NZO/HlLtJ as a novel model for the studies on the role of metabolic syndrome in acute radiation toxicity

<b>Purpose:</b> Growing rates of metabolic syndrome and associated obesity warrant the development of appropriate animal models for better understanding of how those conditions may affect sensitivity to IR exposure. <b>Materials and methods:</b> We subjected male NZO/HlLtJ mice, a strain prone to spontaneous obesity and diabetes, to 0, 5.5, 6.37, 7.4 or 8.5 Gy (¹³⁷Cs) of total body irradiation (TBI). Mice were monitored for 30 days, after which proximal jejunum and colon tissues were collected for further histological and molecular analysis. <b>Results:</b> Obese NZO/HlLtJ male mice are characterized by their lower sensitivity to IR at doses of 6.37 Gy and under, compared to other strains. Further escalation of the dose, however, results in a steep survival curve, reaching LD_100/30 values at a dose of 8.5 Gy. Alterations in the expression of various tight junction-related proteins coupled with activation of inflammatory responses and cell death were the main contributors to the gastrointestinal syndrome. <b>Conclusions:</b> We demonstrate that metabolic syndrome with exhibited hyperglycemia but without alterations to the microvasculature is not a pre-requisite of the increased sensitivity to TBI at high doses. Our studies indicate the potential of NZO/HlLtJ mice for the studies on the role of metabolic syndrome in acute radiation toxicity.

研究目的：代谢综合征（metabolic syndrome）及其伴随肥胖的发病率持续走高，亟需建立合适的动物模型，以深入阐释此类病症如何影响机体对电离辐射（ionizing radiation, IR）暴露的敏感性。
材料与方法：选取易自发肥胖与罹患糖尿病的雄性NZO/HlLtJ小鼠，给予0、5.5、6.37、7.4或8.5 Gy的¹³⁷Cs源全身照射（Total Body Irradiation, TBI）。对小鼠开展为期30天的监测，随后采集近端空肠与结肠组织，用于后续组织学及分子生物学分析。
研究结果：相较于其他品系小鼠，肥胖雄性NZO/HlLtJ小鼠在6.37 Gy及更低剂量下，对电离辐射的敏感性更低。然而，当剂量进一步升高时，小鼠生存率曲线呈现陡降趋势，在8.5 Gy剂量下达到LD₁₀₀/₃₀水平。多种紧密连接（tight junction）相关蛋白的表达异常，伴随炎症应答激活与细胞死亡，是引发胃肠综合征的核心诱因。
研究结论：本研究证实，仅表现为高血糖而无微血管系统异常的代谢综合征，并非高剂量全身照射敏感性升高的必要前置条件。本研究表明，NZO/HlLtJ小鼠可用于探究代谢综合征在急性辐射毒性中的作用。