ABSTRACT
Acute, high-dose radiation exposure results in life-threatening acute radiation syndrome (ARS) and debilitating delayed effects of acute radiation exposure (DEARE). The DEARE are a set of chronic multi-organ illnesses that can result in early death due to malignancy and other diseases. Animal models have proven essential in understanding the natural history of ARS and DEARE and licensure of medical countermeasures (MCM) according to the FDA Animal Rule. Our lab has developed models of hematopoietic (H)-ARS and DEARE in inbred C57BL/6J and Jackson Diversity Outbred (JDO) mice of both sexes and various ages and have used these models to identify mechanisms of radiation damage and effective MCMs. Herein, aggregate data from studies conducted over decades in our lab, consisting of 3,250 total-body lethally irradiated C57BL/6 young adult mice and 1,188 H-ARS survivors from these studies, along with smaller datasets in C57BL/6J pediatric and geriatric mice and JDO mice, were examined for lifespan and development of thymic lymphoma in survivors up to 3 years of age. Lifespan was found to be significantly shortened in H-ARS survivors compared to age-matched nonirradiated controls in all four models. Males and females exhibited similar lifespans except in the young adult C57BL/6J model where males survived longer than females after 16 months of age. The incidence of thymic lymphoma was increased in H-ARS survivors from the young adult and pediatric C57BL/6J models. Consistent with our findings in H-ARS, geriatric mice appeared more radioresistant than other models, with a lifespan and thymic lymphoma incidence more similar to nonirradiated controls than other models. Increased levels of multiple pro-inflammatory cytokines in DEARE bone marrow and serum correlated with shortened lifespan and malignancy, consistent with other animal models and human data. Of interest, G-CSF levels in bone marrow and serum 8-11 months after irradiation were significantly increased in females. Importantly, treatment with granulopoietic cytokine MCM for radiomitigation of H-ARS did not influence the long-term survival rate or incidence of thymic lymphoma in any model. Taken together, these findings indicate that the lifespan of H-ARS survivors was significantly decreased regardless of age at time of exposure or genetic diversity, and was unaffected by earlier treatment with granulopoietic cytokines for radiomitigation of H-ARS.
ABSTRACT
INTRODUCTION: Longitudinal effect of diet-induced obesity on bone is uncertain. Prior work showed both no effect and a decrement in bone density or quality when obesity begins prior to skeletal maturity. We aimed to quantify long-term effects of obesity on bone and bone marrow adipose tissue (BMAT) in adulthood. METHODS: Skeletally mature, female C57BL/6 mice (n = 70) aged 12 weeks were randomly allocated to low-fat diet (LFD; 10% kcal fat; n = 30) or high-fat diet (HFD; 60% kcal fat; n = 30), with analyses at 12, 15, 18, and 24 weeks (n = 10/group). Tibial microarchitecture was analyzed by µCT, and volumetric BMAT was quantified via 9.4T MRI/advanced image analysis. Histomorphometry of adipocytes and osteoclasts, and qPCR were performed. RESULTS: Body weight and visceral white adipose tissue accumulated in response to HFD started in adulthood. Trabecular bone parameters declined with advancing experimental age. BV/TV declined 22% in LFD (p = 0.0001) and 17% in HFD (p = 0.0022) by 24 weeks. HFD failed to appreciably alter BV/TV and had negligible impact on other microarchitecture parameters. Both dietary intervention and age accounted for variance in BMAT, with regional differences: distal femoral BMAT was more responsive to diet, while proximal femoral BMAT was more attenuated by age. BMAT increased 60% in the distal metaphysis in HFD at 18 and 24 weeks (p = 0.0011). BMAT in the proximal femoral diaphysis, unchanged by diet, decreased 45% due to age (p = 0.0002). Marrow adipocyte size via histomorphometry supported MRI quantification. Osteoclast number did not differ between groups. Tibial qPCR showed attenuation of some adipose, metabolism, and bone genes. A regulator of fatty acid ß-oxidation, cytochrome C (CYCS), was 500% more abundant in HFD bone (p < 0.0001; diet effect). CYCS also increased due to age, but to a lesser extent. HFD mildly increased OCN, TRAP, and SOST. CONCLUSIONS: Long-term high fat feeding after skeletal maturity, despite upregulation of visceral adiposity, body weight, and BMAT, failed to attenuate bone microarchitecture. In adulthood, we found aging to be a more potent regulator of microarchitecture than diet-induced obesity.