中国组织工程研究

中国组织工程研究 ›› 2026, Vol. 30 ›› Issue (11): 2752-2763.doi: 10.12307/2026.099

• 组织构建实验造模 experimental modeling in tissue construction • 上一篇    下一篇

孕期低剂量六氟环氧丙烷二聚酸暴露对子代小鼠肾脏毒性的影响机制

洪润洋1，周琦玥1，范臻成1，时语婕1，陈 昊1，2，潘  春1，2
  

  1. 1扬州大学医学院-转化医学研究院，江苏省扬州市   225000；2江苏省非编码 RNA基础与临床转化重点实验室，江苏省扬州市   225000
  • 收稿日期:2025-05-06 接受日期:2025-06-05 出版日期:2026-04-18 发布日期:2025-09-05
  • 通讯作者: 潘春，博士，讲师，扬州大学医学院-转化医学研究院，江苏省扬州市 225000；江苏省非编码 RNA基础与临床转化重点实验室，江苏省扬州市 225000 共同通讯作者：陈昊，博士，教授，博士生导师，扬州大学医学院-转化医学研究院，江苏省扬州市 225000；江苏省非编码 RNA基础与临床转化重点实验室，江苏省扬州市 225000
  • 作者简介:洪润洋，男，2003 年生，江苏省盐城市人，汉族，主要从事环境毒理学方面的研究。
  • 基金资助:
    国家自然科学基金项目(32301416)，项目负责人：潘春；扬州市绿扬金凤计划项目(YZLVJFJH2022YXBS154)，项目负责人：潘春；国家自然科学基金项目(82172468，82372436)，项目负责人：陈昊；2024年扬州大学创新创业学院大学生创新创业训练计划项目(C202411117002Y)，项目负责人：周琦玥

Impact and mechanism of low-dose hexafluoropropylene oxide dimer acid exposure during pregnancy on renal toxicity in offspring mice

Hong Runyang1, Zhou Qiyue1, Fan Zhencheng1, Shi Yujie1, Chen Hao1, 2, Pan Chun1, 2   

  1. 1Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou 225000, Jiangsu Province, China; 2Jiangsu Key Lab of Non-Coding RNA Basic and Clinical Translational Research, Yangzhou 225000, Jiangsu Province, China
  • Received:2025-05-06 Accepted:2025-06-05 Online:2026-04-18 Published:2025-09-05
  • Contact: Pan Chun, PhD, Lecturer, Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou 225000, Jiangsu Province, China; Jiangsu Key Lab of Non-Coding RNA Basic and Clinical Translational Research, Yangzhou 225000, Jiangsu Province, China Co-corresponding author: Chen Hao, PhD, Professor, Doctoral supervisor, Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou 225000, Jiangsu Province, China; Jiangsu Key Lab of Non-Coding RNA Basic and Clinical Translational Research, Yangzhou 225000, Jiangsu Province, China
  • About author:Hong Runyang, Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou 225000, Jiangsu Province, China
  • Supported by:
    National Natural Science Foundation of China, Nos. 32301416 (to PC), 82172468 and 82372436 (both to CH); the Yangzhou Lyu Yang Jin Feng Program, No. YZLVJFJH2022YXBS154 (to PC); the 2024 Innovation and Entrepreneurship Training Program for College Students of Innovation and Entrepreneurship School of Yangzhou University, No. C202411117002Y (to ZQY) 

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摘要：


文题释义：
六氟环氧丙烷二聚酸：为经典的短链多氟烷基物质，从2009年开始作为全氟辛酸的新型替代物被广泛使用在涂料、油墨、抗氧剂及电镀技术领域。多项研究表明，六氟环氧丙烷二聚酸具有多器官毒性，存在极大的健康隐患。
肾脏纤维化：肾脏组织中细胞外基质的过度沉积和异常增生导致肾脏结构和功能受损的一种病理过程。肾脏纤维化是多种慢性肾脏疾病的共同病理特征，最终可能导致肾功能衰竭。

背景：六氟环氧丙烷二聚酸作为全氟辛酸的新型替代物被广泛使用在涂料、油墨及抗氧剂等领域，但六氟环氧丙烷二聚酸具有多器官毒性，并且六氟环氧丙烷二聚酸暴露可引起大鼠血尿素氮水平升高、肾脏病理损伤。
目的：探究孕期低剂量六氟环氧丙烷二聚酸暴露对子代小鼠肾脏的毒性影响及机制。
方法：①动物实验：选用性成熟的8周龄雌性BALB/c小鼠，与雄性小鼠交配见阴道栓后随机分2组干预，对照组(n=6)给予ddH2O灌胃，六氟环氧丙烷二聚酸组(n=6)给予六氟环氧丙烷二聚酸2 mg/(kg·d)灌胃，直至子代小鼠出生。收集两组3周龄和8周龄雌性、雄性子代小鼠肾脏组织，苏木精-伊红染色和Masson染色检测肾脏病理结构和纤维化情况，免疫组化染色检测肾脏组织炎症因子(肿瘤坏死因子α、白细胞介素6)表达，β-半乳糖苷酶染色检测肾脏衰老情况，钙黏蛋白E、波形蛋白免疫荧光染色检测肾脏上皮间质转化情况，免疫荧光染色检测转化生长因子β1表达。②细胞实验：将肾小管上皮细胞HK-2分3组处理：对照组不进行任何处理，六氟环氧丙烷二聚酸组加入600 μmol/L六氟环氧丙烷二聚酸处理72 h，六氟环氧丙烷二聚酸+雷帕霉素组加入10 nmol/L雷帕霉素预处理1 h后加入600 μmol/L六氟环氧丙烷二聚酸处理72 h，取培养上清备用。将肾脏成纤维细胞NRK-49F分3组处理，分别加入上述3组培养上清处理48 h，免疫荧光染色检测成纤维细胞活化标志物α-平滑肌肌动蛋白和纤连蛋白表达。

