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Article(id=1241067203701821929, tenantId=1146029695717560320, journalId=1227665162245664772, issueId=1241067197318091153, articleNumber=null, orderNo=null, doi=10.20043/j.cnki.MPM.202410143, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1728489600000, receivedDateStr=2024-10-10, revisedDate=null, revisedDateStr=null, acceptedDate=null, acceptedDateStr=null, onlineDate=1773823079276, onlineDateStr=2026-03-18, pubDate=1741536000000, pubDateStr=2025-03-10, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1773823079276, onlineIssueDateStr=2026-03-18, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1773823079276, creator=13701087609, updateTime=1773823079276, updator=13701087609, issue=Issue{id=1241067197318091153, tenantId=1146029695717560320, journalId=1227665162245664772, year='2025', volume='52', issue='5', pageStart='769', pageEnd='960', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1773823077754, creator=13701087609, updateTime=1773823268053, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1241067995544482681, tenantId=1146029695717560320, journalId=1227665162245664772, issueId=1241067197318091153, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1241067995544482682, tenantId=1146029695717560320, journalId=1227665162245664772, issueId=1241067197318091153, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=905, endPage=910, ext={EN=ArticleExt(id=1241067204502934055, articleId=1241067203701821929, tenantId=1146029695717560320, journalId=1227665162245664772, language=EN, title=Glyphosate pesticide induces hepatotoxicity in mice by altering liver metabolic profiles, columnId=1228016572065837304, journalTitle=Modern Preventive Medicine, columnName=Experimental Technology and Applications, runingTitle=null, highlight=null, articleAbstract=
Objective

To investigate the hepatotoxic effects and mechanisms of glyphosate using metabolomics approaches.

Methods

Forty male Kunming mice were randomly divided into control, low-dose (50 mg/kg·d), medium-dose (250 mg/kg·d),and high-dose (500 mg/kg·d) groups, with glyphosate administered orally for 30 days. The liver organ coefficients, pathological changes, and liver function parameters were measured. UPLC-MS was employed to analyze the liver metabolic profiles, and multivariate statistical methods were utilized to identify differential metabolites, followed by enrichment analysis based on the KEGG platform.

Results

Compared to the control group, mice exposed to medium and/or high doses of glyphosate exhibited varying degrees of edema and inflammation in liver cells, along with significantly elevated serum levels of ALT, TBILI, DBILI,and GLU. Glyphosate exposure reduced the levels of nucleotide metabolites such as hypoxanthine, xanthine, and pyrimidine, as well as cellular membrane components like choline, phosphatidylcholine, and sphingosine. It also decreased the levels of vitamins such as thiamine and retinal, and amino acid metabolites including Hom vanillic acid and 4-aminobutyraldehyde.Conversely, it increased the levels of carbohydrate metabolites such as glucose-6-phosphate, fructose-1-phosphate, and ribose-1-phosphate. Furthermore, liver function indicators ALT, TBILI, and DBILI were correlated with the aforementioned metabolites.

Conclusion

Glyphosate exposure can damage the structure and function of liver cells in mice by affecting nucleotide metabolism, carbohydrate metabolism, amino acid metabolism, phospholipid metabolism, and vitamin metabolism.

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目的

基于代谢组学方法研究草甘膦的肝脏毒效应及毒作用机制。

方法

40只昆明雄性小鼠随机分为对照组、低剂量组［50 mg/（kg·d）］、中剂量组［250 mg/（kg·d）］和高剂量组［500 mg/（kg·d）］，草甘膦农药经口途径染毒30 d。检测小鼠肝脏脏器系数、病理改变、肝功参数等指标。应用UPLC-MS检测小鼠肝代谢谱，选择多元统计分析方法筛选差异代谢物，基于KEGG平台开展差异代谢物富集分析。

