby increasing the risk of adverse drug reactions and environmental toxicities in\npatients with NASH. Our study design seeks not only to identify phenoconversion of specific renal transporters\nin NASH, but also to pinpoint the associated secretory pathways to better narrow down mechanisms of altered\npharmacokinetics for certain therapeutics and environmental contaminants. Our aims are to: 1) Determine the\nchanges in expression and localization of renal transporters in human NASH patients, 2) Determine the\nfunctional changes in individual secretion pathways and resulting potential for environmental toxicity in a rodent\nmodel of NASH, and 3) Determine the impact of NASH on GFR and select secretion pathways in human patients.\nBy completing these aims, we will be able to identify classes of drugs that present a greater risk of adverse drug\nevents for NASH patients."]
["RESTORING NORTHEAST CAPE FOR THE HEALTH AND WELL-BEING OF THE YUPIK COMMUNITIES OF ST. LAWRENCE ISLAND, ALASKA","Von Hippel, Frank Arthur","University Of Arizona","R01ES032392","ES20-002","O'Fallon, Liam",0,"97 - Partnerships for Environmental Public Health/Community Research","03 - Carcinogenesis/Cell Transformation","Our previous community-based participatory research at Northeast Cape (NEC) on St. Lawrence Island (SLI)\nfound elevated levels of polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs), and mercury\n(Hg) in sediments and biota within the watershed at the formerly used defense (FUD) site. We found elevated\nOCPs and PCBs in serum of the SLI people due to both long-range transport and military-derived sources, with\nthe highest levels of PCBs in people who have traditional and familial connections with NEC, including\nsubsistence. Concentrations of persistent organic pollutants (POPs) in our resident fish model, the stickleback,\nclosely mirror concentrations in the blood serum of SLI residents, indicating their efficacy as sentinel species\non SLI. Despite extensive remediation at NEC, short-lived lower trophic level fish in the Suqitughneq (Suqi)\nRiver remain contaminated with PCBs, OCPs, and Hg originating from the FUD site, at levels that exceed EPA\nfish consumption guidelines for cancer risk. Elevated contaminant levels and disrupted health in Suqi River fish\nindicate potential health threats for residents and that site remediation is incomplete. Our overarching goal is to\nadvance scientific understanding of the exposure pathways and long-term human health consequences\nassociated with contaminant exposure from FUD sites and inform interventions necessary to protect the health\nand long-term well-being of the people of SLI as they re-establish their traditional community at NEC. In Aim 1,\nwe propose to build on our prior discoveries and continue our collaboration with the communities of SLI to\ninvestigate potential exposure pathways and biological impacts of persistent contamination associated with the\nFUD site at NEC on SLI. We will analyze PCBs, OCPs, and Hg in the water of the Suqi and Tapisaggak rivers,\nas well as in traditional foods and air samples to assess ingestion and inhalation as potential exposure\npathways. We will build on work with stickleback as a sentinel species to determine biological effects of\ncontaminants on endocrine function and organ-specific histopathology. In Aim 2, we will characterize and\nquantify body burden of contaminants, and linkages to health outcomes, in people associated with NEC. In Aim\n3, we will inform decisions and interventions to protect the health of the people of SLI and enable re-\nestablishment of the traditional community at NEC. We will provide information that will lead to improved\nremediation, provide data and traditional knowledge to inform public health consultations and assessments,\nand develop a community-based public health action plan and interventions to protect health, ensure equity in\ndecision-making, and restore the NEC community. This study will have local and circumpolar arctic\nimplications for Indigenous communities. Locally, we will provide data and implement actions necessary for re-\nestablishing the community at NEC. Given that thousands of such Cold War military sites exist throughout the\nArctic, often in close proximity to Indigenous communities, our project may serve as a model for environmental\nand health monitoring and policy action by other Arctic Indigenous Peoples."]
