Multi-Organ Toxicology Research Interest Group RIG

Leader:

The Multi-Organ Toxicology RIG led by Dr. Lu Cai is the largest grouping of CIEHS investigators. Multi-organ toxicology stems from tightly interlinked pathologies involving cross communication between the cardiovascular system, the liver, the lungs, and the kidneys. Thus, there are ample opportunities for collaborative projects being exploited by CIEHS members. The group includes Drs. Aruni Bhatnagar (Career Development Leader), Dr. Lu Cai (Director of Pediatric Research), Matthew Cave (IHSFC Director), Daniel Conklin, Wenke Feng, Leila Gobejishivili, Petra Haberzettl, Gary Hoyle, Luz Huntington-Moskos, Irina Kirpich, Craig McClain, Michael Nantz, Rachel Neal, Timothy O’Toole, Jan Sullivan, and Walter Watson. Dr. Srivastava is the Director of the UofL Superfund Center and of the Pathology and Bio-analytics Core in the Diabetes and Obesity Center, of a project in the American Heart Association Tobacco Regulation and Addiction Center (A-TRAC) at UofL and PI of an R01 investigating biomarkers of harm by tobacco products focusing on aldehydes such as acrolein and crotonaldehyde¹. His current research focuses on VOCs and cardiovascular disease. Dr. Cai’s research is focused on how metallothionein induction may be protective against oxidative stress in the context of diabetes development^{2, 3}. Dr. Cave investigates the role of polychlorinated biphenyls (PCBs) in hepatic pathology^{4, 5}. His ELD-RIVER grant supports two broad scientific themes: (i) the impact of endocrine and metabolism disrupting chemicals (EDCs/MDCs) in fatty liver disease, and (ii) other liver diseases (such as liver cancer) associated with chemical exposures. Dr. Conklin investigates how components of e-cigarette vapor initiate cardiovascular disease^{1, 6, 7}. Dr. Feng’s research is identifying prebiotics secreted by Lactobacillus gg that are protective against alcohol induced liver disease^8-15. Dr. Gobejishvili is investigating mechanisms of liver fibrosis, a serious potential outcome of hepatosteatitis^16-18. Her current research focuses on the role of phosphodiesterase 4 family in activation of hepatic stellate cells contributing to fibrosis. Dr. Haberzettl’s studies of PM2.5 on endothelial progenitor cells¹⁹ led to her new R01 to investigate the interconnection between exposure to PM2.5 and disruption of vascular circadian rhythms. Her studies suggest that PM2.5 exposure disrupts vascular circadian rhythms and that this disruption contributes to the development of cardiometabolic disease in a new susceptibility state of circadian dyssynchrony. Dr. Hoyle studies chlorine exposure and chronic lung disease^20-22. Dr. Huntington-Moskos investigates factors modulating outcomes of asthma in older adults in a subcontract of Dr. Polivka’s R01²³.Dr. Kirpich investigates the influence of diet on alcoholic liver disease. Using mouse models, she showed that saturated fat can protect against the effects of alcohol^24-26. Dr. McClain, gastroenterologist and Director of the Alcohol Research Center and of the Hepatobiology and Toxicology COBRE (see letter of support), is a national leader in liver disease research. His interests span the gamut from alcohol to chemical pollutants inducing liver disease and how the microbiome and diet influence liver pathology^27-29. Dr. Nantz is a chemistry professor participating in the Superfund Center. He is developing novel ultrasensitive devices for detecting VOCs the Superfund group studies as cardiovascular disease inducers. Dr. Neal is currently investigating the impact of cigarette smoke exposure on intestinal microbiome development in early life^29-31. Dr. O’Toole’s research is focused on the deleterious impact of particulate matter on endothelial progenitor cells and discovering how these effects contribute to atherogenesis¹⁹. Dr. Sullivan, studies pharmacokinetics in children^32-34. She directs the Kentucky Pediatric Clinical Trials Rural/Urban Partnership which focuses on chronic diseases with potential for intervention in childhood. A major focus of this project is upper and lower airway disease. Dr. Watson’s expertise is sulfhydryl biochemistry and he has shown an age-dependent change in the redox state of mouse lung fibroblasts³⁵. In another project, with collaboration from Dr. States, Dr. Watson is investigating the effects of dietary fat on the hepatotoxicity of environmental arsenic, with a special focus on modulation of HNF4a activity. His recent studies suggest that there is a sex difference in how a high fat diet modulates arsenic induced hepatotoxicity.