结果

与对照组相比较，中剂量和/或高剂量草甘膦染毒小鼠肝细胞呈现不同程度水肿和炎症改变，血清ALT、TBLI、DBILI和GLU水平显著升高。草甘膦降低了肝脏黄嘌呤、次黄嘌呤、嘧啶等核苷酸代谢产物含量，胆碱、卵磷脂和鞘氨醇等细胞膜成分，硫胺素和视黄醛等维生素含量及马尿酸和4-氨基丁醛等氨基酸代谢物含量；提升了葡萄糖-6-磷酸、果糖-1-磷酸、核糖-1-磷酸等糖代谢产物含量。此外，肝功指标ALT、TBLI、DBILI水平与上述代谢物存在相关性。

结论

草甘膦染毒可以通过影响小鼠肝脏核苷酸代谢、糖代谢、氨基酸代谢、磷脂代谢和维生素代谢等途径损伤肝脏细胞结构与功能。

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李刚，E-mail:
, copyrightStatement=本刊刊出的所有文章不代表中华预防医学会和本刊编委会的观点，除非特别声明。, copyrightOwner=中华预防医学会和四川大学华西公共卫生学院, extLink=null, articleAbsUrl=null, sourceXml=lcqpUi/UkPg4O1OBFdRA8g==, magXml=zzKYzkDcK9gSs9OArnM5hQ==, pdfUrl=null, pdf=KOqfElbuikmxnh3t87cD4w==, pdfFileSize=1102066, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=gNRG94L8gMklDuh79UCWMA==, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=RQE8D0/7K9C5G/jpPopEbQ==, mapNumber=null, authorCompany=null, fund=null, authors=

齐磊（1990—），女，博士，讲师，研究方向：食品污染物的毒效应及其毒作用机制

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齐磊（1990—），女，博士，讲师，研究方向：食品污染物的毒效应及其毒作用机制

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齐磊（1990—），女，博士，讲师，研究方向：食品污染物的毒效应及其毒作用机制

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注：图A、B、C、D分别为NC组、LG组、MG组、HG组；黑色箭头，肿胀细胞；蓝色箭头，炎症细胞。

, figureFileSmall=TiJR6jdeneWl+o5eXJ3fLw==, figureFileBig=gNRG94L8gMklDuh79UCWMA==, tableContent=null), ArticleFig(id=1241067217492693148, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1241067203701821929, language=EN, label=Figure 2, caption=Effects of glyphosate on metabolite in mice liver, figureFileSmall=rXvUoBBRo6vYsnjNGaaUPA==, figureFileBig=i6FFq9k1yZHgAD0UYFPlVA==, tableContent=null), ArticleFig(id=1241067217618522280, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1241067203701821929, language=CN, label=图2, caption=草甘膦对小鼠肝脏代谢普的影响

注：图A为正离子模式OPLS-DA得分图；图B为负离子模式OPLS-DA得分图；图A和B中横坐标表示第一主成分的预测主成分得分，纵坐标表示正交主成分得分，每个散点代表一个样本，圆点代表NC组样品，正方块代表HG样品；图C为正离子模式置换检验结果；图D为负离子模式置换检验结果；图C和D中横坐标表示置换检验的置换保留度，纵坐标表示R2Y或Q 2 的取值，绿色圆点表示置换检验得到的R2Y值，蓝色方点表示置换检验得到的Q 2 值，两条虚线分别表示R2Y和Q 2的回归线。

, figureFileSmall=rXvUoBBRo6vYsnjNGaaUPA==, figureFileBig=i6FFq9k1yZHgAD0UYFPlVA==, tableContent=null), ArticleFig(id=1241067217719185584, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1241067203701821929, language=EN, label=Figure 3, caption=Effects of glyphosate on DCMs and metabolic pathways, figureFileSmall=JpwVS+U8Fwvazx2/mY5kPA==, figureFileBig=mKnAI6pk3tVP9wkuZDFfBw==, tableContent=null), ArticleFig(id=1241067217811460279, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1241067203701821929, language=CN, label=图3, caption=草甘膦对代谢物及代谢通路的影响

