Conklin Lab
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About
The Conklin Environmental Cardiology Lab investigates how toxicants impact cardiovascular and pulmonary function by performing controlled exposures in animal models of health and disease. We investigate the effects of air pollution (e.g., particulate matter), gases (e.g., benzene, aldehydes), and electronic cigarettes (E-cig). Overall, we work to establish both biomarkers of exposure by measuring metabolites in biological fluids and sensitive biomarkers of harm including real time changes in cardiopulmonary function such as breathing rate, heart rate, and blood pressure using radiotelemetry to understand how exposure to constituents of complex aerosols leads to disease. We have implicated volatile organic compounds (VOCs) as a general class of inhaled toxicants, and specifically aldehydes, in cardiovascular injury including endothelial dysfunction, inflammation, and atherosclerosis in both animal models and in human studies -- a testament to the power of ‘biological plausibility’ studies. In addition, we have identified targets of aldehydes that mediate and modify their actions including the Transient Potential Receptor Ankyrin-1 (TRPA1) and Glutathione-S-Transferase Pi (GSTP). The TRPA1 is a sensory receptor that regulates cardiopulmonary responses to aldehydes. GSTP is an enzyme that metabolizes aldehydes such as acrolein to detoxify and protect blood vessels and the heart. These are potential targets of therapeutic intervention.
Team
Daniel J. Conklin, PhD (dj.conklin@louisville.edu)
Lexiao Jin, MD, PhD (lexiao.jin@louisville.edu)
Alexis Miller, MS, RLATg (alexis.miller@louisville.edu)
Fenge Li (fenge.li@louisville.edu)
Heather Stowers (heather.stowers@louisville.edu)
Key Research Areas
- Environmental Cardiology
- Air Pollution (PM2.5)
- Electronic Nicotine Delivery Systems (ENDS)
- Volatile Organic Compounds (VOCs)
- Aldehydes (Acrolein, Formaldehyde)
- Detoxification
- Endothelial Dysfunction
- Hypertension
- Atherosclerosis
Current Projects
Cardiopulmonary Toxicity of Electronic Nicotine Delivery Systems, 12/14/2023-12/13/2028
In the proposed studies, we will investigate the cardiovascular and pulmonary toxicity of ENDS (Electronic cigarettes) using animal models and state-of-the-art exposure technology, protocols, and biomarkers of exposure and of harm.
Environmental Exposure and Cardiometabolic Disease, 09/01/2017-03/31/2027
Goal of the SUPERFUND Center is to examine the cellular and molecular mechanisms by which volatile organic compounds (VOCs) exert cardiometabolic toxicity. We hypothesize that environmental toxins induce ER-stress in endothelial cells that leads to vascular insulin resistance, endothelial activation, and atherogenesis.
Mechanisms of Inhaled Combustion Product-Induced Cardiopulmonary and Systemic Toxicity 06/01/2024-05/31/2026
In the proposed studies, we will investigate the cardiovascular and pulmonary toxicity of particulate matter combined with acrolein (aldehyde) using animal models of health (normotensive) and disease (hypertension) and state-of-the-art exposure technology, protocols, and biomarkers of exposure and of harm.
Recent Publications
1. Jin, L., J. Lynch, G. Jagatheesan, L. Guo, and D.J. Conklin. 2020. Crotonaldehyde-induced Vascular Relaxation and Toxicity: Role of Endothelium and Transient Receptor Potential Ankyrin-1 (TRPA1). Toxicol Appl Pharmacol. 398:115012.
2. Zhao, J., D.J. Conklin, Y. Guo, X. Zhang, D. Obal, L. Guo, G. Jagatheesan, K. Katragadda, L. He, X. Yin, M. A. I. Prodhan, J. Shah, D. Hoetker, A. Kumar, V. Kumar, M. Wempe, A. Bhatnagar, and S. Baba. 2020. Cardiospecific overexpression of ATPGD1 increases histidine dipeptide levels and prevents myocardial ischemia-reperfusion injury. J Am Heart Assoc. 9(12):e015222.
