Precision Environmental Health and Exposome RIG

Leader:

Click here for the Precision Environmental Health Research Interest Group Members 

The Precision Environmental Health and Exposome (PEH/E) RIG led by Dr. Carolyn M. Klinge, includes Drs. Jun Cai, Matthew Cave, Natalie DuPre, Xiao-An Fu, Haixun Guo, David W. Hein, Carolyn Klinge, Maiying Kong, Michael Merchant, Juw Won Park, Lonnie Sears, Ted Smith, J. Christopher States, Kira Taylor, and Xiang Zhang. The overall goal for the Precision Environmental Health and Exposome RIG is to integrate data from work on community exposures in air, water, soil, plants, birds, worms, and other species with human exposures. 

Dr. Cai’s research centers on investigating the effects of environmental heavy metal exposures and lifestyle factors, such as sleep disturbances, a high-fat diet, and opioid abuse during early life, on neurodevelopment and the occurrence of malignant brain tumors in offspring (1,2). By exploring these exposomes, his work aims to reveal their neurotoxic and immunotoxic effects, contributing valuable insights to the broader understanding of Precision Environmental Health and further striving to advance the development of precision treatments.

Dr. Cave’s research with the Anniston Community Health Survey and follow up has identified association with serum levels of polychlorinated biphenyls and per- and poly-fluroakyl substances with metabolic diseases including steatotic liver disease and diabetes (3-7).

Dr. Clark’s  research has identified a potential gene (Stard5) x environment (ER stress) interaction that influences hepatic cholesterol and lipid metabolism. The goal is to determine whether STARD5 provides a hepatoprotective role a western diet + polychlorinated biphenyl-induced metabolic associated steatotic liver disease.

Dr. DuPre’s epidemiologic research predominantly focuses on the role of environmental exposures on health outcomes such as cancer and infectious diseases by integrating human biospecimens and neighborhood estimates of environmental pollutants within state registry databases and clinical epidemiologic studies (8-13).

Dr. Guo’s research utilizes non-invasive and clinically-available PET imaging for studying the in vivo copper metabolism upon Cadmium exposure, with potential for individualized diagnosis of Cadmium exposure.

Dr. Hein’s research program investigates gene-environmental interactions between N-acetyltransferase 2 genetic polymorphism and exposures to aromatic and heterocyclic amines on the frequency and severity of environmental disease (14-18).

Dr. Fu’s research focuses on developing novel sensor array and microfabricated devices for measurement and monitoring of volatile organic compounds including benzene, toluene, formaldehyde and acrolein in environmental air and electronic cigarette aerosols (19-22).

Dr. Klinge’s research collaboration with Dr. Caveexamines how chemical modifications of RNA (the epitranscriptome) affect transcript stability, splicing, and translation in diet and polychlorinated biphenyl exposure induced mouse models of metabolic dysfunction-associated steatotic liver disease (MASLD) (5,23-27).

Dr. Kong’s research interest is to study and develop appropriate statistical methods to compare effectiveness of different treatments or exposures based on experimental data and observational data. My other current research interest is to study and develop statistical methods for clinical trials and high dimensional data, and link them with patient outcomes (28).

Dr. Merchant’s research program investigates the development, progression and complications of chronic kidney and liver disease. His interests overlap with the Precision Environmental Health and Exposome (PEHE) Research Interest Group (RIG) with focus on include gene-environment or exposome events contributing to metabolic dyshomeostasis and failure of compensatory mechanisms that promote progression and complications of chronic diseases (29-33).

Dr. Park’s research focuses on the analysis of alternative mRNA splicing and its regulation in eukaryotic cells using high-throughput RNA sequencing (RNA-seq) and related genomic technologies, including their biological applications (34-36). Applying his expertise, Dr. Park has mapped how arsenic exposure rewrites the splicing code in human skin cells, potentially playing a role in carcinogenesis (37). He's also identified the splicing changes triggered by PCBs in mice livers, offering crucial clues about this environmental toxin's effects on health (27).

Dr. Sears studies the effects of environmental exposures on child development through community-engaged research of children living near coal ash storage sites that contain heavy metals (38-42).

Dr. Smith is an Associate Professor of Environmental Medicine, specializing in population health risk surveillance using wastewater monitoring. He employs mixed methods in his research, combining various approaches to improve surveillance techniques. A key aspect of his work is linking monitoring data to public health interventions, with a focus on addressing vulnerabilities in specific communities. His efforts aim to make a practical impact in the field of environmental health through targeted place-based, community-engaged approaches (43-45).