1.         Conklin DJ, Malovichko MV, Zeller I, Das TP, Krivokhizhina TV, Lynch BH, Lorkiewicz P, Agarwal A, Wickramasinghe N, Haberzettl P, Sithu SD, Shah J, O'Toole TE, Rai SN, Bhatnagar A and Srivastava S. Biomarkers of Chronic Acrolein Inhalation Exposure in Mice: Implications for Tobacco Product-Induced Toxicity. Toxicol Sci. 2017;158:263-274.

2.         Sun W, Yang J, Wang W, Hou J, Cheng Y, Fu Y, Xu Z and Cai L. The beneficial effects of Zn on Akt-mediated insulin and cell survival signaling pathways in diabetes. J Trace Elem Med Biol. 2018;46:117-127.

3.         Wang S, Gu J, Xu Z, Zhang Z, Bai T, Xu J, Cai J, Barnes G, Liu QJ, Freedman JH, Wang Y, Liu Q, Zheng Y and Cai L. Zinc rescues obesity-induced cardiac hypertrophy via stimulating metallothionein to suppress oxidative stress-activated BCL10/CARD9/p38 MAPK pathway. J Cell Mol Med. 2017;21:1182-1192.

4.         Wahlang B, Prough RA, Falkner KC, Hardesty JE, Song M, Clair HB, Clark BJ, States JC, Arteel GE and Cave MC. Polychlorinated Biphenyl-Xenobiotic Nuclear Receptor Interactions Regulate Energy Metabolism, Behavior, and Inflammation in Non-alcoholic-Steatohepatitis. Toxicol Sci. 2016;149:396-410.

5.         Hardesty JE, Wahlang B, Falkner KC, Clair HB, Clark BJ, Ceresa BP, Prough RA and Cave MC. Polychlorinated biphenyls disrupt hepatic epidermal growth factor receptor signaling. Xenobiotica. 2017;47:807-820.

6.         Conklin DJ, Haberzettl P, Jagatheesan G, Kong M and Hoyle GW. Role of TRPA1 in acute cardiopulmonary toxicity of inhaled acrolein. Toxicol Appl Pharmacol. 2017;324:61-72.

7.         Ogunwale MA, Li M, Ramakrishnam Raju MV, Chen Y, Nantz MH, Conklin DJ and Fu XA. Aldehyde Detection in Electronic Cigarette Aerosols. ACS Omega. 2017;2:1207-1214.

8.         Wang Y, Kirpich I, Liu Y, Ma Z, Barve S, McClain CJ and Feng W. Lactobacillus rhamnosus GG treatment potentiates intestinal hypoxia-inducible factor, promotes intestinal integrity and ameliorates alcohol-induced liver injury. Am J Pathol. 2011;179:2866-75.

9.         Wang Y, Liu Y, Sidhu A, Ma Z, McClain C and Feng W. Lactobacillus rhamnosus GG culture supernatant ameliorates acute alcohol-induced intestinal permeability and liver injury. Am J Physiol Gastrointest Liver Physiol. 2012;303:G32-41.

10.       Bull-Otterson L, Feng W, Kirpich I, Wang Y, Qin X, Liu Y, Gobejishvili L, Joshi-Barve S, Ayvaz T, Petrosino J, Kong M, Barker D, McClain C and Barve S. Metagenomic analyses of alcohol induced pathogenic alterations in the intestinal microbiome and the effect of Lactobacillus rhamnosus GG treatment. PLoS One. 2013;8:e53028.

