Impairment of IGF-1 Signaling and Antioxidant Response Are Associated with Radiation Sensitivity and Mortality.

Saeed Y Aghdam,Gregory P Holmes-Hampton,Doreswamy Kenchegowda,Sanchita P Ghosh,Maria Moroni

doi:10.3390/ijms22010451

Abstract

Following exposure to high doses of ionizing radiation, diverse strains of vertebrate species will manifest varying levels of radiation sensitivity. To understand the inter-strain cellular and molecular mechanisms of radiation sensitivity, two mouse strains with varying radiosensitivity (C3H/HeN, and CD2F1), were exposed to total body irradiation (TBI). Since Insulin-like Growth Factor-1 (IGF-1) signaling pathway is associated with radiosensitivity, we investigated the link between systemic or tissue-specific IGF-1 signaling and radiosensitivity. Adult male C3H/HeN and CD2F1 mice were irradiated using gamma photons at Lethal Dose-70/30 (LD70/30), 7.8 and 9.35 Gy doses, respectively. Those mice that survived up to 30 days post-irradiation, were termed the survivors. Mice that were euthanized prior to 30 days post-irradiation due to deteriorated health were termed decedents. The analysis of non-irradiated and irradiated survivor and decedent mice showed that inter-strain radiosensitivity and post-irradiation survival outcomes are associated with activation status of tissue and systemic IGF-1 signaling, nuclear factor erythroid 2–related factor 2 (Nrf2) activation, and the gene expression profile of cardiac mitochondrial energy metabolism pathways. Our findings link radiosensitivity with dysregulation of IGF-1 signaling, and highlight the role of antioxidant gene response and mitochondrial function in radiation sensitivity.

Highlights

Acute exposure to ionizing radiation originating from nuclear accidents or malevolent and terror-related use of the radioactive material could compromise the survival of individuals primarily via hematopoietic system impairment
According to our previous in vivo findings obtained from comparison of two radiosensitive and radioresistant minipigs strains, the quality and efficiency of cardiac Insulin-like Growth Factor-1 (IGF-1) signaling is tightly associated with total body radiation (TBI) resistance and post-irradiation survival outcomes [13,16], an observation showing consistency with cardioprotective effects of IGF-1 signaling
Given the established role of IGF-1 signaling in radiation sensitivity [31], in the current report we explored the possibility of whether the link between tissue IGF-1 signaling and radiation sensitivity could be extrapolated to other animal models and if the quality and maintenance of normal IGF-1 signaling in tissues other than heart would show similarities to heart tissue

Summary

Introduction

Acute exposure to ionizing radiation originating from nuclear accidents or malevolent and terror-related use of the radioactive material could compromise the survival of individuals primarily via hematopoietic system impairment. The depletion of the hematopoietic stem cells (HSCs) and reduced hematopoiesis results in the Hematopoietic Acute Radiation Syndrome (H-ARS), which is the primary cause of death following exposure to relatively moderate to higher doses of ionizing radiation. It is very likely that the effects of the ionizing radiation on organs other than the hematopoietic system could potentially explain the differential radiosensitivity between strains of the same vertebrate species. This claim is supported by the comparison between different animal strains within the same species that manifest differences in radiosensitivity, but possess similar profiles of hematopoietic elements before and following irradiation exposure in the recovery phase [2,3]

Methods

Results

Conclusion