Effects of maternal exposure to procymidone on hepatic metabolism in the offspring of mice
Effects of maternal exposure to procymidone on hepatic metabolism in the offspring of mice
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DOI：
10.1002/tox.23729
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发表时间：
2023-01
影响因子：
4.5
通讯作者：
Xiaofang Wang;Lingyu Hu;Cuiyuan Jin;Mingrong Qian;Yuanxiang Jin
中科院分区：
文献类型：
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作者：
Xiaofang Wang;Lingyu Hu;Cuiyuan Jin;Mingrong Qian;Yuanxiang Jin
作为一种在农业生产中广泛使用的有效杀菌剂，在环境和食品中都发现了过量的扑霉灵残留。我们先前的研究表明，PRO可以破坏小鼠的肠道屏障，并具有联合毒性作用。为了探讨母体暴露的跨世代影响，10周龄C57BL/6雌性小鼠在孕期和哺乳期分别给予10 mg/kg体重和100 mg/kg体重的PRO。子代通过胎盘和母乳从母体获得营养，在F1代的肝脏、肠道和粪便中检测到PRO残留。粪便检查发现，当仔鼠生长到35天时，残留的PRO已经完全代谢。F1代雄性小鼠的药物残留量高于雌性小鼠。我们将这一结果归因于雄性和雌性小鼠细胞色素P450(CYP450)酶表达的差异。雌性小鼠的细胞色素P4501A1、细胞色素P1A2、细胞色素P3A4和细胞色素P4504的转录水平和蛋白表达水平较高。此外，靶向血浆MS显示氨基酸水平异常。此外，Pro还能诱导F0和F1-7w小鼠肝脏代谢产物的变化。KEGG途径分析进一步表明，PRO共同改变了母子代氨基酸的生物合成途径。综上所述，这些结果表明，母亲在特定时期接触PRO会干扰自身新陈代谢，子代也会出现代谢紊乱。
As an effective fungicide widely used in agricultural production, the excessive procymidone (PRO) residue has been detected in the environment and food. Our previous study demonstrated that PRO could destroy the intestinal barrier in mice and has a joint toxic effect. To explore the cross‐generational impact of maternal exposure, 10‐week‐old C57BL/6 female mice were orally administrated to 10 and 100 mg/kg body weight/day of PRO during pregnancy and lactation. The offspring obtained nutrients from the maternal through the placenta and breast milk, and PRO residues were detected in the liver, intestine, and feces of F1 generation. Fecal examination found that the residual PRO had been completely metabolized when the offspring mice grew to 35 days. The drug residue of F1 generation male mice was higher than that of female mice. We attributed this result to the difference in cytochrome P450 (CYP450) enzyme expression between male and female mice. The transcriptional levels of CYP1A1, CYP1A2, CYP2D9, and CYP3A4, and CYP450 protein expression levels, were higher in female mice. Furthermore, targeted MS of plasma revealed abnormal amino acid levels. In addition, PRO‐induced hepatic metabolite changes in F0 and F1‐7w mice. KEGG pathway analysis further showed that PRO jointly changed the amino acid biosynthesis pathway of the maternal and offspring. In summary, these results indicated that maternal exposure to PRO during a special period would interfere with self metabolism, and offspring will also have metabolic disorders.