Abstract Body (Do not enter title and authors here): Introduction: Upper body irradiation (UBI) is a clinically relevant modality for thoracic cancer treatment. Ionizing radiation (IR)-induced pathophysiological effects are directly correlated with the radiation dose, with past studies indicating distinct patterns of radiosensitivity between male and female patients. Although chronic cardiopulmonary complications constitute a dose-limiting toxicity in thoracic cancer treatments, the underlying mechanisms involving mitochondrial oxidative phosphorylation (OXPHOS) dysfunction and sex-related response heterogeneity remain understudied.
Hypothesis: Sex-specific chronic differences in overall survival are mediated through mitochondrial OXPHOS impairment in cardiac and pulmonary tissues.
Approach: 10-12 week-old C57BL/6J male and female mice were exposed to 10 and 12Gy UBI using an Xstrahl Small Animal Radiation Research Platform (SARRP) and followed for 9 months. Animals were treated with the superoxide dismutase (SOD) mimic, GC4761 at 10mg/kg or placebo starting the day of UBI, daily for a week following UBI, and once weekly thereafter until euthanasia. Pulmonary function using whole-body plethysmography was assessed at baseline, 3, 6, and 9 months. Overall survival was assessed using Kaplan-Meier curves. Heart weight (HW), lung weight (LW), body weight (BW), and histology were assessed at euthanasia. Cardiac and lung tissues were assessed for differences in OXPHOS activities using biochemical assays.
Results: Our investigations revealed three fundamental findings: (1) Female mice treated with 10Gy UBI demonstrate increased mortality compared to their male counterparts. (2) Comprehensive pulmonary assessment via whole-body plethysmography demonstrates profound respiratory dysfunction 6 months following 12Gy UBI accompanied by profound differences in mitochondrial electron transport chain dysregulation. (3) Treatment with GC4761 significantly improves overall survival in both male (p=0.05) (n=5/group) and female (p=0.008) (n=7/group) mice following 12Gy UBI, indicating broad-spectrum radioprotective efficacy.
Conclusion(s): These findings establish sex-specific UBI-induced differences in radiosensitivity and identify mitochondrial OXPHOS complexes as a mechanism underlying chronic radiation pneumonitis. The efficacy of GC4761 supports the role of oxidative stress as a critical molecular target for radiation countermeasure development, with significant translational implications for thoracic radiotherapy outcomes.