3. Wang, K., Dai, X., He, J., Yan, X., Yang, C., Fan, X., Sun, S., Chen, J., Xu, J., Deng, Z., Fan, J., Yuan, X., Liu, H., Carlson, E., Shen, F., Wintergerst, K., Conklin, D.J., Epstein, P., Lu, C., and Y. Tan. 2020. Endothelial overexpression of metallothionein prevents diabetes mellitus-induced impairment in ischemia angiogenesis via preservation of HIF-1α/SDF-1/VEGF signaling in endothelial progenitor cells. Diabetes. 69(8):1779-1792.
4. Lynch, J., Jin, L., Richardson, A., Jagatheesan, G., Lorkiewicz, P., Xie, Z., Theis, W., Shirk, G., Malovichko, M.V., Bhatnagar, A., Srivastava, S. and D.J. Conklin. 2020. Acute and Chronic Vascular Effects of Inhaled Crotonaldehyde in Mice: Role of TRPA1. Toxicol Appl Pharmacol. 402:115120.
5. Miller, J.M., M.H. Meki, Q. Ou, S.A. George, A. Gams, R.R.E. Abouleisa, X-L.Tang, B.M. Ahern, G.A. Giridharan, A. El-Baz, B.G. Hill, J. Satin, D.J. Conklin, J. Moslehi, R. Bolli, A.J.S. Ribeiro, I.R. Efimov, and T.M.A. Mohamed. 2020. Heart slice culture system reliably demonstrates clinical drug-related cardiotoxicity. Toxicol Appl Pharmacol. 115213.
6. Lin, Q., Huang, Z., Cai, G., Fan, X., Yan, X., Liu, Z., Zhao, Z., Li, J., Shi, H., Kong, M., Zheng, M.H., Conklin, D.J., Epstein, P.N., Kupper, A.W., Mohammadi, M., Cai, L., Li, X., Li, Y., and Y. Tan. 2020. Activating AMP-activated protein kinase mediates fibroblast growth factor 1 protection from nonalcoholic fatty liver disease in mice. Hepatology. doi: 10.1002/hep.31568.
7. Doherty Lyons, S., J.L. Blum, C. Hoffman-Budde, P. Tijerina, M.I. Fiel, D.J. Conklin, F.A. Gany, J.A. Odin, and J.T. Zelikoff. 2020. Prenatal exposure to gutkha, a globally-relevant smokeless tobacco product, induces hepatic changes in adult mice. Int. J. Environ. Res. Public Health. 17(21), 7895.
8. Riggs, D., Yeager, R., D.J. Conklin, DeJarnett, N., Keith, R., DeFilippis, A, Rai, S., and A. Bhatnagar. 2021. Residential proximity to greenness mitigates the hemodynamic effects of ambient air pollution. Am J Physiol Heart Circ Physiol. doi: 10.1152/ajpheart.00689.2020.
9. Jin, L., Lynch, J., Richardson, A., Srivastava, S., Lorkiewicz, P., Theis, W., Shirk, G., Hand, A., Bhatnagar, A., Srivastava, S. and D.J. Conklin. 2021. Electronic cigarette solvents, pulmonary irritation and endothelial dysfunction: role of acetaldehyde and formaldehyde. Am J Physiol Heart Circ Physiol. doi: 10.1152/ajpheart.00878.2020.
10. McGraw, K.E., D.W. Riggs, S. Rai, A. Navas-Acien, Z. Xie, P. Lorkiewicz, J. Lynch, N. Zafar, S. Krishnasamy, K.C. Taylor, D.J. Conklin, A.P. DeFilippis, S. Srivastava, and A. Bhatnagar. 2021. Exposure to Volatile Organic Compounds – Acrolein, 1,3-butadiene, and crotonaldehyde – is associated with vascular dysfunction. Environ Res. doi: 10.1016/j.envres.2021.110903.
11. Tevis, D.S., S.R. Flores, B.M. Kenwood, D. Bhandari, P. Jacob, J. Liu, P.K. Lorkiewicz, D.J. Conklin, S.S. Hecht, M.L. Goniewicz, B.C. Blount, and V.R. DeJesús. 2021. Harmonization of acronyms for volatile organic compound metabolites using a standardized naming system. Int. J. Hyg. Environ. Health. 235:113749. doi: 10.1016/j.ijheh.2021.113749.
