Mechanistic and Translational Toxicology RIG

Leader:

The Mechanistic & Translational Toxicology (MTT) RIG led by Dr. Lu Cai is the largest grouping of CIEHS investigators (currently 32 members). MTT stems from the investigation for the mechanisms underlying the biological responses in molecular, cellular, and systemic (multi-organ or whole body) levels to environmental exposome, including acute and chronic stresses in whole life or life stage, which include biological (such as virus, bacteria and fungi), physical (radiation, temperature and mechanical), life-style, and social challenges. The integrative, comprehensive mechanistic studies in collaboration with other RIGs will help in understanding individual and population pathogenesis (precision health), address environmental justice, effectively develop innovative interventional approaches to avoid toxicity and pathogenesis, and eventually improve human health.

Thus, there are ample opportunities for collaborative projects being exploited by CIEHS members. The group includes Drs. Banerjee, Mayukh; Cai, Lu; Carll, Alex P; Chen, Shao-yu; Conklin, Daniel; Corbitt, Cynthia; Gumpert, Anna; Haberzettl, Petra; He, Liqing; Hill, Bradford; Huang; Jiapeng; Jala, Venkatakrishna; Jophlin, Loretta; Kirpich, Irina; Kouokam, J. Calvin; LeBlanc, Amanda; McCLain, Craig; Neal, Rachel Elizabeth; O'Toole, Timothy Edward; Rane, Madhavi; Sansbury, Brian; Smith, Melissa; States, J. Christopher (PI, Director of CIEHS); Wahlang, Banrida; Watson, Walter H.; Wintergerst, Kupper; Wise, Jr, Johnny; Wise, John Pierce; Wise, Sandra Suanne; Young, Jamie; Zelko, Igor; Zhang, Qunwei. For each member, the name and title as well as department and school information are referred the above link “Mechanistic and Translational Toxicology Interest Group Members”. The following is the representative work for some of the members.

Dr. Banerjee  investigates the mechanisms for and zinc intervention of arsenic carcinogenesis.¹

Dr. Cai’s research is focused on the mechanisms and intervention of diabetic complications ² as well as environmental on the diabetic complications.

Dr. Carll investigates the effects of chemical constituents of e-cigarettes on cardiac electrophysiology ³.

Dr. Chen has been long-term interested in mechanistic investigating the detrimental effects of ethanol on neural crest cell induction, migration, differentiation, and survival.⁴ 

Dr. Conklin investigates how components of e-cigarette vapor initiate cardiovascular disease. ^{3, 5}

Dr. Corbitt’s research focus is behavioral neuroendocrinology (the interaction of hormones, brain, and behavior), with particular interest in the effects of environmental signals on the central nervous system.⁶

Dr. Haberzettl’sgoal is to improve public health by understanding how exposure to polluted air impacts vascular and cardiometabolic health in healthy and susceptible populations (e.g., diet-induced obesity, circadian dyssynchrony).⁷  

Dr. He has been working on the development of new methods with Dr. Xiang Zhang to investigate the concentration change of nucleosides and nucleotides in biological samples for the purposes of biomarker discovery or elucidation of disease mechanisms.⁸

Dr.  Hill’s main research interests include a broad theme entails understanding how changes in metabolism contribute to cardio-metabolic health and disease.⁹

Dr. Huang has a diverse research interests, including pulmonary hypertension,⁵ heart failure, COVID-19, immune dysregulation, and clinical research

Dr. Jala has interest research in understanding the role of Gut microbiota and Microbial Metabolites in regulating inflammation and gut barrier function in gastro-intestinal related disorders.

Dr. Kirpich’s long-standing research interest is in understanding the molecular mechanisms of alcohol-associated liver disease development and progression, identifying new biomarkers of the disease and novel therapeutic targets. 

Dr. Kouokam’s lab studies how chromium induces inflammation to cause lung cancer and seeks to identifies nutraceuticals that could prevent chromium-induced toxicity.¹⁰

Dr. LeBlanc has an extensive research background in cardiovascular physiology, focusing most exclusively on myocardial perfusion and reactivity in models of both aging and sex-specific cardiology. Her lab is developing cell-based therapies designed to improve the function of the microcirculation and involved in advancing an adipose-derived tissue engineering technology to the preclinical phase.”¹¹

Dr. McClain is a widely recognized expert in alcohol-related liver injury/disease, nutrition, and cytokine research; his laboratory currently focuses on nutrition and the gut:liver axis as it relates to alcohol-associated liver disease and alcohol use disorder.¹²

Dr. Neal's research of interest consist of fetal basis of adult disease, adverse health effects of maternal smoking/vaping, health effects of gut microbiome.

