乙醛脱氢酶ALDH2基因敲除对雄性小鼠发育的影响

doi:10.3969/j.issn.1000-1565.2023.05.008

摘要/Abstract

摘要： 为了研究乙醛脱氢酶ALDH2基因敲除对雄性小鼠发育的影响,将不同周龄ALDH2基因敲除的雄性小鼠,通过分析其肝、肾、睾丸脏器质量分数,组织细胞形态,组织抗氧化能力,总产仔数等指标,探讨ALDH2基因敲除对雄性小鼠的影响.结果表明:7、10周龄敲除型(KO)小鼠肝细胞索排列紊乱,10周龄时,多核肝细胞数量明显增多,且肝细胞中黑色沉积物增加;7、10周龄KO小鼠肾脏出现明显的间质水肿;7、10周龄KO小鼠睾丸生精管内晚期精细胞和精子排序紊乱,腔内有脱落的生精细胞,睾丸组织出现纤维化;10周龄KO小鼠肝脏、肾脏总抗氧化能力和3、5周龄KO小鼠睾丸组织总抗氧化能力显著低于野生型(WT)小鼠;KO组小鼠产仔总数显著少于WT小鼠.综上,ALDH2敲除导致小鼠肝脏、肾脏和睾丸组织抗氧化损伤的能力降低,造成其细胞氧化损伤,进而影响雄性小鼠的生育力.该研究结果说明ALDH2基因敲除会引发雄性小鼠组织器官发育异常,进而影响小鼠的个体发育.

关键词: 乙醛脱氢酶2, 肝脏, 肾脏, 睾丸, 组织抗氧化, 生育力

Abstract: In order to study the effects of ALDH2 gene knockout on the development of male mice, the effects of ALDH2 gene knockout on male mice were studied by analyzing the organ mass fraction of liver, kidney and testis, histomorphology, tissue antioxidant capacity and total litter size of mice at different weeks of age. The results showed that the cords of hepatocytes of Knockout type(KO)mice at 7 and 10 weeks of age were disordered. At 10 weeks of age, the number of multinucleated hepatocytes, and the black deposits in hepatocytes increased significantly. The kidneys of KO mice at 7 and 10 weeks of age showed obvious interstitial edema. In 7 and 10 weeks of aged mice, the sequence of late spermatogenic cells and spermatogenic cells in testicular seminiferous tubules were disordered. The total antioxidant capacity of liver and kidney in 10 weeks of age KO mice and the total antioxidant capacity of testis in 3 and 5 weeks of age KO mice were significantly lower than that of wild-type(WT)mice. The total number of pups in KO group was significantly less than that of WT mice. In conclusion, ALDH2 knockout can reduce the ability of anti-oxidative damage in liver, kidney and testis tissue of mice, result in cell damage, and affect the fertility of male mice in turn.The results showed that ALDH2 gene knockout would cause- DOI:10.3969/j.issn.1000-1565.2023.05.008乙醛脱氢酶ALDH2基因敲除对雄性小鼠发育的影响徐文秀,刘庆玲,刘笑含,孔令英,石慧,赵振军(烟台大学生命科学学院,山东烟台 264003)摘要:为了研究乙醛脱氢酶ALDH2基因敲除对雄性小鼠发育的影响,将不同周龄ALDH2基因敲除的雄性小鼠,通过分析其肝、肾、睾丸脏器质量分数,组织细胞形态,组织抗氧化能力,总产仔数等指标,探讨ALDH2基因敲除对雄性小鼠的影响.结果表明:7、10周龄敲除型(KO)小鼠肝细胞索排列紊乱,10周龄时,多核肝细胞数量明显增多,且肝细胞中黑色沉积物增加;7、10周龄KO小鼠肾脏出现明显的间质水肿;7、10周龄KO小鼠睾丸生精管内晚期精细胞和精子排序紊乱,腔内有脱落的生精细胞,睾丸组织出现纤维化;10周龄KO小鼠肝脏、肾脏总抗氧化能力和3、5周龄KO小鼠睾丸组织总抗氧化能力显著低于野生型(WT)小鼠;KO组小鼠产仔总数显著少于WT小鼠.综上,ALDH2敲除导致小鼠肝脏、肾脏和睾丸组织抗氧化损伤的能力降低,造成其细胞氧化损伤,进而影响雄性小鼠的生育力.该研究结果说明ALDH2基因敲除会引发雄性小鼠组织器官发育异常,进而影响小鼠的个体发育.关键词:乙醛脱氢酶2;肝脏;肾脏;睾丸;组织抗氧化;生育力中图分类号:Q954.6 文献标志码:A 文章编号:1000-1565(2023)05-0500-06Effects of ALDH2 gene knockout on the development of male miceXU Wenxiu,LIU Qingling,LIU Xiaohan,KONG Lingying,SHI Hui,ZHAO Zhenjun(School of Life Sciences,Yantai University,Yantai 264003,China)Abstract: In order to study the effects of ALDH2 gene knockout on the development of male mice, the effects of ALDH2 gene knockout on male mice were studied by analyzing the organ mass fraction of liver, kidney and testis, histomorphology, tissue antioxidant capacity and total litter size of mice at different weeks of age. The results showed that the cords of hepatocytes of Knockout type(KO)mice at 7 and 10 weeks of age were disordered. At 10 weeks of age, the number of multinucleated hepatocytes, and the black deposits in hepatocytes increased significantly. The kidneys of KO mice at 7 and 10 weeks of age showed obvious interstitial edema. In 7 and 10 weeks of aged mice, the sequence of late spermatogenic cells and spermatogenic cells in testicular seminiferous tubules were disordered. The total antioxidant capacity of liver and kidney in 10 weeks of age KO mice and the total antioxidant capacity of testis in 3 and 5 weeks of age KO mice were significantly lower than that of wild-type(WT)mice. The total number of pups in KO group was significantly less than that of WT mice. In conclusion, ALDH2 knockout can reduce the ability of anti-oxidative damage in liver, kidney and testis tissue of mice, result in cell damage, and affect the fertility of male mice in turn.The results showed that ALDH2 gene knockout would cause- 收稿日期:2022-10-20 基金项目:国家重点研发计划(2018YFC1003600) 第一作者:徐文秀(1996—),女,山东临沂人,烟台大学在读硕士研究生,主要从事雄性小鼠生殖发育研究.E-mail:xwx5935@163.com 通信作者:赵振军(1976—),男,山东烟台人,烟台大学副教授,博士,主要从事小鼠生殖发育研究. E-mail:zhaozhenjun@ytu.edu.cn第5期徐文秀等:乙醛脱氢酶ALDH2基因敲除对雄性小鼠发育的影响abnormal development of tissues and organs in male mice, and then affect the individual development of mice.