12. Haberzettl, P., Jin, L., Riggs, D., Zhao, J., O'Toole, T., and D.J. Conklin. 2021. Fine particulate matter air pollution and aortic perivascular adipose tissue: oxidative stress, leptin and vascular dysfunction. Phys. Reports. 9(15):e14980. doi: 10.14814/phy2.14980.
13. Li, X., Haberzettl, P., D.J. Conklin, Bhatnagar, A., Rouchka, E.C., Zhang, M. and T. O'Toole. 2021. Exposure to fine particulate matter air pollution alters mRNA and miRNA expression in bone marrow-derived endothelial progenitor cells from mice. Genes. 12(7):1058. doi: 10.3390/genes12071058.
14. Jin, L., Lorkiewicz, P., Xie, Z., Bhatnagar, A., Srivastava, S. and D.J. Conklin. 2021. Acrolein but not its metabolite, 3-hydroxypropylmercapturic acid (3HPMA), activates vascular Transient Receptor Potential Ankyrin-1 (TRPA1): physiological to toxicological implications. Toxicol. Appl. Pharmacol. 115647. doi: 10.1016/j.taap.2021.115647. Online ahead of print. PMID: 34271065.
15. Malovichko MV, Abplanalp WT, McFall SA, Taylor BS, Wickramasinghe NS, Sithu ID, Zelko IN, Uchida S, Hill BG, Sutaria SR, Nantz MH, Bhatnagar A, Conklin D.J., O'Toole TE, S. Srivastava. 2021. Subclinical markers of cardiovascular toxicity of benzene inhalation in mice. Toxicol. Appl. Pharmacol. 115742. doi: 10.1016/j.taap.2021.115742.
16. Zelko, I., S. Dassanayaka, M.V. Malovichko, U. Shizuka, D.J. Conklin, S.P. Jones and S. Srivastava. 2021. Chronic benzene exposure aggravates pressure overload-induced cardiac dysfunction. Toxicol. Sci. kfab125. doi: 10.1093/toxsci/kfab125.
17. Jin, L. and D.J. Conklin. 2021. A novel evaluation of endothelial dysfunction ex vivo. Phys. Reports. 9(21):e15120. doi: 10.14814/phy2.15120.
18. Abouleisa, R., A-B. M. Salama, Q. Ou, X-L. Tang, M. Solanki, Y. Guo, Y. Nong, L. McNally, P.K. Lorkiewicz, K.M. Kassem, B.M. Ahern, K. Choudhary, R. Thomas, Y. Huang, H.R. Juhardeen, A. Siddique, Z. Ifthikar, S.K. Hammad, F. Abdulwali, M.L. Dastagir, A. Gibreil, A.S. Elbaz, K.N. Ivey, D.J. Conklin, J. Satin, B.G. Hill, D. Srivastava, R. Bolli, and T.M.A Mohamed. 2022. Transient cell cycle induction in cardiomyocytes to treat subacute ischemic heart failure. Circulation. 145(17):1339-1355.
19. Lorkiewicz, P., Keith, R., Lynch, J., Jin, L., Theis, W., Krivokhizhina, T., Riggs, D., Bhatnagar, A., Srivastava, S., and D.J. Conklin. 2022. Electronic cigarette solvents, JUUL e-liquids, and biomarkers of exposure: in vivo evidence for acrolein and glycidol in e-cig-derived aerosols. Chem. Res. Toxicol. 35(2):283-292. (Awarded “Best Paper of 2022” from Exposure Specialty Section, Society of Toxicology)
20. Zhao, J., D. Gomes, L. Jin; S.P. Mathis, X. Li, E.C. Rouchka, H. Bodduluri, D.J. Conklin, and T.E. O’Toole. 2022. Polystyrene bead ingestion promotes adiposity and cardiometabolic disease in mice. Ecotoxic. Environ. Safety. 232:113239.
21. Richardson, A., T. Krivokhizhina, P. Lorkiewicz, S. D’Souza, A. Bhatnagar, S. Srivastava, and D.J. Conklin. 2022. Effects of electronic cigarette flavorants on human platelet aggregation ex vivo. Toxicol. Reports. 9:814-820.
