Female Mice are More Resistant to the Mixed-Field (67% Neutron + 33% Gamma) Radiation-Induced Injury in Bone Marrow and Small Intestine than Male Mice due to Sustained Increases in G-CSF and the Bcl-2/Bax Ratio and Lower miR-34a and MAPK Activation.
Female Mice are More Resistant to the Mixed-Field (67% Neutron + 33% Gamma) Radiation-Induced Injury in Bone Marrow and Small Intestine than Male Mice due to Sustained Increases in G-CSF and the Bcl-2/Bax Ratio and Lower miR-34a and MAPK Activation.
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DOI：
10.1667/rade-21-00201.1
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发表时间：
2022-08-01
影响因子：
3.4
通讯作者：
Xiao, Mang
中科院分区：
文献类型：
--
作者：
Kiang, Juliann G.;Cannon, Georgetta;Olson, Matthew G.;Smith, Joan T.;Anderson, Marsha N.;Zhai, Min;Umali, M. Victoria;Ho, Kevin;Ho, Connie;Cui, Wanchang;Xiao, Mang
在核和放射性事件中，过度暴露于电离辐射会危及生命。显然，辐射会消耗血细胞并增加循环细胞因子/趋化因子浓度以及死亡率。虽然已观察到雌性小鼠的小胶质细胞比雄性小鼠的小胶质细胞受到辐射的损伤较少，但尚不清楚性别是否会影响骨髓（BM）和胃肠系统（GI）的生理病理反应。我们将 B6D2F1 雄性和雌性小鼠暴露于 0、1.5、3 或 6 Gy 的混合场辐射，其中含有 67% 中子和 33% 伽马射线，剂量率为 0.6 Gy/min。辐射后第 1、4 和 7 天收集血液和组织。辐射以剂量依赖性方式增加雌性和雄性小鼠股骨和回肠中的细胞因子/趋化因子。细胞因子和趋化因子在第 4 天达到峰值，并在第 7 天下降，但 G-CSF 除外，在雌性小鼠中，G-CSF 在第 7 天继续增加，但在雄性小鼠中则没有。在胸骨、股骨中测量 MiR-34a（一种 Bcl-2 抑制剂）、G-CSF（一种 miR-34a 抑制剂）、MAPK 激活（促细胞死亡）和瓜氨酸（上皮内增殖的生物标志物）、活性 caspase-3（细胞凋亡的生物标志物）和 caspase-1 激活的gasdermin D（细胞焦亡生物标志物） BM 和回肠。 H&E 染色、股骨 BM 细胞计数以及 Flt-3L 的胸骨组织病理学分析表明，女性的 BM 细胞结构并未减少，而男性在照射后第 7 天显示出 50% 的下降，主要由细胞焦亡介导，如股骨 BM 样本中 Gasdermin D 的增加所示。回肠损伤，如绒毛高度和隐窝深度，也分别为 43% 和 30%，女性受损程度低于男性。两性损伤的严重程度与瓜氨酸和活性 caspase-3 测量值以及活性 caspase-1 和gasdermin D 测量值一致，表明发生了细胞凋亡和细胞焦亡。第7天，雌性小鼠回肠中的G-CSF继续升高七倍，而雄性小鼠回肠中的G-CSF恢复到基线。此外，已知 G-CSF 可以抑制 miR-34a 的表达，在混合场（67% 中子 + 33% γ）照射后，第 1 天雌性小鼠回肠中的 miR-34a 表达增加了 3 至 4 倍，而雄性小鼠中则增加了 5 至 9 倍。此外，miR-34a 阻断 Bcl-2 表达。混合场（60% 中子 + 33% 伽马）辐射在女性中诱导出比男性更多的 Bcl-2。第 7 天，在雌性和雄性的回肠中发现 AKT 激活。然而，女性回肠中包括 ERK、JNK 和 p38 在内的 MAPK 激活没有变化（0 倍；P > 0.05），而男性回肠中 MAPK 激活增加（100 倍；P < 0.05）。总而言之，结果表明，混合场（67% 中子 + 33% 伽马）辐射造成的器官损伤在女性中比男性要轻，这可能是由于 G-CSF 增加、MAPK 激活减少、miR-34a 低和 Bcl-2/Bax 比率增加所致。
In nuclear and radiological incidents, overexposure to ionizing radiation is life-threatening. It is evident that radiation depletes blood cells and increases circulating cytokine/chemokine concentrations as well as mortality. While microglia cells of female mice have been observed to be less damaged by radiation than in male mice, it is unclear whether sex affects physio-pathological responses in the bone marrow (BM) and gastrointestinal system (GI). We exposed B6D2F1 male and female mice to 0, 1.5, 3, or 6 Gy with mixed-field radiation containing 67% neutron and 33% gamma at a dose rate of 0.6 Gy/min. Blood and tissues were collected on days 1, 4, and 7 postirradiation. Radiation increased cytokines/chemokines in the femurs and ilea of female and male mice in a dose-dependent manner. Cytokines and chemokines reached a peak on day 4 and declined on day 7 with the exception of G-CSF which continued to increase on day 7 in female mice but not in male mice. MiR-34a (a Bcl-2 inhibitor), G-CSF (a miR-34a inhibitor), MAPK activation (pro-cell death), and citrulline (a biomarker of entroepithelial proliferation), active caspase-3 (a biomarker of apoptosis) and caspase-1 activated gasdermin D (a pyroptosis biomarker) were measured in the sternum, femur BM and ileum. Sternum histopathology analysis with H&E staining and femur BM cell counts as well as Flt-3L showed that BM cellularity was not as diminished in females, with males showing a 50% greater decline on day 7 postirradiation, mainly mediated by pyroptosis as indicated by increased gasdermin D in femur BM samples. Ileum injury, such as villus height and crypt depth, was also 43% and 30%, respectively, less damaged in females than in males. The severity of injury in both sexes was consistent with the citrulline and active caspase-3 measurements as well as active caspase-1 and gasdermin D measurements, suggesting apoptosis and pyroptosis occurred. On day 7, G-CSF in the ileum of female mice continued to be elevated by sevenfold, whereas G-CSF in the ileum of male mice returned to baseline. Furthermore, G-CSF is known to inhibit miR-34a expression, which in ileum on day 1 displayed a 3- to 4-fold increase in female mice after mixed-field (67% neutron + 33% gamma) irradiation, as compared to a 5- to 9-fold increase in male mice. Moreover, miR-34a blocked Bcl-2 expression. Mixed-field (60% neutron + 33% gamma) radiation induced more Bcl-2 in females than in males. On day 7, AKT activation was found in the ileums of females and males. However, MAPK activation including ERK, JNK, and p38 showed no changes in the ileum of females (by 0-fold; P > 0.05), whereas the MAPK activation was increased in the ileum of males (by 100-fold; P < 0.05). Taken together, the results suggest that organ injury from mixed-field (67% neutron + 33% gamma) radiation is less severe in females than in males, likely due to increased G-CSF, less MAPK activation, low miR-34a and increased Bcl-2/Bax ratio.
影响因子：
3.7
作者：
Li XH;Ha CT;Fu D;Xiao M
通讯作者：
Xiao M