Key words: aldehyde dehydrogenase 2, liver, kidney, teste, tissue oxidation resistance, fertility

中图分类号:

Q954.6

徐文秀,刘庆玲,刘笑含,孔令英,石慧,赵振军. 乙醛脱氢酶ALDH2基因敲除对雄性小鼠发育的影响[J]. 河北大学学报(自然科学版), 2023, 43(5): 500-505.

XU Wenxiu,LIU Qingling,LIU Xiaohan,KONG Lingying,SHI Hui,ZHAO Zhenjun. Effects of ALDH2 gene knockout on the development of male mice[J]. Journal of Hebei University(Natural Science Edition), 2023, 43(5): 500-505.

参考文献

[1] ZHANG H,FU L. The role of ALDH2 in tumorigenesis and tumor progression: Targeting ALDH2 as a potential cancer treatment [J]. Acta Pharm Sin B, 2021, 11(6): 1400-1411. DOI: 10.1016/j.apsb.2021.02.008.
[2] HEYMANN H M, GARDNER A M, GROSS E R. Aldehyde-induced DNA and protein adducts as biomarker tools for alcohol use disorder[J]. Trends Mol Med,2018, 24(2): 144-155. DOI: 10.1016/j.molmed.2017.12.003.
[3] WANG C, FAN F, CAO Q, et al. Mitochondrial aldehyde dehydrogenase 2 deficiency aggravates energy metabolism disturbance and diastolic dysfunction in diabetic mice[J]. J Mol Med(Berl),2016, 94(11): 1229-1240. DOI: 10.1007/s00109-016-1449-5.
[4] ZHANG Y, WANG C, ZHOU J, et al. Complex inhibition of autophagy by mitochondrial aldehyde dehydrogenase shortens lifespan and exacerbates cardiac aging[J]. Biochim Biophys Acta Mol Basis Dis, 2017, 1863(8): 1919-1932. DOI: 10.1016/j.bbadis.2017.03.016.
[5] D’SOUZA Y, EIHARRAM A, SOON-SHIONG R, et al.Bennett BM Characterization of Aldh2^(-/-) mice as an age-related model of cognitive impairment and Alzheimer’s disease[J]. Mol Brain,2015, 8: 27.DOI: 10.1186/s13041-015-0117-y.
[6] WANG B, WANG J, ZHOU S, et al. The association of mitochondrial aldehyde dehydrogenase gene(ALDH2)polymorphism with susceptibility to late-onset Alzheimer’s disease in Chinese[J]. Neurol Sci, 2008, 268(1/2): 172-175.DOI: 10.1016/j.jns.2007.12.006.
[7] WANG S, WANG C, TURDI S,et al. ALDH2 protects against high fat diet-induced obesity cardiomyopathy and defective autophagy: role of CaM kinase II, histone H3K9 methyltransferase SUV39H, Sirt1, and PGC-1a deacetylation[J]. Int J Obes(Lond), 2018, 42(5): 1073-1087.DOI: 10.1038/s41366-018-0030-4.
[8] HOSHI H, HAO W, FUJITA Y,et al. Aldehyde-stress resulting from Aldh2 mutation promotes osteoporosis due to impaired osteoblastogenesis[J]. Bone Miner Res, 2012, 27(9): 2015-2023.DOI: 10.1002/jbmr.1634.
[9] KOYANAGI Y N, SUZUKI E, IMOTO I, et al. Across-site differences in the mechanism of alcohol-induced digestive tract carcinogenesis: an evaluation by mediation analysis[J]. Cancer Res, 2020, 80(7): 1601-1012. DOI: 10.1158/0008-5472.CAN-19-2685.
[10] YU C, GUO Y, BIAN Z,et al. Association of low-activity ALDH2 and alcohol consumption with risk of esophageal cancer in Chinese adults: a population-based cohort study[J]. Int J Cancer, 2018, 143(7): 1652-1661.DOI: 10.1002/ijc.31566.
[11] HIDAKA A, SASAZUKI S, MATSUO K, et al. Genetic polymorphisms of ADH1B, ADH1C and ALDH2, alcohol consumption, and the risk of gastric cancer: the Japan Public Health Center-based prospective study[J]. Carcinogenesis, 2015, 36(2): 223-231.DOI: 10.1093/carcin/bgu244.