Dr. States’ research has focused on the role of environmental arsenic exposure in development of chronic disease including cancer and atherosclerosis. This work has focused on the molecular mechanisms by which arsenic disrupts cellular processes. He has expanded his interests to community exposomics using measurements of metals and other toxicants in wastewater (46,47).

Dr. Taylor’s research examines the effects of behavioral and environmental exposures such as volatile organic compounds, polybrominated biphenyls and tobacco smoke on cardiovascular and reproductive health outcomes (48-52).

Dr. Zhang’s  group develops bioanalytical technologies for quantitative metabolomics (53,54), lipidomics (55), and epitranscriptomics (56). They further employ the developed technologies to support biomedical research at the UofL and other institutes.

Thus, the members of the PEHE RIG investigate the role of several community environmental exposures in human health and disease in multiple tissues and models.

References Cited

1. Gibson JM, Chu T, Zeng W, Wethall AC, Kong M, Mellen N, Devlin Phinney LA, Cai J. Perinatal methadone exposure attenuates myelination and induces oligodendrocyte apoptosis in neonatal rat brain. Experimental Biology and Medicine 2022; 247:1067-1079
2. Cai J, Tuong CM, Zhang Y, Shields CB, Guo G, Fu H, Gozal D. Mouse intermittent hypoxia mimicking apnoea of prematurity: effects on myelinogenesis and axonal maturation. The Journal of Pathology 2012; 226:495-508
3. Clair HB, Prough RA, Cave MC, Brock GN, Pinkston CM, Rai SN, McClain CJ, Falkner KC, Pavuk M, Dutton ND. Liver Disease in a Residential Cohort With Elevated Polychlorinated Biphenyl Exposures. Toxicological Sciences 2018; 164:39-49
4. Pavuk M, Serio TC, Cusack C, Cave M, Rosenbaum PF, Birnbaum LS. Hypertension in Relation to Dioxins and Polychlorinated Biphenyls from the Anniston Community Health Survey Follow-Up. Environ Health Perspect 2019; 127:127007
5. Cave M, C., Pinkston C, M., Rai SN, Wahlang B, Pavuk M, Head K, Z., Carswell G, K., Nelson G, M., Klinge C, M., Bell D, A., Birnbaum L, S., Chorley B, N. Circulating MicroRNAs, Polychlorinated Biphenyls, and Environmental Liver Disease in the Anniston Community Health Survey. Environmental Health Perspectives 2022; 130:017003
6. Petriello MC, Mottaleb MA, Serio TC, Balyan B, Cave MC, Pavuk M, Birnbaum LS, Morris AJ. Serum concentrations of legacy and emerging per- and polyfluoroalkyl substances in the Anniston Community Health Surveys (ACHS I and ACHS II). Environment International 2022; 158:106907
7. Pavuk M, Rosenbaum PF, Lewin MD, Serio TC, Rago P, Cave MC, Birnbaum LS. Polychlorinated biphenyls, polychlorinated dibenzo-p-dioxins, polychlorinated dibenzofurans, pesticides, and diabetes in the Anniston Community Health Survey follow-up (ACHS II): single exposure and mixture analysis approaches. Science of The Total Environment 2023; 877:162920
8. Peng C, DuPre N, VoPham T, Heng YJ, Baker GM, Rubadue CA, Glass K, Sonawane A, Zeleznik O, Kraft P, Hankinson SE, Eliassen AH, Hart JE, Laden F, Tamimi RM. Low dose environmental radon exposure and breast tumor gene expression. BMC Cancer 2020; 20:695
9. Blair LK, Warner ET, James P, Hart JE, VoPham T, Barnard ME, Newton JD, Murthy DJ, Laden F, Tamimi RM, DuPre NC. Exposure to natural vegetation in relation to mammographic density in a Massachusetts-based clinical cohort. Environmental Epidemiology 2022; 6
10. DuPre NC, Karimi S, Zhang CH, Blair L, Gupta A, Alharbi LMA, Alluhibi M, Mitra R, McKinney WP, Little B. County-level demographic, social, economic, and lifestyle correlates of COVID-19 infection and death trajectories during the first wave of the pandemic in the United States. Science of The Total Environment 2021; 786:147495