11.       Wang Y, Liu Y, Kirpich I, Ma Z, Wang C, Zhang M, Suttles J, McClain C and Feng W. Lactobacillus rhamnosus GG reduces hepatic TNFalpha production and inflammation in chronic alcohol-induced liver injury. J Nutr Biochem. 2013;24:1609-15.

12.       Shi X, Wei X, Yin X, Wang Y, Zhang M, Zhao C, Zhao H, McClain CJ, Feng W and Zhang X. Hepatic and fecal metabolomic analysis of the effects of Lactobacillus rhamnosus GG on alcoholic fatty liver disease in mice. J Proteome Res. 2015;14:1174-82.

13.       Zhang M, Wang C, Wang C, Zhao H, Zhao C, Chen Y, Wang Y, McClain C and Feng W. Enhanced AMPK phosphorylation contributes to the beneficial effects of Lactobacillus rhamnosus GG supernatant on chronic-alcohol-induced fatty liver disease. J Nutr Biochem. 2015;26:337-44.

14.       Zhao H, Zhao C, Dong Y, Zhang M, Wang Y, Li F, Li X, McClain C, Yang S and Feng W. Inhibition of miR122a by Lactobacillus rhamnosus GG culture supernatant increases intestinal occludin expression and protects mice from alcoholic liver disease. Toxicol Lett. 2015;234:194-200.

15.       Chen RC, Xu LM, Du SJ, Huang SS, Wu H, Dong JJ, Huang JR, Wang XD, Feng WK and Chen YP. Lactobacillus rhamnosus GG supernatant promotes intestinal barrier function, balances Treg and TH17 cells and ameliorates hepatic injury in a mouse model of chronic-binge alcohol feeding. Toxicol Lett. 2016;241:103-10.

16.       Gobejishvili L, Barve S, Breitkopf-Heinlein K, Li Y, Zhang J, Avila DV, Dooley S and McClain CJ. Rolipram attenuates bile duct ligation-induced liver injury in rats: a potential pathogenic role of PDE4. J Pharmacol Exp Ther. 2013;347:80-90.

17.       Kirpich IA, Gobejishvili LN, Bon Homme M, Waigel S,Cave M, Arteel G, Barve SS, McClain CJ and Deaciuc IV. Integrated hepatic transcriptome and proteome analysis of mice with high-fat diet-induced nonalcoholic fatty liver disease. J Nutr Biochem. 2011;22:38-45.

18.       Vatsalya V, Avila D, Frimodig JC, Barve SS, McClain CJ and Gobejishvili L. Liver Injury Assessment by Vetscan VS2 Analyzer and Most Frequently Used ALT/GTP Reagent. Gastroenterol Hepatol (Bartlesville). 2016;4.

19.       Haberzettl P, Conklin DJ, Abplanalp WT, Bhatnagar A and O'Toole TE. Inhalation of Fine Particulate Matter Impairs Endothelial Progenitor Cell Function Via Pulmonary Oxidative Stress. Arterioscler Thromb Vasc Biol. 2018;38:131-142.

20.       Hoyle GW, Chen J, Schlueter CF, Mo Y, Humphrey DM, Jr., Rawson G, Nino JA and Carson KH. Development and assessment of countermeasure formulations for treatment of lung injury induced by chlorine inhalation. Toxicol Appl Pharmacol. 2016;298:9-18.

21.       Hoyle GW and Svendsen ER. Persistent effects of chlorine inhalation on respiratory health. Ann N Y Acad Sci. 2016;1378:33-40.

22.       Musah S, Schlueter CF, Humphrey DM, Jr., Powell KS, Roberts AM and Hoyle GW. Acute lung injury and persistent small airway disease in a rabbit model of chlorine inhalation. Toxicol Appl Pharmacol. 2017;315:1-11.

23.       Huntington-Moskos L, Rayens MK, Hall LA and Hahn EJ. The Peer and Family Smoking Index: A Valid Measure of Secondhand Smoke Exposure in Adolescents. J Adolesc Health. 2016;58:446-450.

