Protection From Radiation-Induced Neuroanatomic Deficits by CCL2 Deficiency Is Dependent on Sex

Purpose Cranial radiation therapy for the treatment of pediatric brain tumors results in changes to brain development that are detectable with magnetic resonance imaging. We have previously demonstrated similar structural changes in both humans and mice. The goal of the current study was to examine the role of inflammation in this response. Because neuroanatomic volume deficits in pediatric survivors are more pronounced in female patients, we also evaluated possible dependence on sex. Methods and Materials Other studies have shown that male mice deficient in the C-C chemokine ligand 2 gene (Ccl2; previously Mcp-1) have a muted neuroinflammatory response after irradiation. We irradiated Ccl2-/- (HOM; female = 12, male = 13), Ccl2–/+ (HET; female = 13, male = 16), and Ccl2+/+ (WT; female = 11, male = 13) mice with a whole brain dose of 7 Gy during infancy. Control mice (with approximately equal group sizes) were anesthetized but not irradiated. In vivo magnetic resonance images were acquired at 4 time points up to 3 months after irradiation, and deformation-based morphometry was used to identify volume differences. Results Irradiation of WT mice resulted in a deficit in neuroanatomic growth with limited sex dependence. HOM and HET male mice were significantly protected from this radiation-induced damage, whereas HOM and HET female mice were not. Conclusions Interventions aimed at mitigating the effects of cranial radiation therapy in pediatric cancer survivors by modulating inflammatory response will need to consider patient sex. Cranial radiation therapy for the treatment of pediatric brain tumors results in changes to brain development that are detectable with magnetic resonance imaging. We have previously demonstrated similar structural changes in both humans and mice. The goal of the current study was to examine the role of inflammation in this response. Because neuroanatomic volume deficits in pediatric survivors are more pronounced in female patients, we also evaluated possible dependence on sex. Other studies have shown that male mice deficient in the C-C chemokine ligand 2 gene (Ccl2; previously Mcp-1) have a muted neuroinflammatory response after irradiation. We irradiated Ccl2-/- (HOM; female = 12, male = 13), Ccl2–/+ (HET; female = 13, male = 16), and Ccl2+/+ (WT; female = 11, male = 13) mice with a whole brain dose of 7 Gy during infancy. Control mice (with approximately equal group sizes) were anesthetized but not irradiated. In vivo magnetic resonance images were acquired at 4 time points up to 3 months after irradiation, and deformation-based morphometry was used to identify volume differences. Irradiation of WT mice resulted in a deficit in neuroanatomic growth with limited sex dependence. HOM and HET male mice were significantly protected from this radiation-induced damage, whereas HOM and HET female mice were not. Interventions aimed at mitigating the effects of cranial radiation therapy in pediatric cancer survivors by modulating inflammatory response will need to consider patient sex.