11. DuPre N, Blair L, Moyer S, Cook EF, Little B, Howard J. Hepatitis A Outbreaks Associated With the Opioid Epidemic in Kentucky Counties, 2017–2018. American Journal of Public Health 2020; 110:1332
12. DuPré NC, Heng YJ, Raby BA, Glass K, Hart JE, Chu J-h, Askew C, Eliassen AH, Hankinson SE, Kraft P, Laden F, Tamimi RM. Involvement of fine particulate matter exposure with gene expression pathways in breast tumor and adjacent-normal breast tissue. Environmental Research 2020; 186:109535
13. Blair LK, Howard J, Peiper NC, Little BB, Taylor KC, Baumgartner R, Creel L, DuPre NC. Residence in urban or rural counties in relation to opioid overdose mortality among Kentucky hospitalizations before and during the COVID-19 pandemic. International Journal of Drug Policy 2023; 119:104122
14. Hein DW, Salazar-González RA, Doll MA, Zang Y. The effect of the rs1799931 G857A (G286E) polymorphism on N-acetyltransferase 2-mediated carcinogen metabolism and genotoxicity differs with heterocyclic amine exposure. Archives of Toxicology 2023; 97:2697-2705
15. Walls KM, Hong KU, Hein DW. Induction of glucose production by heterocyclic amines is dependent on N-acetyltransferase 2 genetic polymorphism in cryopreserved human hepatocytes. Toxicology Letters 2023; 383:192-195
16. Habil MR, Salazar-González RA, Doll MA, Hein DW. Effect of N-acetyltransferase 2 genetic polymorphism on 4,4′-methylenebis(2-chloroaniline)-induced genotoxicity and oxidative stress. Archives of Toxicology 2023; 97:1773-1781
17. Walls KM, Hong KU, Hein DW. Heterocyclic amines reduce insulin-induced AKT phosphorylation and induce gluconeogenic gene expression in human hepatocytes. Arch Toxicol 2023; 97:1613–1626
18. Habil MR, Salazar-González RA, Doll MA, Hein DW. N-acetyltransferase 2 acetylator genotype-dependent N-acetylation and toxicity of the arylamine carcinogen β-naphthylamine in cryopreserved human hepatocytes. Archives of Toxicology 2022; 96:3257-3263
19. Katsaros G, Smith SA, Shacklette S, Trivedi J, Garr S, Parrish LW, Xie Z, Fu XA, Powell K, Pantalos G, van Berkel V. Identification of a marker of infection in the breath using a porcine pneumonia model. JTCVS open 2023; 16:1063-1069
20. Xie Z, Morris JD, Mattingly SJ, Sutaria SR, Huang J, Nantz MH, Fu X-A. Analysis of a Broad Range of Carbonyl Metabolites in Exhaled Breath by UHPLC-MS. Analytical Chemistry 2023; 95:4344-4352
21. Adhihetty PK, Halder S, Jasinski JB, Fu X-A, Nantz MH. Harnessing the cation-π interactions of metalated gold monolayer-protected clusters to detect aromatic volatile organic compounds. Talanta 2023; 253:123915
22. Halder S, Xie Z, Nantz MH, Fu X-A. Integration of a micropreconcentrator with solid-phase microextraction for analysis of trace volatile organic compounds by gas chromatography-mass spectrometry. Journal of Chromatography A 2022; 1673:463083
23. Klinge CM, Piell KM, Petri BJ, He L, Zhang X, Pan J, Rai SN, Andreeva K, Rouchka EC, Wahlang B, Beier JI, Cave MC. Combined exposure to polychlorinated biphenyls and high-fat diet modifies the global epitranscriptomic landscape in mouse liver. Environmental Epigenetics 2021; 7:dvab008
24. Petri BJ, Piell KM, Wahlang B, Head KZ, Andreeva K, Rouchka EC, Pan J, Rai SN, Cave MC, Klinge CM. Multiomics analysis of the impact of polychlorinated biphenyls on environmental liver disease in a mouse model. Environmental Toxicology and Pharmacology 2022; 94:103928
25. Petri BJ, Cave MC, Klinge CM. Changes in m6A in Steatotic Liver Disease. Genes 2023; 14:1653
26. Petri BJ, Piell KM, Wahlang B, Head KZ, Andreeva K, Rouchka EC, Cave MC, Klinge CM. Polychlorinated biphenyls alter hepatic m6A mRNA methylation in a mouse model of environmental liver disease. Environmental Research 2023; 216:114686