注：图A为正离子模式差异代谢物火柴杆图；图B为负离子模式差异代谢物火柴杆图；图A、B竖线右侧代表上调倍数，左侧代表下调倍数；VIP表示变量投影重要度，黑色圆点颜色越深，代表VIP越大；图C为正离子模式代谢通路气泡图；图D为负离子模式代谢通路气泡图；每一个气泡代表一个代谢通路；图C、D横坐标表示该通路在拓扑分析中的影响因子大小，纵坐标表示富集分析的P值［取负自然对数，即-ln（p）］。

, figureFileSmall=JpwVS+U8Fwvazx2/mY5kPA==, figureFileBig=mKnAI6pk3tVP9wkuZDFfBw==, tableContent=null), ArticleFig(id=1241067217920512196, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1241067203701821929, language=EN, label=Figure 4, caption=The correlation between liver injury indicators and DCMs, figureFileSmall=i13yi8vs+zwRaIDei6TqOw==, figureFileBig=wF1XyCizHTuF0lxPbuIKZA==, tableContent=null), ArticleFig(id=1241067218042147022, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1241067203701821929, language=CN, label=图4, caption=肝脏损伤指标与差异代谢物存在相关关系

注：无×的圆形点表示存在相关性，有×的圆形点表示不在存在相关性；DBIL直接胆红素；TBIL总胆红素；ALT谷丙转氨酶；R-1-P核糖-1-磷酸；ADR腺苷二磷酸核糖；CMP-NGCMP-N-糖基尿苷酸；F-1-P果糖-1-磷酸；G-6-P为葡萄糖-6-磷酸；4-ABA为4-氨基丁醛；HA马尿酸。

, figureFileSmall=i13yi8vs+zwRaIDei6TqOw==, figureFileBig=wF1XyCizHTuF0lxPbuIKZA==, tableContent=null), ArticleFig(id=1241067221410173137, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1241067203701821929, language=EN, label=Table 1, caption=

The effect of glyphosate on liver coefficient and function indicators of mice ［，n=10］

, figureFileSmall=null, figureFileBig=null, tableContent=
指标NCLGMGHGF值P值
LV×100.48±0.010.49±0.020.51±0.030.52±0.032.570.069
ALT (U/L)13.00±3.0714.36±2.7521.04±6.91a24.3±10.45b6.670.001
AST (U/L)149.7±1.8148.5±1.2153.5±5.0157.7±16.72.220.102
DBIL(mmol/L)4.30±2.336.58±3.848.19±3.929.99±4.19b4.40.01
TBIL (mmol/L)17.47±5.4318.96±5.7740.57±23.98a52.94±30.37b7.62<0.001
GLU (mmol /L)7.54±1.027.63±1.028.75±1.519.34±1.22a5.280.004
TG(U/L)1.82±0.411.71±0.342.15±0.622.23±0.472.830.052
), ArticleFig(id=1241067221552779481, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1241067203701821929, language=CN, label=表1, caption=

草甘膦对小鼠肝脏系数和肝功能指标的影响［（），n=10］

, figureFileSmall=null, figureFileBig=null, tableContent=
指标NCLGMGHGF值P值
LV×100.48±0.010.49±0.020.51±0.030.52±0.032.570.069
ALT (U/L)13.00±3.0714.36±2.7521.04±6.91a24.3±10.45b6.670.001
AST (U/L)149.7±1.8148.5±1.2153.5±5.0157.7±16.72.220.102
DBIL(mmol/L)4.30±2.336.58±3.848.19±3.929.99±4.19b4.40.01
TBIL (mmol/L)17.47±5.4318.96±5.7740.57±23.98a52.94±30.37b7.62<0.001
GLU (mmol /L)7.54±1.027.63±1.028.75±1.519.34±1.22a5.280.004
TG(U/L)1.82±0.411.71±0.342.15±0.622.23±0.472.830.052
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草甘膦农药通过改变小鼠肝脏代谢谱引起肝毒性
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齐磊 1, 2 , 程宇 1 , 钞虹 1 , 杨晓蕾 1 , 朱金峰 1 , 李洪杰 1 , 李刚 1, 2
现代预防医学 | 实验技术及其应用 2025,52(5): 905-910
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现代预防医学 | 实验技术及其应用 2025, 52(5): 905-910
草甘膦农药通过改变小鼠肝脏代谢谱引起肝毒性
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齐磊1, 2, 程宇1, 钞虹1, 杨晓蕾1, 朱金峰1, 李洪杰1, 李刚1, 2
作者信息
  • 1.齐齐哈尔医学院公共卫生学院，黑龙江 齐齐哈尔 161006
  • 2.齐齐哈尔医学科学院，黑龙江 齐齐哈尔 161006