["SOUTHWEST CENTER ON RESILIENCE FOR CLIMATE CHANGE AND HEALTH (SCORCH)","Ernst, Kacey C","University Of Arizona","P20ES036112","ES23-007","Quinn, Ashlinn",0,"98 - Global Health/Climate Change","03 - Carcinogenesis/Cell Transformation","PROJECT ABSTRACT – Component: Overall\nArid lands are home to one in three people, totaling a population of more than 2 billion spanning the globe. Arid\nland communities are facing multiple climate change-exacerbated threats impacting health including extreme\nheat events, wildfires, dust storms, biodiversity loss, emerging pathogens, poor air quality, and drought. The\nSouthwest Center on Resilience for Climate Change and Health (SCORCH) brings together\ntransdisciplinary research groups to conduct team-science projects addressing the health needs of arid lands\ncommunities adapting to climate change. The Center's overarching mission is to improve health equity across\nthe lifespan by enhancing community partnerships and supporting adaptation efforts by Indigenous, Latinx,\nlow-resource urban, and rural communities in the Southwestern United States and globally. Based at the\nUniversity of Arizona (UArizona), home of internationally recognized climate science and adaptation\nresearchers and Centers, SCORCH will serve as a foundation for expanding UArizona campus initiatives\naiming to increase health research at the intersection of climate change science. The three-year planning\nphase will be used to identify researchers whose expertise align with climate change and health across\nUArizona and the region, build transdisciplinary teams, identify priority research areas for community\nadaptation planning, and implement two research projects to develop our initial Research Focus Group (RFG)\nthemes. Our initial three RFGs build on the expertise of the current SCORCH team members and are\npurposefully broad to encompass evolving research priorities. These three themes include: 1) Health impacts\nof extreme weather events; 2) Forecasting and early warning of climate change health outcomes; and 3)\nAdaptive responses in the built environment. Research Project 1 aligns with RFG 2 and 3, to develop an\nassessment tool that can predict potential health outcomes of greenspace designs. Research Project 2 aligns\nwith RFG 1 to examine the role of maternal exposure to extreme heat and long-term child health outcomes.\nThrough community engaged activities founded on respect and trust, led by the Community Engagement Core,\nand novel data visualization services, led by the Integrated Data Visualization Core, we will deepen existing\nand develop new partnerships with academic and community entities with diverse lived experiences and\nknowledge frameworks. The geographic location of SCORCH in the Southwestern United States provides\nunique research opportunities to support adaptation and resilience efforts of Indigenous, Latinx, low-resource\nurban, and rural communities in the region as well as addressing the unique circumstances found in borderland\nareas. The potential international reach of SCORCH enables high-impact climate change and health initiatives\nthat will translate globally."]
["SOUTHWEST ENVIRONMENTAL HEALTH SCIENCES CENTER","Cherrington, Nathan J","University Of Arizona","P30ES006694","ES20-006","Thompson, Claudia",0,"31 - Environmental Health Sciences Centers"," - ","The Strategic Vision of the Southwest Environmental Health Sciences Center (SWEHSC) is to facilitate and\nimplement innovative research and community engagement aimed at understanding the mechanisms underlying\nenvironmental health (EHS) risks and disease among people living in arid environments undergoing climate\nchange. Importantly, the SWEHSC strategic vision supports our long-term goal of uniting interdisciplinary\nscientists to study environmental effects on the health and well-being of unique populations in the Southwest\nUS, including Native American, Latinx, and rural communities. Because the unique conditions of the arid desert\nSouthwest environment mirror those of many other global desert climates, the interdisciplinary research\nconducted by the SWEHSC could also improve the lives of the 2.1 billion people globally who live in arid lands.\nAs climate change increases the burden on human health through water and respiratory exposures due to\ndrought, wildfires, and decreasing water supply, the arid Southwest serves as the proverbial `canary in the coal\nmine' for the resulting health effects. Specifically, research within the SWEHSC focuses on 1) routes of exposure\nin arid environments, including exposure to groundwater contaminants and inhalation, 2) the adverse health\noutcomes following inhalation of air pollutants, and 3) the molecular pathways of adaptive responses to\nenvironmental exposures such as arsenic and ultraviolet light. If climate change is not reversed, the EHS factors\nprevalent in the desert Southwest will forecast the future concerns of much of the rest of the US. Accordingly,\nour mission impacts not only the health and well-being of the arid Southwest populations, but also the billions of\npeople across the planet affected by climate change.\nThe SWEHSC will continue to improve the health of people in arid lands by developing rational approaches to\nidentifying and mitigating hazardous environmental exposures. The geographic location of the SWEHSC, with\nits large Latinx, Native American, and rural communities, provides unique research opportunities to identify and\naddress basic environmental health hazards that impact these populations. Moreover, strengthening ties\nbetween SWEHSC faculty and academic and governmental agencies in Mexico enables impactful binational\nEHS initiatives, with the tangible ability to improve public health along the US-Mexico border and for broad\ntranslation to global stakeholders."]