22. Kuehl, P.J., McDonald, J.D., Weber, D.T., Khlystov, A., Nystoriak, M.A., Conklin, D.J. 2022. Composition of aerosols from thermal degradation of flavors used in ends and tobacco products. Inhalation Toxicology. 1-10. doi: 10.1080/08958378.2022.2103602.
23. Dai, X., K. Wang, J. Fan, H. Liu, X. Fan, Q. Lin, Y. Chen, H. Chen, Y. Li, H. Liu, O. Chen, J. Chen, X. Li, D. Ren, J. Li, D.J. Conklin, K.A. Wintergerst, Y. Li, L. Cai, Z. Deng, X. Yan, Y. Tan. 2022. Nrf2 Transcriptional Upregulation of IDH2 to Tune Mitochondrial Dynamics and Rescue Angiogenic Function of Diabetic EPCs. Redox Biology. 56:102449.
24. Carll, A., C. Arab, R. Salatini, M. Miles, M. Nystoriak, K. Fulghum, D. Riggs, G. Shirk, W. Theis, N. Talebi, A. Bhatnagar, and D.J. Conklin. 2022. E-cigarettes and their lone constituents induce cardiac arrhythmia and conduction defects in mice. Nature Comm. 13(1):6088. doi: 10.1038/s41467-022-33203-1.
25. Majid S, Weisbrod RM, Fetterman JL, Keith RJ, Rizvi SHM, Zhou Y, Behrooz L, Robertson RM, Bhatnagar A, Conklin D.J., Hamburg NM. 2023. Pod-based e-liquids impair human vascular endothelial cell function. PLoS One. 18(1):e0280674.
26. Ribble, A., Hellmann, J., Conklin, D.J., Bhatnagar, A., P. Haberzettl. 2023. Fine Particulate Matter (PM2.5)-induced Pulmonary Oxidative Stress Contributes to Increases in Glucose Intolerance and Insulin Resistance in a Mouse Model of Circadian Dyssynchrony. Science of the Total Environment. 877:162934.
27. Jin, L., Z. Xie, P. Lorkiewicz, S. Srivastava, A. Bhatnagar, D.J. Conklin. 2023. Endothelial-dependent Relaxation of Alpha-Pinene and Two Metabolites, Myrtenol and Verbenol, in Isolated Murine Blood Vessels. Am Jrl Phys-Heart Circ Phys. 325(6):H1446-H1460.
28. Conklin, D.J., P. Haberzettl, K.G. MacKinlay, D. Murphy, L. Jin, F. Yuan, S. Srivastava, and A. Bhatnagar. 2023. Aldose Reductase (AR) Mediates and Perivascular Adipose Tissue (PVAT) Modulates Endothelial Dysfunction of Short-Term High-Fat Diet Feeding in Mice. Metabolites. 13(12):1172.
29. Xie, Z, Sutaria, SR, Chen, JY, Gao, H, Conklin, D.J., Keith, RJ, Srivastava, S, Lorkiewicz, P, Bhatnagar, A. 2024. Evaluation of Urinary Limonene Metabolites as Biomarkers of Exposure to Greenness. Environ Res. 245:117991.
30. Abouleisa, R., Tang, X-L., Ou, Q., Salama, A.B.M., Woolard, A., Hammouri, D., Cayton, S., Sameeha, K., Arai, M., Sithu, I., Conklin, D.J., Bolli, R., and T.A.M. Mohamed. 2024. Gene Therapy Encoding Cell Cycle Factors to Treat Chronic Ischemic Heart Failure in Rats. Cardiovasc. Research. 2024 120(2):152-163.
31. Zhao, J., N. Adiele, D. Gomes, M. Malovichko, D.J. Conklin, A. Ekuban, J. Luo, T. Gripshover, W.H. Watson, M. Banerjee, M.L. Smith, E.C. Rouchka, R. Xu, X. Zhang, M.C. Cave, and T.E. O’Toole. 2024. Obesogenic Polystyrene Microplastic Exposures Disrupt the Gut-Liver-Adipose Axis. Toxicol. Sci. 198(2):210-220.
32. Asplund, H., H. Dreyer, T. O’Toole, R. Singhal, E.C. Rouchka, P. Haberzettl, D.J. Conklin, and B.E. Sansbury. 2024. Exposure to Fine Particulate Matter (PM2.5) Air Pollution Disrupts Erythrocyte Turnover. Circ. Res. 134(9):1224-1227.