27. Petri BJ, Piell KM, Wahlang B, Head KZ, Rouchka EC, Park JW, Hwang JY, Banerjee M, Cave MC, Klinge CM. Altered splicing factor and alternative splicing events in a mouse model of diet- and polychlorinated biphenyl-induced liver disease. Environmental Toxicology and Pharmacology 2023; 103:104260
28. Sun J, Duncan S, Pal S, Kong M. Directed Acyclic Graph Assisted Method For Estimating Average Treatment Effect. Journal of biopharmaceutical statistics 2023:1-20
29. Brier ME, Gooding JR, Harrington JM, Burgess JP, McRitchie SL, Zhang X, Rovin BH, Klein JB, Himmelfarb J, Sumner SJ, Merchant ML. Serum trace metal association with response to erythropoiesis stimulating agents in incident and prevalent hemodialysis patients. Scientific reports 2020; 10:20202
30. Wheelock KM, Cai J, Looker HC, Merchant ML, Nelson RG, Fufaa GD, Weil EJ, Feldman HI, Vasan RS, Kimmel PL, Rovin BH, Mauer M, Klein JB. Plasma bradykinin and early diabetic nephropathy lesions in type 1 diabetes mellitus. PloS one 2017; 12:e0180964
31. Massey VL, Dolin CE, Poole LG, Hudson SV, Siow DL, Brock GN, Merchant ML, Wilkey DW, Arteel GE. The hepatic “matrisome” responds dynamically to injury: Characterization of transitional changes to the extracellular matrix in mice. Hepatology (Baltimore, Md) 2016; 65:969-982
32. Birmingham DJ, Merchant M, Waikar SS, Nagaraja H, Klein JB, Rovin BH. Biomarkers of lupus nephritis histology and flare: deciphering the relevant amidst the noise. Nephrology Dialysis Transplantation 2017; 32:i71-i79
33. Merchant ML, Niewczas MA, Ficociello LH, Lukenbill JA, Wilkey DW, Li M, Khundmiri SJ, Warram JH, Krolewski AS, Klein JB. Plasma kininogen and kininogen fragments are biomarkers of progressive renal decline in type 1 diabetes. Kidney International 2013; 83:1177-1184
34. Shen S, Park JW, Lu Z-x, Lin L, Henry MD, Wu YN, Zhou Q, Xing Y. rMATS: Robust and flexible detection of differential alternative splicing from replicate RNA-Seq data. Proceedings of the National Academy of Sciences 2014; 111:E5593-E5601
35. Hwang JY, Jung S, Kook TL, Rouchka EC, Bok J, Park JW. rMAPS2: an update of the RNA map analysis and plotting server for alternative splicing regulation. Nucleic Acids Research 2020; 48:W300-W306
36. Chaabane M, Williams RM, Stephens AT, Park JW. circDeep: deep learning approach for circular RNA classification from other long non-coding RNA. Bioinformatics 2020; 36:73-80
37. Ferragut Cardoso AP, Banerjee M, Al-Eryani L, Sayed M, Wilkey DW, Merchant ML, Park JW, States JC. Temporal Modulation of Differential Alternative Splicing in HaCaT Human Keratinocyte Cell Line Chronically Exposed to Arsenic for up to 28 Wk. Environmental health perspectives 2022; 130:17011
38. Zhang CH, Sears L, Myers JV, Brock GN, Sears CG, Zierold KM. Proximity to coal-fired power plants and neurobehavioral symptoms in children. J Expo Sci Environ Epidemiol 2022; 32:124-134
39. Sears CG, Sears L, Zierold KM. Sex differences in the association between exposure to indoor particulate matter and cognitive control among children (age 6–14 years) living near coal-fired power plants. Neurotoxicology and Teratology 2020; 78:106855
40. Sears L, Myers JV, Sears CG, Brock GN, Zhang C, Zierold KM. Manganese body burden in children is associated with reduced visual motor and attention skills. Neurotoxicology and Teratology 2021; 88:107021
41. Zierold KM, Myers JV, Brock GN, Sears CG, Sears LL, Zhang CH. Nail Samples of Children Living near Coal Ash Storage Facilities Suggest Fly Ash Exposure and Elevated Concentrations of Metal(loid)s. Environmental Science & Technology 2021; 55:9074-9086