    • 齐磊（1990—），女，博士，讲师，研究方向：食品污染物的毒效应及其毒作用机制

通讯作者:

李刚，E-mail:
Glyphosate pesticide induces hepatotoxicity in mice by altering liver metabolic profiles
Lei QI1, 2, Yu CHENG1, Hong CHAO1, Xiao-lei YANG1, Jin-feng ZHU1, Hong-jie LI1, Gang LI1, 2
Affiliations
  • School of Public Health, Qiqihar Medical University, Qiqihar, Heilongjiang 161006, China
出版时间: 2025-03-10 doi: 10.20043/j.cnki.MPM.202410143
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摘要
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目的

基于代谢组学方法研究草甘膦的肝脏毒效应及毒作用机制。

方法

40只昆明雄性小鼠随机分为对照组、低剂量组［50 mg/（kg·d）］、中剂量组［250 mg/（kg·d）］和高剂量组［500 mg/（kg·d）］，草甘膦农药经口途径染毒30 d。检测小鼠肝脏脏器系数、病理改变、肝功参数等指标。应用UPLC-MS检测小鼠肝代谢谱，选择多元统计分析方法筛选差异代谢物，基于KEGG平台开展差异代谢物富集分析。

结果

与对照组相比较，中剂量和/或高剂量草甘膦染毒小鼠肝细胞呈现不同程度水肿和炎症改变，血清ALT、TBLI、DBILI和GLU水平显著升高。草甘膦降低了肝脏黄嘌呤、次黄嘌呤、嘧啶等核苷酸代谢产物含量，胆碱、卵磷脂和鞘氨醇等细胞膜成分，硫胺素和视黄醛等维生素含量及马尿酸和4-氨基丁醛等氨基酸代谢物含量；提升了葡萄糖-6-磷酸、果糖-1-磷酸、核糖-1-磷酸等糖代谢产物含量。此外，肝功指标ALT、TBLI、DBILI水平与上述代谢物存在相关性。

结论

草甘膦染毒可以通过影响小鼠肝脏核苷酸代谢、糖代谢、氨基酸代谢、磷脂代谢和维生素代谢等途径损伤肝脏细胞结构与功能。

草甘膦农药  /  肝脏  /  代谢组学  /  毒效应
Objective

To investigate the hepatotoxic effects and mechanisms of glyphosate using metabolomics approaches.

Methods

Forty male Kunming mice were randomly divided into control, low-dose (50 mg/kg·d), medium-dose (250 mg/kg·d),and high-dose (500 mg/kg·d) groups, with glyphosate administered orally for 30 days. The liver organ coefficients, pathological changes, and liver function parameters were measured. UPLC-MS was employed to analyze the liver metabolic profiles, and multivariate statistical methods were utilized to identify differential metabolites, followed by enrichment analysis based on the KEGG platform.

Results

Compared to the control group, mice exposed to medium and/or high doses of glyphosate exhibited varying degrees of edema and inflammation in liver cells, along with significantly elevated serum levels of ALT, TBILI, DBILI,and GLU. Glyphosate exposure reduced the levels of nucleotide metabolites such as hypoxanthine, xanthine, and pyrimidine, as well as cellular membrane components like choline, phosphatidylcholine, and sphingosine. It also decreased the levels of vitamins such as thiamine and retinal, and amino acid metabolites including Hom vanillic acid and 4-aminobutyraldehyde.Conversely, it increased the levels of carbohydrate metabolites such as glucose-6-phosphate, fructose-1-phosphate, and ribose-1-phosphate. Furthermore, liver function indicators ALT, TBILI, and DBILI were correlated with the aforementioned metabolites.