结果与结论：①动物实验：孕期低剂量六氟环氧丙烷二聚酸暴露可导致雌性、雄性子代小鼠肾脏结构损伤与组织纤维化，引发雌性、雄性子代小鼠肾脏组织炎症反应与肾脏衰老，诱导雌性、雄性子代小鼠肾脏组织上皮间充质转化的发生，提高雌性、雄性子代小鼠肾脏内转化生长因子β1表达；②细胞实验：免疫荧光染色显示，六氟环氧丙烷二聚酸处理后的HK-2细胞培养上清显著增加NRK-49F细胞α-平滑肌肌动蛋白和纤连蛋白表达，但该作用可被衰老抑制剂雷帕霉素抑制；③结果表明，孕期六氟环氧丙烷二聚酸暴露对子代小鼠肾脏具有毒副作用，引起肾脏炎症和纤维化的发生，主要通过加速肾小管上皮细胞衰老、促进肾上皮细胞间质转化、促进成纤维细胞增殖活化最终导致肾纤维化的发生。

https://orcid.org/0009-0000-9861-2184 (洪润洋) 

中国组织工程研究杂志出版内容重点：干细胞；骨髓干细胞；造血干细胞；脂肪干细胞；肿瘤干细胞；胚胎干细胞；脐带脐血干细胞；干细胞诱导；干细胞分化；组织工程

关键词: 六氟环氧丙烷二聚酸, 肾纤维化, 衰老, 上皮间充质转化, 肾脏毒性, 子代小鼠

Abstract: BACKGROUND: Hexafluoropropylene oxide dimer acid (also known as GenX) is widely used as a novel substitute for perfluorooctanoic acid in coatings, inks, antioxidants, and other fields. However, GenX exhibits multi-organ toxicity, and exposure to GenX can lead to elevated blood urea nitrogen levels and renal pathological damage in rats. 
OBJECTIVE: To investigate the toxic effects and mechanism of low-dose GenX exposure during pregnancy on the kidney of offspring mice.
METHODS: (1) Animal experiment: Sexually mature 8-week-old female BALB/c mice were randomly divided into normal control group and GenX group after mating with male mice and showing vaginal plug, with six mice in each group. The control group was gavaged with ddH2O, while the GenX group was gavaged with GenX (2 mg/kg/d) until birth. Kidney tissues of male and female offspring mice were collected at 3 and 8 weeks after birth. Hematoxylin-eosin staining and Masson staining were used to explore the effects of GenX on the pathological structure and fibrosis of the kidney in offspring mice of different sexes. Immunohistochemical staining was used to detect the expression of inflammatory factors (tumor necrosis factor α and interleukin 6) in renal tissues. β-galactosidase staining was used to detect renal aging. Immunofluorescence staining of calcineurin E and vimentin expression was used to detect renal epithelial-mesenchymal transition, and immunofluorescence staining was used to detect transforming growth factor β1 expression. (2) Cell experiment: Renal tubular epithelial cells HK-2 were divided into three groups: control group with no treatment, GenX group treated with 600 μmol/L GenX for 72 hours, and GenX+rapamycin group with 10 nmol/L rapamycin pretreatment for 1 hour followed by addition of 600 μmol/L GenX for 72 hours. Cell supernatant was taken for use in the following experiment. Kidney fibroblasts NRK-49F were treated in three groups, and the culture supernatants of the above three groups were added and treated for 48 hours. Immunofluorescence staining was performed to detect the expression of fibroblast activation markers α-smooth muscle actin and fibronectin.
RESULTS AND CONCLUSION: (1) Animal experiment: Exposure to low-dose GenX during pregnancy could cause structural damage and tissue fibrosis in the kidneys of female and male offspring mice, trigger inflammatory responses and renal senescence in female and male offspring mice, induce the development of epithelial-mesenchymal transition in the kidneys of female and male offspring mice, and increase the expression of transforming growth factor β1 in the kidneys of female and male offspring mice. (2) Cell experiment: Immunofluorescence staining showed that hexafluoropropylene oxide dimer acid-treated HK-2 cell culture supernatants significantly increased α-smooth muscle actin and fibronectin expression in NRK-49F cells, but this effect was inhibited by the senescence inhibitor rapamycin. To conclude, GenX exposure during pregnancy is toxic to the kidneys of offspring mice, causing the development of renal inflammation and fibrosis, mainly through accelerating the senescence of renal tubular epithelial cells, promoting epithelial-mesenchymal transition, and promoting the proliferation and activation of fibroblasts, and ultimately leading to the development of renal fibrosis.

Key words: GenX, renal fibrosis, aging, epithelial-mesenchymal transition, renal toxicity, offspring mice

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