33. Yang, J.Y., G. Mondéjar-Parreño, J.W.S. Jahng, Y. Lu, N. Hamburg, K.C. Nadeau, D.J. Conklin, R. Liao, M. Chandy, and J.C. Wu. 2024. Elucidating Effects of the Environmental Pollutant Benzo[a]pyrene [BaP] on Cardiac Arrhythmogenicity. Jrl. Mol. Cell. Cardiol. 191:23-26.
34. Jin, L., A. Richardson, J. Lynch, P. Lorkiewicz, S. Srivastava, L. Fryar, A. Miller, W. Theis, G. Shirk, A. Bhatnagar, S. Srivastava, D.W. Riggs, and D.J. Conklin. 2024. Formaldehyde and the Transient Receptor Potential Ankyrin-1 Contribute to Electronic Cigarette Aerosol-induced Endothelial Dysfunction in Mice. Toxicol Sci. 201(2):331-347. doi: 10.1093/toxsci/kfae096. (Featured on Cover Page of October 2024 issue.)
1. Mohamed, T.M.A., and D.J. Conklin. 2020. Emerging Technology and Platforms for Cardiotoxicity Testing. Toxicol Appl Pharmacol. doi: 10.1016/j.taap.2020.115262.
2. Chandy, M., and D.J. Conklin. 2023. Recent Advances in the Cardiotoxicity of Anti-Cancer Drugs: Navigating the Landscape of Anthracycline-Induced Cardiotoxicity. Toxicol Appl Pharmacol. doi.org/10.1016/j.taap.2023.116791.
1. Boor, P.J. and D.J. Conklin. 2010. Chapter 7.09. Methods of Analysis: Morphologic Techniques in the Evaluation of the Heart and Blood Vessels. In: Cardiovascular Toxicology (ed. C. McQueen) of Comprehensive Toxicology Series. Elsevier. Amsterdam, The Netherlands. (revised 2016; 2024).
2. Conklin, D. J. & Bhatnagar, A. 2018. Aldehydes and Cardiovascular Disease. In: McQueen, C. A., Comprehensive Toxicology, Third Edition. Vol. 13, pp. 514–537. Oxford: Elsevier Ltd. (revised 2024).
1. Basner, M., Riggs, D.W. and D.J. Conklin. 2020. Environmental Determinants of Hypertension and Diabetes: Sounding Off About the Effects of Noise. J Am Heart Assoc. 9(6):e016048.
2. Lynch, J., Jin, L., Richardson, A., and D.J. Conklin. 2020. Tobacco Smoke and Endothelial Dysfunction: Role of Aldehydes? Curr Hypertension Reports. 22(9):73.
3. Mohamed, T.M.A., and D.J. Conklin. 2020. Emerging Technology and Platforms for Cardiotoxicity Testing. Toxicol Appl Pharmacol. 115262. doi: 10.1016/j.taap.2020.115262.
4. Singh, P., T. O'Toole, D.J. Conklin, B.G. Hill, and P. Haberzettl. 2021. Endothelial Progenitor Cells as Critical Mediators of Environmental Air Pollution-Induced Cardiovascular Toxicity. Am J Physiol Heart Circ Physiol. doi: 10.1152/ajpheart.00804.2020.
5. Conklin, D.J. 2022. How Irritating! Why Electronic Cigarettes Are Not “95% Less Harmful” Than Combustible Cigarettes for Cardiovascular Disease. Mechanistic Insights of Endothelial Dysfunction. Arterioscler. Thromb. Vasc. Biol. 42(11):1351-1354.
6. Chandy, M., T. Hill III, N. Jimenez-Tellez, J.C. Wu, S.E. Sarles, E. Hensel, Q. Wang, I. Rahman, and D.J. Conklin. 2024. Addressing Cardiovascular Toxicity Risk of Electronic Nicotine Delivery Systems in the 21st Century: “What Are the Tools Needed for the Job?” and “Do We Have Them?” Cardiovasc Toxicol. 24(5):435-471. doi: 10.1007/s12012-024-09850-9.