Conclusion

Glyphosate exposure can damage the structure and function of liver cells in mice by affecting nucleotide metabolism, carbohydrate metabolism, amino acid metabolism, phospholipid metabolism, and vitamin metabolism.

Glyphosate pesticide  /  Liver  /  Metabolomics  /  Toxic effects
齐磊, 程宇, 钞虹, 杨晓蕾, 朱金峰, 李洪杰, 李刚. 草甘膦农药通过改变小鼠肝脏代谢谱引起肝毒性. 现代预防医学, 2025 , 52 (5) : 905 -910 . DOI: 10.20043/j.cnki.MPM.202410143
Lei QI, Yu CHENG, Hong CHAO, Xiao-lei YANG, Jin-feng ZHU, Hong-jie LI, Gang LI. Glyphosate pesticide induces hepatotoxicity in mice by altering liver metabolic profiles[J]. Modern Preventive Medicine, 2025 , 52 (5) : 905 -910 . DOI: 10.20043/j.cnki.MPM.202410143
正文
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草甘膦农药（glyphosate-based herbicides，GBH）是农业中使用最多的除草剂，约占全球总使用量的20%[1]。近年来，研究表明草甘膦暴露能够产生神经毒性、生殖毒性和内分泌毒性等损伤作用[2-3]。因此，随着GBH的大量使用，其造成人群健康损害已引起全球范围的广泛关注。
肝脏是机体的重要代谢器官，也是草甘膦毒作用的靶器官。研究发现草甘膦暴露能够引起肝脏组织病理改变，并增加血清肝功生化标志物的水平[4-5]。证据表明草甘膦可能是通过诱发过量活性氧，抑制抗氧化酶活性，破坏肝内氧化-抗氧化平衡而诱发肝毒性作用[6]。然而，任何外源化合物的毒作用都是一个错综复杂的过程，当前研究尚不能全面揭示草甘膦农药暴露对机体代谢产物的改变及其相应的生理机制，因此，需要更多的实验予以补充和论证。
代谢组学能够以代谢物变化的特征作为一种特定指纹来判断外源化合物对机体的作用，具有高分辨率和灵敏度的优势，容易与传统检测结果相联系，发现环境污染物对机体作用的生物化学物质基础和作用机制，可以弥补当前研究方法的不足。Jia等[7]基于代谢组学方法发现双酚类化合物通过影响关键代谢物的合成与分解而抑制肝细胞糖酵解、细胞增殖和核苷酸合成，导致肝脏毒性损伤。可见，代谢组学能够系统描述生物体特定组织和细胞中已经发生了哪些代谢产物变化及其可能影响的生理通路，构建毒物代谢过程中的调控网络，有利于生物体病理生理改变的系统认识。然而，当前关于草甘膦所引起的肝毒性及其作用机制的代谢组学研究仍然有限。在本研究中，我们通过代谢组学系统地研究了草甘膦暴露对小鼠肝脏的毒作用及其代谢调控机制，这有利于阐明有机磷农药的肝脏毒性和毒作用机制。
1　材料与方法
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1.1　材料
40只雄性昆明小鼠（7周龄，27～34 g）购买于北京维通利华实验动物技术有限公司。动物饲养环境简介如下：SPF级动物饲养室；温度（21±2）°C；湿度（50±10）%；光暗循环为12：12。实验符合实验动物伦理委员会要求并获得批准(QMU-ACEE-2022-137)。
