Sex differences in a mouse model of radiation-induced cardiomyopathy

Abstract Background Radiation-induced heart disease (RIHD) may develop months to years following radiation therapy for cancers near the heart such as lung or breast cancer. Several mouse models of RIHD exist to study the pathogenesis of disease, but to our knowledge no studies have examined whether sex differences exist in RIHD in mice. Methods Female and male BALB/cJ mice received a single whole-heart dose of 22 Gy (Gy) radiation via a C5 collimator vs. sham controls that received 0 Gy, anesthesia and were placed in the X-ray machine for the same length of time. Endpoints were examined at 24 h (innate), day 10 (acute) and day 35 (chronic) post irradiation. Results Females and males developed dsDNA breaks from radiation at day 10 but females had more damage than males ( p < 0.001). Vessel area and wall thickness were increased by radiation at day 10 and 35 but vessel area was greater in irradiated males than females at day 35 ( p = 0.003). Bulk RNA sequencing of the heart at day 10 revealed that females and males developed similar gene pathway responses to radiation by upregulating cellular repair pathways and developing mitochondrial dysfunction. However, females upregulated the master regulator of mitochondrial function, Pgc1α ( p = 0.0001), suggesting possible improved mitochondrial repair in females. By day 35, females developed mild cardiomyopathy while males developed myocardial and perivascular fibrosis and inflammatory dilated cardiomyopathy (iDCM). Conclusions We observed sex differences in most cardiac parameters that we examined following radiation exposure. BALB/c males exposed to 22 Gy radiation developed iDCM by day 35 while females developed mild cardiomyopathy. Further research is needed to better understand mechanisms driving sex differences in RIHD using translational animal models.