24.       Kirpich I and McClain C. More Alcohol, More Liver Injury: Not Always True. Alcohol Alcohol. 2017;52:627-628.

25.       Kirpich IA, Petrosino J, Ajami N, Feng W, Wang Y, Liu Y, Beier JI, Barve SS, Yin X, Wei X, Zhang X and McClain CJ. Saturated and Unsaturated Dietary Fats Differentially Modulate Ethanol-Induced Changes in Gut Microbiome and Metabolome in a Mouse Model of Alcoholic Liver Disease. Am J Pathol. 2016;186:765-76.

26.       Warner DR, Liu H, Miller ME, Ramsden CE, Gao B, Feldstein AE, Schuster S, McClain CJ and Kirpich IA. Dietary Linoleic Acid and Its Oxidized Metabolites Exacerbate Liver Injury Caused by Ethanol via Induction of Hepatic Proinflammatory Response in Mice. Am J Pathol. 2017;187:2232-2245.

27.       Dickerson RN, Patel JJ and McClain CJ. Protein and Calorie Requirements Associated With the Presence of Obesity. Nutr Clin Pract. 2017;32:86S-93S.

28.       Song M, Li X, Zhang X, Shi H, Vos MB, Wei X, Wang Y, Gao H, Rouchka EC, Yin X, Zhou Z, Prough RA, Cave MC and McClain CJ. Dietary copper-fructose interactions alter gut microbial activity in male rats. Am J Physiol Gastrointest Liver Physiol. 2018;314:G119-G130.

29.       Vatsalya V, Liaquat HB, Ghosh K, Mokshagundam SP and McClain CJ. A Review on the Sex Differences in Organ and System Pathology with Alcohol Drinking. Curr Drug Abuse Rev. 2017;9:87-92.

30.       Neal RE, Chen J, Webb C, Stocke K, Gambrell C, Greene RM and Pisano MM. Developmental cigarette smoke exposure II: Hepatic proteome profiles in 6 month old adult offspring. Reprod Toxicol. 2016;65:414-424.

31.       Neal RE, Jagadapillai R, Chen J, Webb C, Stocke K, Greene RM and Pisano MM. Developmental cigarette smoke exposure II: Hippocampus proteome and metabolome profiles in adult offspring. Reprod Toxicol. 2016;65:436-447.

32.       Autmizguine J, Melloni C, Hornik CP, Dallefeld S, Harper B, Yogev R, Sullivan JE, Atz AM, Al-Uzri A, Mendley S, Poindexter B, Mitchell J, Lewandowski A, Delmore P, Cohen-Wolkowiez M, Gonzalez D and the Pediatric Trials Network Steering C. Population Pharmacokinetics of Trimethoprim-Sulfamethoxazole in Infants and Children. Antimicrob Agents Chemother. 2018;62.

33.       Dallefeld SH, Atz AM, Yogev R, Sullivan JE, Al-Uzri A, Mendley SR, Laughon M, Hornik CP, Melloni C, Harper B, Lewandowski A, Mitchell J, Wu H, Green TP and Cohen-Wolkowiez M. A pharmacokinetic model for amiodarone in infants developed from an opportunistic sampling trial and published literature data. J Pharmacokinet Pharmacodyn. 2018.

34.       Le J, Poindexter B, Sullivan JE, Laughon M, Delmore P, Blackford M, Yogev R, James LP, Melloni C, Harper B, Mitchell J, Benjamin DK, Jr., Boakye-Agyeman F and Cohen-Wolkowiez M. Comparative Analysis of Ampicillin Plasma and Dried Blood Spot Pharmacokinetics in Neonates. Ther Drug Monit. 2018;40:103-108.

35.       Zheng Y, Ritzenthaler JD, Burke TJ, Otero J, Roman J and Watson WH. Age-dependent oxidation of extracellular cysteine/cystine redox state (Eh(Cys/CySS)) in mouse lung fibroblasts is mediated by a decline in Slc7a11 expression. Free Radic Biol Med. 2018;118:13-22.