42. Zierold KM, Sears CG, Myers JV, Brock GN, Zhang CH, Sears L. Exposure to coal ash and depression in children aged 6–14 years old. Environmental Research 2022; 214:114005
43. Anderson LB, Ness HD, Holm RH, Smith T. Wastewater-Informed Digital Advertising as a COVID-19 Geotargeted Neighborhood Intervention: Jefferson County, Kentucky, 2021-2022. Am J Public Health 2024; 114:34-37
44. Holm RH, Pocock G, Severson MA, Huber VC, Smith T, McFadden LM. Using wastewater to overcome health disparities among rural residents. Geoforum; journal of physical, human, and regional geosciences 2023; 144:103816
45. Keith RJ, Holm RH, Amraotkar AR, Bezold MM, Brick JM, Bushau-Sprinkle AM, Hamorsky KT, Kitterman KT, Palmer KE, Smith T, Yeager R, Bhatnagar A. Stratified Simple Random Sampling Versus Volunteer Community-Wide Sampling for Estimates of COVID-19 Prevalence. American Journal of Public Health 2023; 113:768-777
46. Stingone JA, Geller AM, Hood DB, Makris KC, Mouton CP, States JC, Sumner SJ, Wu KL, Rajasekar AK, Members of the Exposomics C. Community-level exposomics: A population-centered approach to address public health concerns. Exposome 2023:osad009
47. Lu C, Rochelle HH, Donald JB, Charlie HZ, Daymond T, Ted S, States JC. Wastewater-based epidemiology for comprehensive communitywide exposome surveillance: A gradient of metals exposure. medRxiv 2023:2023.2009.2026.23295844
48. Howards PP, Terrell ML, Jacobson MH, Taylor KC, Kesner JS, Meadows JW, Spencer JB, Manatunga AK, Marcus M. Polybrominated Biphenyl Exposure and Menstrual Cycle Function. Epidemiology 2019; 30
49. Konkle SL, Zierold KM, Taylor KC, Riggs DW, Bhatnagar A. National secular trends in ambient air volatile organic compound levels and biomarkers of exposure in the United States. Environmental Research 2020; 182:108991
50. McGraw KE, Riggs DW, Rai S, Navas-Acien A, Xie Z, Lorkiewicz P, Lynch J, Zafar N, Krishnasamy S, Taylor KC, Conklin DJ, DeFilippis AP, Srivastava S, Bhatnagar A. Exposure to volatile organic compounds – acrolein, 1,3-butadiene, and crotonaldehyde – is associated with vascular dysfunction. Environmental Research 2021; 196:110903
51. Anwar MY, Marcus M, Taylor KC. The association between alcohol intake and fecundability during menstrual cycle phases. Human Reproduction 2021; 36:2538-2548
52. Oladipupo I, Ali Ts, Hein DW, Pagidas K, Bohler H, Doll MA, Mann ML, Gentry A, Chiang JL, Pierson RC, Torres S, Reece E, Taylor KC. Association between cigarette smoking and ovarian reserve among women seeking fertility care. PloS one 2022; 17:e0278998
53. Xu R, Vatsalya V, He L, Ma X, Feng W, McClain CJ, Zhang X. Altered urinary tryptophan metabolites in alcohol-associated liver disease. Alcohol: Clinical and Experimental Research 2023; 47:1665-1676
54. Morrissey SM, Zhang F, Ding C, Montoya-Durango DE, Hu X, Yang C, Wang Z, Yuan F, Fox M, Zhang H-g, Guo H, Tieri D, Kong M, Watson CT, Mitchell RA, Zhang X, McMasters KM, Huang J, Yan J. Tumor-derived exosomes drive immunosuppressive macrophages in a pre-metastatic niche through glycolytic dominant metabolic reprogramming. Cell Metabolism 2021; 33:2040-2058.e2010
55. Ding C, Shrestha R, Zhu X, Geller AE, Wu S, Woeste MR, Li W, Wang H, Yuan F, Xu R, Chariker JH, Hu X, Li H, Tieri D, Zhang H-G, Rouchka EC, Mitchell R, Siskind LJ, Zhang X, Xu XG, McMasters KM, Yu Y, Yan J. Inducing trained immunity in pro-metastatic macrophages to control tumor metastasis. Nature Immunology 2023; 24:239-254
56. He L, Vatsalya V, Ma X, Klinge CM, Cave MC, Feng W, McClain CJ, Zhang X. Metabolic Analysis of Nucleosides/Bases in the Urine and Serum of Patients with Alcohol-Associated Liver Disease. Metabolites 2022;12(12):1187. https://www.mdpi.com/2218-1989/12/12/1187.