Dr. O’Toole’s lab group is interested in determining how environmental contaminants, such as fine air borne particulate matter (PM2.5) and microplastics, impact health outcomes in humans, with a particular interest in cardiovascular health.¹³

Dr. Sansbury’swork is focused on understanding the mechanisms by which inflammation is actively resolved and the roles of specific immune cell populations in this process. He is particularly interested in studying how the resolution of inflammation becomes dysregulated during cardiovascular disease and as a result of exposure to environmental pollution.¹⁴

Dr. Smith’s research focuses on developing novel experimental and analytic methods to identify and characterize the impact of genomic variation on immune repertoires, viral evolution, and response to infections, vaccination, and immunotherapies.¹⁵

Dr. Wahlang’s research interest includes sex differences in liver diseases associated with environmental chemical exposures and existing knowledge gaps.¹⁶

Dr. Waston's research interest consists of oxidative stress and redox signaling, alcoholic liver disease, role of environmental agents in nonalcoholic fatty liver disease.

Dr. Wintergerst’s primary research interests involve work in type 1 and type 2 diabetes mellitus, including the study of advanced technology, therapeutics, and environmental and social factors influencing disease and health outcomes.

Dr. Johnny Wise, Jr.'s research interest is in the relationship between aging and toxicology, focusing on the impacts of heavy metals on the brain.

Dr. John Pierce Wise, Sr. conducts basic and translation research studying how environmental chemicals transform normal cells into tumor cells focusing on chromosomes and how chemicals alter the number and structure of chromosomes leading to chromosome instability and cancer. Research projects in the laboratory include understanding DNA damage, DNA repair, mitosis, centrosome biology, cell-cell communication, chromatin folding, the fourth dimensional genome; all in a one environmental health context.

Dr. Sandra Wise's research interests include how environmental chemicals, such as hexavalent chromium, depleted uranium and other metals, can transform normal cells into cancer cells. These studies have focused on DNA repair deficiency and its impact on chromosome instability as a driving mechanism to cellular transformation and the development of disease. Currently, she is pursuing how cells exposed to these chemicals induce DNA and chromosomal damage yet are able to survive and evade the normal cell death pathways that should occur in order to protect the organism from disease.

Dr. Jamie Young Wise’s research seeks to develop insight into how environmental toxicants (i.e., heavy metals and PFAS) affect health and cause disease, focusing on environmental liver disease (ELD). Her research considers impact of life-style factors (i.e., diet) and sex and age as biological risk factors in disease initiation and severity, with the goal of providing a platform for the creation of novel target therapies and diagnostic tools.¹⁷

Dr. Zelko’s research focuses on the systemic effects of inhaled pollutants as well as the local pulmonary inflammatory processes that generate and release significant quantities of free radicals. The central theme of Dr. Zelko's research is how these free radicals cause pulmonary and cardiovascular injury, predisposing affected individuals to chronic and acute diseases.¹⁸ 

Dr. Zhang’s laboratory is investigating the mechanisms underlying metal nanoparticle-related lung injury, inflammation, fibrosis, and cancer.¹⁹

