Abstract 266: Sex Differences in Anthracycline-Induced Cardiotoxicity in Young Mice

Abstract

Introduction: The role of sex as a risk factor for Anthracycline-Induced Cardiotoxicity (AIC) is not well defined. In pediatric cancer patients, most studies report that female sex is a significant risk factor for AIC. Conversely, in adult preclinical rodent studies, there is clear evidence that female sex is protective against AIC, with a possible protective role of female sex hormones and/or a detrimental role of male sex hormones. However, sex differences in AIC have not been reported in young experimental animals. Therefore, the current work aims to characterize sex differences in AIC in young male and female mice. Methods: Five-week old male and female C57Bl/6 mice were injected with doxorubicin (DOX) 4 mg/kg/week IP for 3 to 6 weeks. After a 5-week recovery period, a cohort of control and DOX-treated mice were administered daily IP injections of isoproterenol (10 mg/kg) for 14 days to determine the effect of catecholamine stress on cardiac function and morphometry in DOX-exposed mice. Another cohort of gonadectomized and sham-operated male and female mice were injected with DOX 4 mg/kg/week for 5 weeks. Cardiac function and morphometry were measured by trans-thoracic echocardiography 5 weeks after the last DOX injection and after 14 days of isoproterenol injections. Results: In male mice only, DOX 4 mg/kg/week for 3 to 5 weeks caused cardiac atrophy without decline in cardiac function, whereas DOX administration for 6 weeks caused cardiac atrophy and dysfunction. Female mice were protected from both cardiac atrophy and dysfunction at the 3-6 weeks regimens. Isoproterenol caused cardiac dysfunction in male and female control and DOX-treated mice. Male, but not female, DOX-exposed mice failed to develop cardiac hypertrophy when challenged by isoproterenol. Intriguingly, castration of male mice exacerbated DOX-induced cardiac atrophy, while ovariectomy had no significant effect. Conclusion: In contrast to most clinical studies, young female mice are protected against DOX-induced cardiac atrophy and dysfunction. Juvenile exposure to DOX modulated the cardiac response to isoproterenol in a sex-dependent manner. Deprivation of sex hormones by gonadectomy did not reverse this sexual dimorphism, suggesting that other mechanisms are implicated.