["THE ABILITY OF GLYPHOSATE TO IMPAIR METABOLIC HOMEOSTASIS VIA THE GUT MICROBIOME AND METABOLITES","Duca, Frank Anthony","University Of Arizona","R01ES033993","PA20-185","Dzierlenga, Anika",0,"68 - Microbiome","03 - Carcinogenesis/Cell Transformation","PROJECT SUMMARY\nThe prevalence of obesity and diabetes continue to rise unabated in the United States,\ncreating a grave social and economic burden. Although development of these diseases is\nmulti-faceted and complex, there is accumulating evidence for the impact of environmental\nchemical exposures on metabolic homeostasis. Currently, glyphosate is the most commonly\nused herbicide in the United States, however, to date, no studies have ever assessed whether\nglyphosate exposure impacts the development of obesity and diabetes. Thus, the long-term\ngoal of this project is to better understand how recent and current pesticide usage can impact\nlong-term metabolic homeostasis.\n Glyphosate targets the shikimate pathway found in plants, and not mammals, leading\nto the assumption of its general safety. However, glyphosate can also target bacteria, and\nglyphosate exposure results in an altered gut microbiome profile. Despite the fact that\nprevious pesticides are associated with metabolic disease, and that glyphosate is known to\nalter the gut microbiota which can impact energy and glucose homeostasis, no study has ever\nexamined whether exposure to glyphosate can result in development of obesity and/or\ndiabetes. One of the main roles of the gut microbiota is bile acid metabolism, and studies\nsuggest that alterations in bile acid signaling represent a plausible link between the gut\nmicrobiota and regulation of metabolic homeostasis via changes in Farnesoid X receptor\n(FXR) signaling. These facts, coupled with our preliminary data, led to the hypothesis that\nexposure to glyphosate shifts the gut microbiome, leading to altered intestinal bile acid\nsignaling that contributes to impairments in energy and glucose homeostasis. This hypothesis\nwill be tested in 3 aims: 1) assess if exposure to glyphosate during different developmental\ntimepoints promotes metabolic dysfunction in male and female mice on a chow or high-fat diet,\n2) determine the role of the gut microbiome in the effects of glyphosate exposure on metabolic\nhomeostasis, and 3) identify the impact of altered bile acid signaling via glyphosate exposure\nin impaired metabolic homeostasis. The proposed study will be the first ever to provide\nmechanistic insight of the effects of glyphosate exposure on metabolic homeostasis. This\nproposal will provide valuable data leading to further research examining how environmental\npesticide usage can affect human health, and possibly identify microbial targets to offset the\ndetrimental effects of environmental chemical use."]
["THE EFFECTS OF DEPLETED URANIUM SHRAPNEL ON MITOCHONDRIAL CELLULAR FUNCTION.","Salanga, Matthew ","Northern Arizona University","R15ES032923","PAR18-714","Humble, Michael",0,"58 - Skin","03 - Carcinogenesis/Cell Transformation","Project Abstract\n A consequence of modern combat is exposure to depleted uranium through the use of uranium-containing\nmunitions. Understanding the effects of environmental or occupational exposure to depleted uranium is important\nfor protecting human health. Research in the area of uranium chemical toxicology has yielded mixed results,\nraising uncertainty as to the risks of depleted uranium exposure and mechanisms of action. The research\nproposed here will address depleted uranium chemical toxicity in vivo and the role ultraviolet radiation may play\nin potentiating (or synergizing) uranium’s mechanisms of action. The central question being addressed is if\ndepleted uranium internalized through shrapnel or wound contamination causes persistent cellular and genetic\ndamage including mitochondrial dysfunction and DNA damage, both of which are observed in cancer states.\n In addition to the critical biomedical science encompassed by this project, an overarching goal of R15 awards\nis to involve students with all aspects of the proposed research activities to engage the next generation of STEM\ninvestigators. Students will carry out experiments using zebrafish (embryos, larvae and adults), to test the\nhypothesis that internalized depleted uranium, in amounts that are occupationally and environmentally-relevant,\ndisrupts mitochondrial function and genomic stability. We will also test the hypothesis that ultraviolet B-ray (UV-\nB) radiation interact with DU leading to synergistically increased genotoxicity. Notably, humans exposed to\ndepleted uranium, particularly as a consequence of shrapnel, may carry the metal burden in or near their skin\nwhere interaction with sun exposure (including UV-B) may occur.\n Our studies leverage a pigment-free strain of zebrafish that enables longitudinal tracking of uranium implants,\nas the animal’s skin is transparent as a larva and translucent as an adult. Our unique study system is tractable\nfor students as demonstrated by our preliminary data in which the great majority of data was produced by student\nresearchers in the PI’s laboratory group. Furthermore, the zebrafish is less costly than rodent models and\nrelatively easy to maintain, making longitudinal studies well within our capabilities.\n Outcomes derived from these studies will provide evidence for or against uranium chemical toxicology from\nacute or persistent exposure from multiple routes of internalization. We assert this is a comprehensive approach\nto assess the risk depleted uranium poses to humans while addressing potential risk modifiers."]