1.2　实验设计
小鼠按体重随机分为四组（10只/组）：对照组［NC，0 mg/（kg·d）］、低剂量组［LG，50 mg/（kg·d）］、中剂量组［MG，250 mg/（kg·d）］和高剂量组［HG，500 mg/（kg·d）］。HG组剂量选择依据一项慢性和亚慢性草甘膦毒性研究，该研究发现500 mg/（kg·d）的草甘膦农药导致明显的脏器损伤[8]。小鼠每日上午灌胃草甘膦生理盐水和不同剂量的草甘膦农药，染毒30 d，自由进食和饮水。体重每两天记录一次，并根据体重调整草甘膦灌胃量。实验结束时，采集血液和肝脏，称量后分割部分组织贮存于10%福尔马林中，余下组织冻存处理。
1.3　肝脏系数的计算
小鼠肝脏系数（liver coefficient, LV）的计算公式为：LV=（小鼠肝脏湿重/小鼠体重）×100%。
1.4　肝脏病理观察
肝脏组织经包埋、切片、展片、烘干、脱蜡和脱水等处理后，采用苏木精-伊红（hematoxylin-eosin，HE）染色。光学显微镜下观察肝组织病理改变。
1.5　肝功指标检测
应用试剂盒检测谷丙转氨酶（alanine transaminase，ALT）、谷草转氨酶（aspartate transaminase，AST）、总胆红素（total bilirubin，TBLI）、直接胆红素（direct bilirubin，DBILI）、葡萄糖（glucose，GLU）和甘油三酯（triglyceride，TG）。试剂盒均购自南京建诚生物科技有限公司（中国南京）。
1.6　肝脏代谢组学检测与分析
从NC组和HG量组各随机抽取6份肝脏样品开展非靶代谢组学检测，相关检测工作委托上海百趣生物公司完成（中国，上海）。主要步骤如下：样品前处理后应用Vanquish超高效液相色谱仪检测。色谱柱为Waters ACQUITY UPLC BEH Amide (2.1 mm × 100 mm, 1.7 μm)。流动相A液为乙酸铵（25 mmol/L）和氨水（pH=9.75，25 mmol/L）混合液，流动相B液为乙腈。应用Q Exactive HFX质谱仪采集代谢物质谱信息。数据前处理后，应用BiotreeDB-V2.1数据库注释代谢物。通过正交偏最小二乘法-判别分析（orthogonal projections to latent structures discriminant analysis，OPLS-DA）描述组间分布差异。两组间代谢物t检验结果P<0.05且变量投影重要度（variable importance in projection，VIP）大于1判定为差异代谢物（differentially change metabolites，DCMs）。基于京都基因与基因组百科全书（Kyoto encyclopedia of genes and genomes，KEGG）数据库筛选差异代谢通路。
1.7　统计分析方法
应用SPSS 17.0（北京统计数据挖掘有限公司，中国北京）分析实验数据。所有定量数据均以（均值±标准差）的形式呈现。应用方差分析比较多组间均数差异，Dunnett-t检验分析各实验组与对照组间的差异。Spearman相关分析用于检验肝功指标与代谢物强度的相关性。检验水准α=0.05。
2　结果
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2.1　小鼠肝脏重量和功能的变化
如表1所示，各组小鼠LV、血清AST和TG水平无统计学差异。与NC组相比较，HG组和MG组小鼠血清ALT和TBIL水平升高（P<0.05），其余组间未见显著差异。与NC组相比较，HG组小鼠血清DBIL和血糖水平升高（P<0.05），其余组间未见显著差异。
2.2　小鼠肝脏病理改变
NC组和LG组肝脏HE染色显示肝小叶形态清晰完好，细胞排列整齐，无堆积和空泡化改变。MG组肝小叶结构轻度紊乱，肝索排列不规则，轻度肿大。HG组肝脏细胞排列紊乱，呈现明显的水样变和肿胀，炎症细胞浸润。见图1。
