NZO/HlLtJ as a novel model for the studies on the role of metabolic syndrome in acute radiation toxicity

Abstract

Purpose: Growing rates of metabolic syndrome and associated obesity warrant the development of appropriate animal models for better understanding of how those conditions may affect sensitivity to IR exposure.

Materials and methods: We subjected male NZO/HlLtJ mice, a strain prone to spontaneous obesity and diabetes, to 0, 5.5, 6.37, 7.4 or 8.5 Gy (¹³⁷Cs) of total body irradiation (TBI). Mice were monitored for 30 days, after which proximal jejunum and colon tissues were collected for further histological and molecular analysis.

Results: Obese NZO/HlLtJ male mice are characterized by their lower sensitivity to IR at doses of 6.37 Gy and under, compared to other strains. Further escalation of the dose, however, results in a steep survival curve, reaching LD_100/30 values at a dose of 8.5 Gy. Alterations in the expression of various tight junction-related proteins coupled with activation of inflammatory responses and cell death were the main contributors to the gastrointestinal syndrome.

Conclusions: We demonstrate that metabolic syndrome with exhibited hyperglycemia but without alterations to the microvasculature is not a pre-requisite of the increased sensitivity to TBI at high doses. Our studies indicate the potential of NZO/HlLtJ mice for the studies on the role of metabolic syndrome in acute radiation toxicity.

Keywords:

• Acute radiation gastrointestinal injury
• glucose metabolism
• metabolic syndrome
• obesity
• tight junction-related proteins

Acknowledgments

IK would like to acknowledge the guidance provided during preparation of this manuscript made possible via R25CA203650 (Yale University, PI: Melinda Irwin). We are thankful to Dr. Christine Simecka, Robin Mulkey and Bridget Engi for excellent animal care, and to Christopher Fettes for editing this manuscript.

Ethical statement

All animal experiments were approved by the UAMS IACUC.

Disclosure statement

The authors have no conflicts of interest to disclose.

Notes on contributors

The focus of Igor’s research is to understand: 1) epigenetic and metabolic mechanisms of the normal and cancer tissue responses to radiation, and how the diet can modulate those responses; and 2) safety, efficacy and mechanisms of action of dietary supplements. He has published over 80 peer-reviewed articles and book chapters. Igor’s research has received uninterrupted extramural funding since the beginning of his independent career. Dr. Koturbash is a recipient of numerous prestigious awards and honors, including the Michael Fry Award from the Radiation Research Society and an Award for Faculty Excellence in Research from UAMS. Igor is a current President of the South-Central Chapter of the Society of Toxicology, and serves as an Associate Editor for Radiation Research and an Editorial Board Member for Chemico-Biological Interactions.

Additional information

Funding

This work was supported by National Institutes of Health [1P20GM109005], the Arkansas Biosciences Institute, and National Institute of General Medical Sciences [T32GM106999].

Notes on contributors

Laura E. Ewing

Laura E. Ewing, MS is a PhD candidate at the University of Arkansas for Medical Sciences in the Department of Pharmacology and Toxicology. Her dissertation research is on the interaction effects of dietary methionine and the microbiome on radiation-induced gastrointestinal injury.

Isabelle R. Miousse

Isabelle Miousse, PhD is an Assistant Professor in Biochemistry and Molecular Biology at the University of Arkansas for Medical Sciences. She received her Ph.D in Human Genetics from McGill University in Canada. She specializes in one-carbon metabolism and her work focuses on the role of methyl donors in cancer epigenetics.

Rupak Pathak

Rupak Pathak, PhD investigates the mechanisms of radiation-induced normal tissue toxicity and how the damage can be attenuated or suppressed following radiotherapy or accidental overexposure to ionizing radiation using in vitro and in vivo models. His research interest also includes the effects of space factors, such as space radiation and microgravity, on tissue toxicity and also to develop a medical countermeasure.

Charles M. Skinner

Charles Skinner, BS is a Research Associate for the Environmental and Occupational Health Division of the College of Public Health at the University of Arkansas for Medical Sciences. He received his Bachelor’s degree in biology from the University of Arkansas at Little Rock, and he also has a degree in the field of Bio Medical Technology which he received from UAMS. He is currently the lab manager for a research laboratory at UAMS. The laboratory mainly focuses on the effects of dietary methionine and the microbiome on radiation-induced gastrointestinal injuries. Other areas of focus include the testing of dietary supplements and their effects on animals and humans.

Stanley Kosanke

Stanley Kosanke, DVM, PhD, DAVCP, DACLAM received his DVM degree from Oklahoma State University in 1970 and PhD from Texas A&M University in 1975. He is board-certified in both veterinary pathology, by the ACVP, and laboratory animal medicine, by ACLAM. Dr. Kosanke has over 43 years of experience as a comparative veterinary pathologist, mostly while employed at the Oklahoma University Health Sciences Center for 40 of those years. His expertise is mainly in the areas of spontaneous and experimentally-induced disease conditions in both domestic and laboratory animals. He has over 100 publications mostly related to chemical- induced and transgenic carcinogenesis, septic and hemorrhagic shock, organ transplantation, rheumatic fever, and chemical and radiation-induced toxicity.

Marjan Boerma

Marjan Boerma, PhD is a radiation biologist at the University of Arkansas for Medical Sciences, Division of Radiation Health with a particular research interest in the effects of ionizing radiation on the cardiovascular system.

Martin Hauer-Jensen

Martin Hauer-Jensen, MD, PhD, FACS is recognized as an authority on radiation effects in normal tissues. His research is focused on determining mechanisms of injury and developing strategies to prevent side effects after radiation therapy in cancer patients, on medical countermeasures for radiological emergencies, and on studies of space radiation. His research has been recognized with the prestigious MERIT Award from the National Cancer Institute (NCI). Dr. Hauer-Jensen serves on numerous national and international advisory boards, review panels, and editorial boards. He has been Chair of the Radiation Study Section of the National Institutes of Health (NIH), a consultant on radiological emergencies to the World Health Organization (WHO), a council member of the National Council on Radiation Protection and Measurements (NCRP), and President of the Radiation Research Society (RRS).

Igor Koturbash

Igor Koturbash, MD, PHD is an Associate Professor at the Department of Environmental and Occupational Health, University of Arkansas for Medical Sciences (Little Rock, AR). He received his M.D. from the State Medical University in Ivano-Frankivsk, Ukraine (2001), and his Ph.D. in Biomolecular Sciences from the University of Lethbridge, Canada (2008). Dr. Koturbash completed his training as an Oak Ridge Institute for Science and Education Research (ORISE) Fellow at the National Center for Toxicological Research, US Food and Drug Administration in Jefferson, AR.