["TRAINING IN ENVIRONMENTAL TOXICOLOGY OF HUMAN DISEASE","Cherrington, Nathan J","University Of Arizona","T32ES007091","PA23-048","Shreffler, Carol",0,"87 - Institutional Training/Institutional Career Development Grants"," - ","Environmental Health Sciences at the University of Arizona has a long-standing reputation for excellence in\ntraining Ph.D. and postdoctoral scientists, as evidenced by the fact that many of our graduates are leaders in\nacademia, industry, and government. To this end, our graduate program has evolved from a systems-based\ntoxicology experience to a curriculum in which students are trained to apply state-of-the art techniques to solve\nmechanisms of environmental toxicity affecting human diseases in various organ systems. Training of nine\npredoc and three postdoc students in the cutting-edge research programs of 29 Training Grant Faculty members\nare augmented by innovative technologies developed at the University of Arizona in association with the\nSouthwest Environmental Health Sciences and BIO5 Centers. Additionally, translational approaches undertaken\nby our NIEHS Superfund Program, One Health Research Initiative, and the EPA Environmental Justice Thriving\nCommunities Technical Assistance Center provide an exceptionally stimulating environment for the training of\ngraduate students and postdoctoral fellows. Our track record of diversity is indicative of the University’s\ndesignation as a Hispanic Serving Institution and the top-rated university for AI/AN PhDs. The interactive\nresearch of our Training Grant Faculty and our state-of-the-art Facility Cores extend the training environment\nfrom a single laboratory-oriented domain to a multidisciplinary experience strongly supportive of collaborative\nresearch. Current trainees are now selected through a University-wide competition and the UA Graduate College\nprovides financial support for all first year Ph.D. students through an umbrella recruitment program, providing a\nlarge pool of highly qualified candidates for competitive selection of predoctoral trainees. Predoctoral training is\nachieved through a combination of coursework, laboratory research, and supplemental enrichment activities.\nPostdoctoral trainees participate in innovative research programs and are guided to develop professional skills\nin oral and written communication and leadership. Over the past five years, our curricular changes have\nparalleled the evolving expertise of the Training Grant Faculty. We have recruited six senior full Professors, two\nAssociate Professors, and five junior Assistant Professors into the Training Grant, which significantly enhanced\nour core strengths in mechanistic-based molecular toxicology training. The request for continuation of NIEHS\nsupport is justified by the highly successful nature of our program, clear demand for our graduates, strong\nemphasis we place on leadership skills for our trainees and postdoctoral fellows, increasing number of students\ninterested in toxicology and environmental health, substantial institutional commitment, strong and well-funded\nresearch programs of our faculty, and the excellence of the training environment."]
["WILDFIRES AND FLASH FLOODS: USING EXPOSURE SCIENCE TO IDENTIFY RURAL ARIZONA MINING COMMUNITIES AT RISK FROM THE RELEASE AND REMOBILIZATION OF CONTAMINANTS","Ramirez-Andreotta, Monica D.","University Of Arizona","R21ES034591","ES19-011","Henry, Heather",0,"98 - Global Health/Climate Change","03 - Carcinogenesis/Cell Transformation","PROJECT SUMMARY\nCompound events due to climate change, combined with resource extraction and social\njustice are exacerbating exiting vulnerabilities and creating new ones. The Telegraph-\nMescal fires in Gila County, Arizona in 2021 consumed 180,757 acres and 37% of the soil burn\nseverity was moderate to high. These fires occurred in a region with 13 different resource\nextraction activities, including three copper mines. Shortly after the fires, the area had a record\nmonsoon season, with over 14 inches of rainfall. Most of the mine waste in the area are un-\nrehabilitated, leaving them prone to mechanical dispersion, which may increase their mobility and\nbioavailability. Areas that have been burned by wildfires are susceptible to flash flooding and the\nTown of Miami and City of Globe were severely impacted. Fire events are able to alter the\nphysical, chemical, and biogeochemical properties of the soil and surface materials and release\nand (re)mobilize metal(loid)s and radioactive materials, and produce polycyclic aromatic\nhydrocarbons (PAHs) that can impact public health. Over 3,000 metric tons of potentially\ncontaminated sediment accumulated on public roads and sidewalks in Miami and some residents\nreported that 12 inches of sediment settled in their yards and in some cases, entered their homes.\nThe extent of toxic contamination of the soil and dust in the Miami/Globe areas after the\nfire and flooding have not been assessed. It is critical to determine the extent of post-wildfire\ndebris flows and erosion from mine tailings and whether these geohazards are presenting\nexposure pathways to metal(loid)s, radioactive materials, and PAHs in neighboring rural,\nmedically underserved, environmental justice (EJ) communities. To do this, we will: (1) survey\nfamilies to identify the impacted areas and determine individual- and community-level\nvulnerabilities and resiliencies, (2) build human capacity through empowerment education and\ncommunity science, (3) characterize contaminants released during wildfires in soil and settled\ndust, and (4) use an equity-centered community design approach to report all findings and provide\nimmediate intervention and prevention strategies. EJ communities refers to areas affected by\ndisproportionate exposure to environmental hazards and increased vulnerability to those hazards.\nThe compound event described has significantly impacted these rural communities that are\nsurrounded by active/legacy mines and smelter operations, further exacerbating the possible\nexposure to contaminants, increasing their risk, and exploiting the structural inequalities and\nenvironmental health disparities in these areas."]