2.3　小鼠肝脏代谢谱变化
如图2A、B所示，两组样品在OPLS-DA得分图中各自聚集，分离较好。原模型R2Y非常接近1，说明建立的模型符合样本数据的真实情况；置换检验随机模型的Q 2值均小于原模型的Q 2 值；Q 2 的回归线与纵轴的截距小于零；同时随着置换保留度逐渐降低，置换的Y变量比例增大，随机模型的Q 2逐渐下降。该模型置换检验结果表明模型符合样本数据的真实情况，具有良好的稳健性，不存在过拟合现象，见图2C、D。
正离子模式下共筛选出差异代谢物51个，其中22个代谢物拥有KEEG ID信息，见图3A、表1。PC[20:2(11Z,14Z)/15:0]，PC[22:2(13Z,16Z)/15:0]和LysoPC(17:0)是正离子模式VIP值最高的3种代谢产物（2.58，2.31，2.29）。负离子模式下共筛选出差异代谢物14个，其中12个代谢物拥有KEEG ID信息，见图3B。马尿酸，56-DHET和次黄嘌呤是VIP值最高的3种代谢产物（2.40，1.90，1.85）。如图3 C和D所示，KEGG富集分析显示正离子模式共富集17条代谢通路，其中磷酸戊糖途径，淀粉和蔗糖代谢，糖酵解/糖异生，硫胺素代谢和泛酸与CoA生物合成等能量代谢相关通路变化明显。负离子模式共富集4条代谢通路，分别是嘌呤代谢、磷酸戊糖途径、淀粉和蔗糖代谢、花生四烯酸代谢。
2.4　小鼠肝脏损伤指标与DCMs存在相关关系
对差异通路上的差异代谢物与肝功指标进行相关分析，结果表明血清DBIL水平与黄嘌呤、次黄嘌呤、嘧啶、鞘氨醇、5,6-DHET、4-氨基丁醛、胆碱、马尿酸、视黄醛和硫胺素相对强度负相关，与核糖-1-磷酸、葡萄糖-6-磷酸、果糖-1-磷酸和CMP-N-糖基尿苷酸正相关；TBIL水平与代谢物嘧啶、鞘氨醇、5,6-DHET、4-氨基丁醛和马尿酸相对强度负相关，与L-组氨酸、葡萄糖-6-磷酸、果糖-1-磷酸和CMP-N-糖基尿苷酸正相关；ALT水平与代谢物4-氨基丁醛相对强度负相关，与L-组氨酸、果糖-1-磷酸和CMP-N-糖基尿苷酸正相关。见图4。
3　讨论
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研究发现草甘膦染毒可导致肝脏病理损伤和功能障碍，包括肝细胞水肿、排列紊乱、炎症细胞浸润和肝功指标改变等[9-10]。与此一致，本研究发现随着GBH染毒剂量的增加，小鼠肝脏细胞水肿状态越明显，在HG组中发现少量炎症细胞浸润。同时，本研究发现与对照组相比较，MG组和HG组小鼠血清肝功指标DBIL、TBIL和ALT水平显著增加，表明草甘膦引起了小鼠肝细胞结构与功能损伤。
由于HG组小鼠在草甘膦短期染毒后出现明显的肝脏病理和功能损伤，因此，本研究对NC与HG组进行代谢组学检测与分析，以识别草甘膦产生肝脏毒性的标志物。嘌呤和嘧啶是构成核酸的基础物质，可通过磷酸戊糖途径合成而来[11]。黄嘌呤和次黄嘌呤是肝脏内嘌呤代谢的中间产物，二者可在黄嘌呤氧化酶作用下代谢为终产物尿酸[12]。本研究发现草甘膦提升了肝脏内参与磷酸戊糖代谢的ADR和R-1-P含量，但却降低了黄嘌呤、次黄嘌呤和嘧啶的含量，这说明草甘膦染毒抑制了核苷酸的合成和分解代谢，导致磷酸戊糖途径代谢物的堆积，干扰了核苷酸的正常代谢，引起肝细胞更新障碍。
体内黄嘌呤和次黄嘌呤还可以由含腺嘌呤的三磷酸腺苷（adenosine triphosphate，ATP）转化代谢而来[13]。ATP是人体能量代谢的分子基础，受到糖代谢相关通路上能量物质代谢的直接调控而处于不断地合成与分解状态。当前研究不仅发现草甘膦降低了黄嘌呤和次黄嘌呤的含量，且提升G-6-P、F-1-P、和CMP-NG等糖代谢重要代谢物的含量，这些结果表明草甘膦抑制了糖酵解途径，引起上述糖代谢相关代谢物代谢障碍和ATP合成与利用受阻，导致肝脏能量代谢障碍。
