High-LET Radiation Induces Less Injury in the bone marrow of Female Mice than in Male Mice due to Increasing IL-2 and SAA, Maintaining CD27, and Lowering the miR-34a-Regulated Pyroptosis in Female Mice

High-LET radiation induces less injury in the bone marrow of female mice than in male mice due to increasing IL-2 and SAA, maintaining CD27, and lowering the miR-34a-regulated pyroptosisin female mice RESULTS MATERIALS & METHDS INTRODUCTION ExposurePreviousreportshaveindicatedthatmixed-field(neutron+gamma)irradiationcausessignificantlyincreasedmortality,decreasedsurvivaltimeandlatencyinacuteradiationsyndrome(ARS),andevendelayedhealingofinjuries(woundand/orburn)sufferedincombinationwithradiation[LedneyandElliott2010]comparedwithpurephotonirradiation.Asmechanismsofinjurybylow-LETradiationaredifferentfromthoseofhigh-LETradiation,thismayaffectdoseassessmentandcountermeasureefficacy[MacVittieetal.1991;Ledneyetal.1991and2000;Caryetal.2012].High-LETincreasesC-reactiveprotein(CRP),complementcomponent3(C3),IgMandPGE2incirculation[KiangandLedney,2013].Moreover,reductionofbloodcellcountsandincreasesincirculatingIL-18,G-CSFandGM-CSFafterhigh-LET[Ossetrovaetal.,2018a]aregreaterthanthatobservedafterlow-LET[Ossetrovaetal.,2018b;Kiangetal.,2018].In2018,SusannaRosiandhercolleagues[Krukowskietal.,2018]investigatedforthefirsttimehowcombinedgalacticcosmicradiation(GCR)exposureimpactslong-termbehavioralandcellularresponsesinmaleandfemalemousebrains.TheyfoundthatasingleexposuretosimulatedGCRinducedlong-termcognitiveandbehavioraldeficitsinmalecohorts,includingdiminishedsocialinteraction,increasedanxiety-likephenotypeandimpairedrecognitionmemory.Remarkably,femalecohortsdidnotdisplayanycognitiveorbehavioraldeficitsafterGCRexposure.Theirresultsidentifiedsex-dependentdifferencesinbehavioralandcognitivedomains.Inconcordancewiththesefindings,ourpreviousreports[Kiangetal.,2022]observedthathigh-LETradiationinducedhigherlevelsofmiR-34ainmaleileumcomparedtofemaleileum.Moreover,histologicalexaminationsofsternumsandileumsalongwithassessmentsoftheirtissuecitrullinelevels(biomarkerforentero-epithelialcellproliferation)suggestedorganinjurytobemoresevereinmalesthanfemales.Inthisreport,weinvestigatedbiomo
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Overexposure to ionizing radiation (IR) is life-threatening in nuclear and radiological incidents. IR depletes blood cell sand increases circulating cytokine/chemokine concentrations as well as mortality. It is reported that microglia cells of female mice are less damaged than those in male mice by IR. We have reported that the GI of female mice is more resistant to IR than the GI of male mice mediated by increases in G-CSF which down-regulate the IR-induced elevation of miR-34a and Bax, leading to decreases in both caspase 3-dependent apoptosis and caspase 1-dependent pyroptosis. It is unclear whether sex varied physiopathological responses in bone marrow (BM) and/or how it happened. We exposed B6D2F1 male and female mice to 0,1.5,3,or 6 Gy with radiation containing 67% neutrons and 33% gamma at 0.6 Gy/min. Blood, sternums and femurs were collected on days 1, 4,and 7. On day 7, IR increased adipocytes and depleted BM cells and megakaryocytes in a radiation dose-dependent manner. However, females exhibited less damage in sternum BM histology than males, which was also confirmed with Flt-3 lig and measurements. IR increased cytokines/chemokines in femurs of females and males in a dose-dependent manner, Cytokines and chemokines generally peaked on day 4 and declined on day 7 in femoral BM cells of both males and females. However, IL-2 (a promoter of T reg cells) increased on days 1 and 4 and returned to the baseline on day 7 in females but decreased on days 4 and 7 in males. IR persistently increased serum amyloid A (SAA) and maintained CD 27 (for Ig production) from day 1 to day 7 in females, where as IR decreased both on day 7 in males. MiR-34a is known to trigger gasderm in D-mediated pyroptosis viacaspase-1 activation. IR significantly increased mi R-34a, caspase-1 activation and gasderm in D activation in males but did little in females, suggesting the presence of pyroptosis in males but not females. No apoptosis was found with BM. The results indicate that BM in