Abstract 1660: JP4-039/F14 treatment of E13 pregnant mice 24 hours after total body irradiation (TBI) improves survival, growth and development of fetal mice

Abstract

Abstract Purpose: A practical radiation mitigator must be safe in pregnant females. Irradiation during pregnancy can induce fetal death, stunt growth, and/or lead to teratogenic and carcinogenic effects dependent on stage of gestation. We evaluated the mitochondrial targeted GS-nitroxide mitigator JP4-039 for effects on total body irradiated (TBI) pregnant mice. Methods: Timed pregnant C57Bl/6NHsd mice at E13 were irradiated to 3 Gy, subgroups were injected IV 24 hr later (E14) with JP4-039 in F14 emulsion (4 ug JP4-039 in 100 ul of F14). Mice were followed for number of pups born, weight of pups at day 5 after birth, and for number of survivors at time of weaning. In other studies of irradiation effects, new- born pups, on the day of delivery, were euthanized, fixed, sectioned and examined microscopically. Results: Nonirradiated mice showed 97 ± 2% of newborn surviving until weaning. Pups born to 3 Gy irradiated E13 pregnant mice had decreased survival (8.3 ± 8.7%) (p < 0.0001). Control nonirradiated pregnant mice receiving JP4-039/F14 or F14 alone showed no effect on pup survival (85 ± 10% at weaning) (p = 0.1453). The survival of pups from 3 Gy irradiated E13 pregnant mice that received JP4-039/F14 24 hr after irradiation was significantly decreased (45 ± 16.4% compared to nonirradiated controls (p = 0.0230). All newborn pups were weighed at 5 days after birth: those surviving 3 Gy in utero had significantly decreased weight of 1.64 ± 0.04 g compared to 2.73 ± 0.08 g for nonirradiated controls (p < 0.0001). In contrast, while the 3 Gy TBI E13 irradiated pups from mothers that received JP4-039/F14 showed no significant weight change compared to control nonirradiated pups (2.44 ± 0.15 and 2.73 ± 0.08, respectively, p = 0.0799). Their weight was significantly increased compared to the 3 Gy irradiated group (2.44 ± 0.15 and 1.64 ± 0.04 g, respectively, p = 0.0433). Pups from nonirradiated mothers that were administered JP4-039/F14 had a significantly increased weight on day 5 compared to nonirradiated mice (3.32 ± 0.10 and 2.73 ± 0.08 g, respectively, p < 0.0001). Microscopic examination of irradiated pups dying at day of birth, revealed: 1) increased number of hematopoietic precursors in liver and decreased glycogen stores in the hepatocytes; 2)adrenal glands were enlarged and contain severely hypertrophied cortical cells; 3) brain, showed necrosis and loss of parenchyma within the intermediate zone of white matter and cell debris in the lateral ventricles. These changes were not observed in pups from JP4-039/F14 treated mothers, sacrificed on the day of birth. Conclusions: Treatment of total body irradiated E13 pregnant mice at E14 with JP4-039/F14 was safe and effective as a radiation mitigator, led to increased numbers of surviving newborns, improved growth and development, and after weaning over 21 days, and increased body weight with no late deaths. Supported by NIAID/NIH U19-AI068021 Citation Format: Michael W. Epperly, Lora Rigatti, Tracy Dixon, Song Li, Joel S. Greenberger. JP4-039/F14 treatment of E13 pregnant mice 24 hours after total body irradiation (TBI) improves survival, growth and development of fetal mice. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1660.