胆碱通常被认为是一种维生素，是卵磷脂的重要前体。卵磷脂是细胞的重要组成部分，能够促进肝内脂质的代谢，预防脂肪肝病的发生[14]。鞘氨醇是一种鞘脂类化合物，是其他鞘脂的构成基础，参与细胞膜的组成。本研究发现草甘膦染毒能够降低肝内胆碱、系列卵磷脂和植物鞘氨醇的含量，且血清中ALT水平的显著上调，提示肝细胞膜稳定性受损和肝内脂代谢紊乱的存在。
马尿酸是一种苯甲酸与甘氨酸结合产物，可以促进肝内苯甲酸解毒，通常被认为是一种健康的标志物[15]。本研究发现草甘膦导致小鼠肝内马尿酸含量下降，且其相对强度与肝氧化损伤标志物DBIL和TBIL水平显著负相关，表明肝脏代谢解毒能力降低。L-组氨酸是一种重要的氨基酸，在机体内具有抗氧化和抗炎作用[16]。本研究发现草甘膦染毒导致小鼠肝内L-组氨酸含量增加，这可能是肝脏应对氧化损伤和炎症反应的应激表现。4-氨基丁醛是γ-氨基丁酸的前体，后者能够促进脑内能量代谢、乙酰胆碱合成和激素分泌进而影响认知和寿命[17]。本研究发现草甘膦染毒导致小鼠肝内4-氨基丁醛含量降低，提示草甘膦可通过影响肝内物质代谢潜在影响神经系统功能。
硫胺素通常以焦磷酸硫胺素辅酶形式参与到丙酮酸代谢和磷酸戊糖途径的转酮醇酶反应。本研究发现草甘膦染毒降低了小鼠肝脏硫胺素含量，且磷酸戊糖途径和以丙酮酸为中心的糖酵解/糖异生和淀粉与蔗糖代谢等通路上的代谢物显著改变。这些结果表明草甘膦染毒导致的肝脏能量代谢障碍与硫胺素的含量密切相关。研究表明，肝视黄醛缺乏将导致维甲酸受体过度激活，从而增强肝糖异生而升高血糖[18]。本研究发现草甘膦染毒引起肝脏视黄醛含量下降，但血糖含量增加，提示肝糖代谢紊乱可能与草甘膦导致的视黄醛代谢障碍相关。
综上所述，本研究发现草甘膦染毒可引起小鼠肝脏核酸代谢、糖代谢、氨基酸代谢、磷脂代谢及维生素代谢紊乱，进而导致肝脏病理改变和功能损伤。
基金
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  • 齐齐哈尔市科技计划联合引导项目(LSFGG-2024100)
  • 国家自然科学基金项目(82103869)
  • 齐齐哈尔医学科学院科研项目(QMSI2019M-23; QMSI2023B-13; 2024-ZDPY-003; QMSI2019M-05)
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2025年第52卷第5期
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doi: 10.20043/j.cnki.MPM.202410143
  • 接收时间：2024-10-10
  • 首发时间：2026-03-18
  • 出版时间：2025-03-10
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  • 收稿日期：2024-10-10
基金
齐齐哈尔市科技计划联合引导项目(LSFGG-2024100)
国家自然科学基金项目(82103869)
齐齐哈尔医学科学院科研项目(QMSI2019M-23; QMSI2023B-13; 2024-ZDPY-003; QMSI2019M-05)
作者信息
    1.齐齐哈尔医学院公共卫生学院，黑龙江 齐齐哈尔 161006
    2.齐齐哈尔医学科学院，黑龙江 齐齐哈尔 161006

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2种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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