Age and Sex Divergence in Hematopoietic Radiosensitivity in Aged Mouse Models of the Hematopoietic Acute Radiation Syndrome.
Journal
Radiation research
ISSN: 1938-5404
Titre abrégé: Radiat Res
Pays: United States
ID NLM: 0401245
Informations de publication
Date de publication:
01 09 2022
01 09 2022
Historique:
received:
17
04
2022
accepted:
11
06
2022
pubmed:
15
7
2022
medline:
11
9
2022
entrez:
14
7
2022
Statut:
ppublish
Résumé
The hematopoietic system is highly sensitive to stress from both aging and radiation exposure, and the hematopoietic acute radiation syndrome (H-ARS) should be modeled in the geriatric context separately from young for development of age-appropriate medical countermeasures (MCMs). Here we developed aging murine H-ARS models, defining radiation dose response relationships (DRRs) in 12-month-old middle-aged and 24-month-old geriatric male and female C57BL/6J mice, and characterized diverse factors affecting geriatric MCM testing. Groups of approximately 20 mice were exposed to ∼10 different doses of radiation to establish radiation DRRs for estimation of the LD50/30. Radioresistance increased with age and diverged dramatically between sexes. The LD50/30 in young adult mice averaged 853 cGy and was similar between sexes, but increased in middle age to 1,005 cGy in males and 920 cGy in females, with further sex divergence in geriatric mice to 1,008 cGy in males but 842 cGy in females. Correspondingly, neutrophils, platelets, and functional hematopoietic progenitor cells were all increased with age and rebounded faster after irradiation. These effects were higher in aged males, and neutrophil dysfunction was observed in aged females. Upstream of blood production, hematopoietic stem cell (HSC) markers associated with age and myeloid bias (CD61 and CD150) were higher in geriatric males vs. females, and sex-divergent gene signatures were found in HSCs relating to cholesterol metabolism, interferon signaling, and GIMAP family members. Fluid intake per gram body weight decreased with age in males, and decreased after irradiation in all mice. Geriatric mice of substrain C57BL/6JN sourced from the National Institute on Aging were significantly more radiosensitive than C57BL/6J mice from Jackson Labs aged at our institution, indicating mouse source and substrain should be considered in geriatric radiation studies. This work highlights the importance of sex, vendor, and other considerations in studies relating to hematopoiesis and aging, identifies novel sex-specific functional and molecular changes in aging hematopoietic cells at steady state and after irradiation, and presents well-characterized aging mouse models poised for MCM efficacy testing for treatment of acute radiation effects in the elderly.
Identifiants
pubmed: 35834823
pii: 483832
doi: 10.1667/RADE-22-00071.1
pmc: PMC9512046
mid: NIHMS1835263
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
221-242Subventions
Organisme : NIA NIH HHS
ID : R01 AG046246
Pays : United States
Organisme : NIAID NIH HHS
ID : UH2 AI128894
Pays : United States
Organisme : NIAID NIH HHS
ID : HHSN272201000046C
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA082709
Pays : United States
Organisme : NIAID NIH HHS
ID : U01 AI107340
Pays : United States
Organisme : NIAID NIH HHS
ID : UH3 AI128894
Pays : United States
Informations de copyright
©2022 by Radiation Research Society. All rights of reproduction in any form reserved.
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