["WILDLAND-URBAN INTERFACE FIRE EXPOSURES, EFFECTS, AND INTERVENTIONS: A COLLABORATIVE RESEARCH-TO-ACTION PARTNERSHIP WITH FIREFIGHTERS","Burgess, Jefferey L.","University Of Arizona","R01ES035965","PAR22-210","O'Fallon, Liam",0,"97 - Partnerships for Environmental Public Health/Community Research","03 - Carcinogenesis/Cell Transformation","Climate change is increasing the risk of wildfires which frequently extend into the wildland-urban interface (WUI).\nWUI fires burn a mixture of vegetation, structures and vehicles and there is a marked research gap regarding\npopulation exposures and health effects. Woodsmoke contains a toxic mixture of known and suspect\ncarcinogens including but not limited to benzene, aldehydes, and polycyclic aromatic hydrocarbons (PAHs).\nHowever, wildland fire exposure monitoring has generally been limited to particulates for the general public and\nPAHs for firefighters. Firefighters, a high exposure group, are requesting participatory research to measure WUI\nfire exposures and effects and identify effective interventions. Silicone wrist bands can measure exposure\nbeyond PAHs, and urine metabolomics can identify both exposures and effects. While cancer or other diseases\ncaused by firefighting exposures can take many years to develop, metabolomic and epigenetic (microRNA and\nDNA methylation) endpoints can serve as sub-clinical biomarkers of toxicity. Interventions of firefighter interest\ninclude rapid provision of exposure data, improved personal protective equipment (PPE), more rapid dermal\ndecontamination, and administrative controls. We hypothesize that: a) use of silicone wristbands and targeted\nurinary analyses (hydroxylated PAHs) will identify high-exposure settings and activities, and that untargeted\nmetabolomics will reveal novel environmental compounds of concern; b) the urine metabolome and microRNAs\nwill change acutely with exposures and cumulative exposures will be associated with long-term DNA methylation\nchanges in firefighters; and c) interventions chosen by firefighters will significantly reduce exposures. We will\ntest these hypotheses through evaluating firefighter exposures during WUI responses, measuring toxic effects,\nand evaluating interventions to reduce exposures. Our fire service research champions have enrolled Los\nAngeles County and Orange County firefighters who could respond to WUI fires in the Fire Fighter Cancer Cohort\nStudy (FFCCS), a fire service-academic community-engaged research collaborative. For the proposed research\nwe will measure exposures of firefighters during WUI responses using silicone wristbands and pre- and post-\nexposure urine for targeted (hydroxylated PAHs) and untargeted (metabolomics) analyses. Occupational\nfireground characteristics (type of fire, PPE, time at fire, activities) will be recorded. Using urine and blood\ncollected at baseline and post-exposure, we will evaluate acute effects with changes in endogenous metabolites\n(pre/post urine) and microRNA (pre/post blood). Longer-term changes in DNA methylation will be evaluated\ncomparing baseline blood samples to three years afterwards. Exposure reduction interventions selected by the\nfire service will be evaluated comparing intervention and activity control groups with pre- and post-exposure\nwristband and urinary PAH metabolite measurements. We anticipate that the proposed research will provide a\nmore complete measure of the WUI fire exposure and associated toxicity, and identify interventions that\nsignificantly reduce chemical exposures to firefighters and inform overall public health responses."]

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