[12] ISHIOKA K, MASAOKA H, ITO H, et al. Association between ALDH2 and ADH1B polymorphisms, alcohol drinking and gastric cancer: a replication and mediation analysis[J]. Gastric Cancer, 2018, 21(6): 936-945.DOI: 10.1007/s10120-018-0823-0.
[13] SEO W, GAO Y, HE Y, et al. ALDH2 deficiency promotes alcohol-associated liver cancer by activating oncogenic pathways via oxidized DNA-enriched extracellular vesicles[J]. J Hepatol, 2019, 71(5): 1000-1011.DOI: 10.1016/j.jhep.2019.06.018.
[14] XU F, CHEN Y, LV R, et al. ALDH2 genetic polymorphism and the risk of type II diabetes mellitus in CAD patients[J]. Hypertens Res, 2010, 33(1): 49-55.DOI: 10.1038/hr.2009.178.
[15] 李响,蒲连美,阮杨,等.汉族人群ADIPOR1 rs753942与冠状动脉粥样硬化性心脏病和2型糖尿病的关联分析[J].首都医科大学学报,2020,41(6):935-942. DOI: 10.3969/j.issn.1006-7795.2020.06.012.
[16] PATIL S S,HERNÁNDEZ-CUERVO H,FUKUMOTO J, et al. Alda-1 attenuates hyperoxia-induced mitochondrial dysfunction in lung vascular endothelial cells[J]. Aging(Albany NY),2019, 11(12): 3909-3918. DOI: 10.18632/aging.102012.
[17] ZHUANG X, ZHANG W, CHEN Y,et al.Doxorubicin-enriched, ALDHbr mouse breast cancer stem cells are treatable to oncolytic herpes simplex virus type 1[J].Bmc Cancer, 2012,12(1):549-564.DOI:10.1186/1471-2407-12-549.
[18] YOVAL-SÁNCHEZ B, RODRÍGUEZ-ZAVALA J S. Differences in susceptibility to inactivation of human aldehyde dehydrogenases by lipid peroxidation byproducts[J]. Chem Res Toxicol, 2012, 25(3): 722-729.DOI: 10.1021/tx2005184.
[19] JIN S,CHEN J,CHEN L,et al. ALDH2(E487K)mutation increases protein turnover and promotes murine hepatocarcinogenesis[J]. Proc Natl Acad Sci U S A, 2015, 112(29): 9088-9093.DOI: 10.1073/pnas.1510757112.
[20] HOU G, CHEN L, LIU G,et al. Aldehyde dehydrogenase-2(ALDH2)opposes hepatocellular carcinoma progression by regulating AMP-activated protein kinase signaling in mice[J]. Hepatology, 2017, 65(5): 1628-1644.DOI: 10.1002/hep.29006.
[21] HU J F, WANG H X, Li H H, et al. Inhibition of ALDH2 expression aggravates renal injury in a rat sepsis syndrome model[J]. Exp Ther Med, 2017, 14(3): 2249-2254.DOI: 10.3892/etm.2017.4785.
[22] 闫丹丹,白剑英,梁瑞峰,等.醛对肝细胞脂肪代谢的影响[Z].中国环境诱变剂学会两专委会、五省市学术联合学术会议暨环境、辐射与健康防护学术交流会,太原:2013.
[23] HU X Y,FANG Q,WANG J S,et al. Over-expression of aldehyde dehydrogenase-2 protects against H₂O₂-induced oxidative damage and apoptosis in peripheral blood mononuclear cells[J]. Acta Pharmacol Sin, 2011, 32(2): 245-252.DOI: 10.1038/aps.2010.203.
[24] LI S Y, LI Q, SHEN J J, et al. Attenuation of acetaldehyde-induced cell injury by overexpression of aldehyde dehydrogenase-2(ALDH2)transgene in human cardiac myocytes: role of MAP kinase signaling[J]. J Mol Cell Cardiol, 2006, 40(2): 283-294.DOI: 10.1016/j.yjmcc.2005.11.006.
[25] HSU L A,TSAI F C,YEH Y H, et al. Aldehyde dehydrogenase 2 ameliorates chronic alcohol consumption-induced atrial fibrillation through detoxification of 4-HNE[J]. Int J Mol Sci, 2020, 21(18): E6678. DOI: 10.3390/ijms21186678. (