縮水甘油 (Glycidol) 是在植物油精製的除臭過程中產生的污染物。已知 Glycidol具有基因毒性會誘導 DNA 損傷，目前被 IARC 歸類為 2A 級致癌物。在本研究室先前進行的體內試驗觀察到 Glycidol 會造成小鼠的腎小管細胞退化，並在體外試驗發現Glycidol 會誘導 NRK-52E 大鼠腎小管上皮細胞進行程序性細胞死亡，包含自噬作用(Autophagy)、細胞焦亡 (Pyroptosis)、鐵依賴性死亡 (Ferroptosis) 和壞死性凋亡(Necroptosis)，但Glycidol 誘導 DNA 損傷與腎毒性的機制目前還不清楚。本研究的目的是進行體內及體外試驗，探討 Glycidol 誘導 DNA 損傷和粒線體自噬作用導致腎毒性的機制。本研究使用 C57BL/6 小鼠經口給予 Glycidol (1、5、10、15、20、25、50 mg/kg) 進行 28 天亞急毒性試驗，檢測血清和尿液中的肝臟及腎臟損傷指標，並收取腎臟和 其他器官從組織病理學評估損傷程度，以及由尿液代謝體學分析和腸道菌次世代定序 來推測可能的路徑。於回復性試驗使用 MIOX 基因轉殖小鼠，以第一型馬兜鈴酸 (Aristolochic acid I) 作為陽性控制組和 Glycidol (25、50、100 mg/kg) 連續 28 天後停止暴露，繼續放置 28 天後犧牲，於實驗期間每週測定尿液中腎臟損傷指標和冷光蛋白表現量，以即時觀察Glycidol 造成的腎臟損傷是否於停止暴露後可回復，並於犧牲後從組織病理學評估腎臟損傷程度及由尿液代謝體學分析路徑變化。此外，本研究使用 NRK-52E 細胞探討其腎毒性機制，使用微核和彗星試驗測定其基因毒性，並檢測細胞週期停滯區間、粒線體功能和動態平衡及程序性細胞死亡路徑。在體內試驗方面，從 28 天亞急毒性試驗觀察到 Glycidol 於每日餵食 10 mg/kg 的劑量即可對腎臟造成損傷，在回復性試驗中則發現 Glycidol 造成的腎臟損傷於停止暴露後具有部分回復性。在體外試驗方面，我們證實 Glycidol 具有基因毒性造成 DNA 受損，提升 γ-H2AX 和p-ATM 表現，進而抑制 CDK1/Cyclin B 表達使細胞週期停滯於 G2/M 期，並且藉由Drp1 表達上升、Mfn1 表達下降使粒線體動態失衡趨向於分裂狀態，伴隨著 ROS 增加、膜電位下降，最終走向粒線體自體吞噬、細胞焦亡之程序性細胞死亡。

In this research, we focused on the genotoxicity and renal toxicity induced by glycidol in 28-day repeated dose exposure, the reversibility, and the underlying mechanisms leading to kidney injury. We used C57BL/6 mice in a 28-day sub-acute toxicity study, analyzing the biochemistry values of liver and renal function, and evaluating the degree of kidney injury from histopathology. In the reversibility study, MIOX gene transgenic mice were used. We collected the urine and analyzed the biochemistry values of renal function and nanoLuc luciferase expression every week to monitor the reversibility of glycidol. In addition, we used NRK-52E as the cell model to investigate the mechanisms of DNA damage, cell cycle arrest, mitochondrial dysfunction, and programmed cell death induced by glycidol. In the
present study, we observed that exposure to 10 mg/kg glycidol for 28 days could induce kidney injury. However, the injury could be reversed after stopping exposure. We revealed that the renal toxicity may be initiated from the sensing of γ-H2AX and p-ATM to the DNA damage, subsequently inhibited CDK1/cyclin B expression and arrested cell cycle in the G2/M phase. The mitochondrial dynamics were imbalanced due to the up-regulation of Drp1 and down-regulation of Mfn1, accompanied by ROS production and decreased mitochondrial membrane potential. Eventually, glycidol induced programmed cell death including mitophagy and pyroptosis, leading to renal toxicity.

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