References Cited

1. Banerjee M, Yaddanapudi K, States JC: Zinc supplementation prevents mitotic accumulation in human keratinocyte cell lines upon environmentally relevant arsenic exposure. Toxicol Appl Pharmacol 2022, 454:116255.
2. Tan Y, Zhang Z, Zheng C, Wintergerst KA, Keller BB, Cai L: Mechanisms of diabetic cardiomyopathy and potential therapeutic strategies: preclinical and clinical evidence. Nat Rev Cardiol 2020, 17:585-607.
3. Carll AP, Arab C, Salatini R, Miles MD, Nystoriak MA, Fulghum KL, Riggs DW, Shirk GA, Theis WS, Talebi N, Bhatnagar A, Conklin DJ: E-cigarettes and their lone constituents induce cardiac arrhythmia and conduction defects in mice. Nat Commun 2022, 13:6088.
4. Chen SY, Kannan M: Neural crest cells and fetal alcohol spectrum disorders: Mechanisms and potential targets for prevention. Pharmacol Res 2023, 194:106855.
5. Conklin DJ, Haberzettl P, MacKinlay KG, Murphy D, Jin L, Yuan F, Srivastava S, Bhatnagar A: Aldose Reductase (AR) Mediates and Perivascular Adipose Tissue (PVAT) Modulates Endothelial Dysfunction of Short-Term High-Fat Diet Feeding in Mice. Metabolites 2023, 13.
6. Gordon EA, Corbitt C: Investigation of pre-pubertal sex differences in wheel running and social behavior in three mouse strains. J Ethol 2015, 33:177-87.
7. Haberzettl P, Conklin DJ, Abplanalp WT, Bhatnagar A, O'Toole TE: Inhalation of Fine Particulate Matter Impairs Endothelial Progenitor Cell Function Via Pulmonary Oxidative Stress. Arterioscler Thromb Vasc Biol 2018, 38:131-42.
8. He L, Wei X, Ma X, Yin X, Song M, Donninger H, Yaddanapudi K, McClain CJ, Zhang X: Simultaneous Quantification of Nucleosides and Nucleotides from Biological Samples. J Am Soc Mass Spectrom 2019, 30:987-1000.
9. Zheng Y, Gibb AA, Xu H, Liu S, Hill BG: The metabolic state of the heart regulates mitochondrial supercomplex abundance in mice. Redox Biol 2023, 63:102740.
10.  Kouokam JC, Meaza I, Wise JP Sr. Inflammatory effects of hexavalent chromium in the lung: A comprehensive review. Toxicol Appl Pharmacol. 2022 Nov 15;455:116265. doi: 10.1016/j.taap.2022.116265. Epub 2022 Oct 5. PMID: 36208701; PMCID: PMC10024459.
11. Tracy EP, Dukes M, Rowe G, Beare JE, Nair R, LeBlanc AJ. Stromal Vascular Fraction Restores Vasodilatory Function by Reducing Oxidative Stress in Aging-Induced Coronary Microvascular Disease. Antioxid Redox Signal. 2023 Feb;38(4-6):261-281. doi: 10.1089/ars.2021.0249. Epub 2022 Sep 28. PubMed PMID: 35950616; PubMed Central PMCID: PMC9968627
12. Vatsalya V, Feng W, Kong M, Hu H, Szabo G, McCullough A, Dasarathy S, Nagy LE, Radaeva S, Barton B, Mitchell M, McClain CJ. The Beneficial Effects of Lactobacillus GG Therapy on Liver and Drinking Assessments in Patients with Moderate Alcohol-Associated Hepatitis. Am J Gastroenterol. 2023 Apr 11. doi: 10.14309/ajg.0000000000002283. PMID: 37040544
13. Polystyrene bead ingestion promotes adiposity and cardiometabolic disease in mice. Ecotoxicology and Environmental Safety 2022, 232: 113239 (O'Toole)
14. Sansbury BE, Li X, Wong B, Patsalos A, Giannakis N, Zhang MJ, Nagy L, Spite M. Myeloid ALX/FPR2 regulates vascularization following tissue injury. 2020. Proc Natl Acad Sci U S A. 117:14354-14364. PMCID: PMC7321964.
15. Rodriguez OL, Safonova Y, Silver CA, Shields K, Gibson WS, Kos JT, Tieri D, Ke H, Jackson KJL, Boyd SD, Smith ML, Marasco WA, Watson CT. Genetic variation in the immunoglobulin heavy chain locus shapes the human antibody repertoire. Nat Commun. 2023 Jul 21;14(1):4419. doi: 10.1038/s41467-023-40070-x. PMID: 37479682
16. Wahlang B. RISING STARS: Sex differences in toxicant-associated fatty liver disease. J Endocrinol. 2023 Jun 16;258(1):e220247. doi: 10.1530/JOE-22-0247. PMID: 37074385; PMCID: PMC10330380.
17. Bolatimi, OE., Head, KZ., Luo, J., Gripshover, TC., Lin, Q., Adiele, NV., Watson, WH., Wilkerson, C., Cai, L., Cave, MC., & Young, JL (2023). Can Zinc Supplementation Attenuate High Fat Diet-Induced Non-Alcoholic Fatty Liver Disease?. International journal of molecular sciences, 24(2), 1763. https://doi.org/10.3390/ijms24021763
18. Zelko I.N., Dassanayaka S., Malovichko M.V., Howard C.M., Garrett L.F., Uchida S., Brittian K.R., Conklin D.J., Jones S.P. and Srivastava S. Chronic benzene exposure aggravates pressure overload-induced cardiac dysfunction. Toxicological Sciences, 185(1): p64-76, 2021, PMID: 34718823
19. Mo Y, Zhang Y, Zhang Y, Yuan J, Mo L, Zhang Q. Nickel nanoparticle-induced cell transformation: involvement of DNA damage and DNA repair defect through HIF-1α/miR-210/Rad52 pathway. J Nanobiotechnology. 2021 Nov 17;19(1):370. doi: 10.1186/s12951-021-01117-7.