Man Yang , Yinchao Li , Lei Lei , Shangnan Zou , Huanling Lai , Yue Xing , Yubao Fang , Qihang Zou , Yaqian Zhang , Xiaofeng Yang , Liemin Zhou
{"title":"丙戊酸暴露后小鼠模型中亚甲基四氢叶酸677C >t变异的影响","authors":"Man Yang , Yinchao Li , Lei Lei , Shangnan Zou , Huanling Lai , Yue Xing , Yubao Fang , Qihang Zou , Yaqian Zhang , Xiaofeng Yang , Liemin Zhou","doi":"10.1016/j.reprotox.2025.108995","DOIUrl":null,"url":null,"abstract":"<div><div>The teratogenic effects of valproic acid (VPA) can lead to abnormal fetal development, which may be related to abnormal maternal one-carbon metabolism. Methylene-tetrahydrofolate reductase (MTHFR) is a key enzyme involved in one-carbon metabolism. Variations in <em>MTHFR</em>, particularly 677 C>T, are associated with susceptibility to teratogenicity. However, the current research is limited to clinical practice. Therefore, an <em>Mthfr</em><sup><em>677C>T</em></sup> mouse model was constructed to explore whether the 677 C > T polymorphism increases the teratogenic susceptibility to VPA. Pregnant wild type and <em>Mthfr</em><sup><em>677C>T</em></sup> mice were exposed to a single teratogenic dose of 400 mg/kg VPA or saline via intraperitoneal injection on day 7.5 of gestation (E7.5), and fetuses were harvested on E18.5. Resorbed fetuses, malformations, including neural tube defects (NTDs) increased in the VPA-treated group. Consistent with the clinical data, <em>Mthfr</em><sup><em>677C>T</em></sup> mice also showed lower liver MTHFR enzymatic activity and elevated serum homocysteine (Hcy) levels. No abnormalities were observed in the saline-treated groups. Therefore, intraperitoneal injected VPA significantly increased the malformation rate of CT and TT heterozygote and homozygote mice, respectively, compared to that of CC mice (P < 0.05). In this study, an association between the 677 C > T polymorphism of <em>MTHFR</em> and susceptibility to VPA-induced teratogenesis in mice, especially in TT mice, was found. This may be related to changes in Hcy metabolism. Collectively, these data have important implications for exploring the different responses of individuals to drug-induced teratogenesis, which may help guide the adjustment of drug selection during pregnancy.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"137 ","pages":"Article 108995"},"PeriodicalIF":2.8000,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Influence of methylenetetrahydrofolate 677C > T variant in murine models following valproic acid exposure\",\"authors\":\"Man Yang , Yinchao Li , Lei Lei , Shangnan Zou , Huanling Lai , Yue Xing , Yubao Fang , Qihang Zou , Yaqian Zhang , Xiaofeng Yang , Liemin Zhou\",\"doi\":\"10.1016/j.reprotox.2025.108995\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>The teratogenic effects of valproic acid (VPA) can lead to abnormal fetal development, which may be related to abnormal maternal one-carbon metabolism. Methylene-tetrahydrofolate reductase (MTHFR) is a key enzyme involved in one-carbon metabolism. Variations in <em>MTHFR</em>, particularly 677 C>T, are associated with susceptibility to teratogenicity. However, the current research is limited to clinical practice. Therefore, an <em>Mthfr</em><sup><em>677C>T</em></sup> mouse model was constructed to explore whether the 677 C > T polymorphism increases the teratogenic susceptibility to VPA. Pregnant wild type and <em>Mthfr</em><sup><em>677C>T</em></sup> mice were exposed to a single teratogenic dose of 400 mg/kg VPA or saline via intraperitoneal injection on day 7.5 of gestation (E7.5), and fetuses were harvested on E18.5. Resorbed fetuses, malformations, including neural tube defects (NTDs) increased in the VPA-treated group. Consistent with the clinical data, <em>Mthfr</em><sup><em>677C>T</em></sup> mice also showed lower liver MTHFR enzymatic activity and elevated serum homocysteine (Hcy) levels. No abnormalities were observed in the saline-treated groups. Therefore, intraperitoneal injected VPA significantly increased the malformation rate of CT and TT heterozygote and homozygote mice, respectively, compared to that of CC mice (P < 0.05). In this study, an association between the 677 C > T polymorphism of <em>MTHFR</em> and susceptibility to VPA-induced teratogenesis in mice, especially in TT mice, was found. This may be related to changes in Hcy metabolism. Collectively, these data have important implications for exploring the different responses of individuals to drug-induced teratogenesis, which may help guide the adjustment of drug selection during pregnancy.</div></div>\",\"PeriodicalId\":21137,\"journal\":{\"name\":\"Reproductive toxicology\",\"volume\":\"137 \",\"pages\":\"Article 108995\"},\"PeriodicalIF\":2.8000,\"publicationDate\":\"2025-07-09\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Reproductive toxicology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0890623825001662\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"REPRODUCTIVE BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Reproductive toxicology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0890623825001662","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"REPRODUCTIVE BIOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
丙戊酸(VPA)的致畸作用可导致胎儿发育异常,这可能与母体单碳代谢异常有关。亚甲基四氢叶酸还原酶(MTHFR)是参与单碳代谢的关键酶。MTHFR的变异,特别是677 C>;T,与致畸易感性有关。然而,目前的研究仅限于临床实践。因此,我们构建Mthfr677C>;T小鼠模型,探讨677 C >; T多态性是否会增加VPA致畸易感性。妊娠野生型和Mthfr677C>;T小鼠于妊娠第7.5天(E7.5)腹腔注射单次致畸剂量400 mg/kg VPA或生理盐水,并于E18.5收获胎儿。vpa处理组吸收胎儿畸形,包括神经管缺陷(NTDs)增加。与临床数据一致,Mthfr677C>;T小鼠也表现出肝脏MTHFR酶活性降低和血清同型半胱氨酸(Hcy)水平升高。盐水处理组未见异常。因此,与CC小鼠相比,腹腔注射VPA显著增加了CT、TT杂合子和纯合子小鼠的畸形率(P <; 0.05)。在本研究中,我们发现MTHFR的677 C >; T多态性与小鼠特别是TT小鼠对vpa诱导的致畸易感性之间存在关联。这可能与Hcy代谢的变化有关。总的来说,这些数据对于探索个体对药物性畸胎症的不同反应具有重要意义,这可能有助于指导妊娠期间药物选择的调整。
Influence of methylenetetrahydrofolate 677C > T variant in murine models following valproic acid exposure
The teratogenic effects of valproic acid (VPA) can lead to abnormal fetal development, which may be related to abnormal maternal one-carbon metabolism. Methylene-tetrahydrofolate reductase (MTHFR) is a key enzyme involved in one-carbon metabolism. Variations in MTHFR, particularly 677 C>T, are associated with susceptibility to teratogenicity. However, the current research is limited to clinical practice. Therefore, an Mthfr677C>T mouse model was constructed to explore whether the 677 C > T polymorphism increases the teratogenic susceptibility to VPA. Pregnant wild type and Mthfr677C>T mice were exposed to a single teratogenic dose of 400 mg/kg VPA or saline via intraperitoneal injection on day 7.5 of gestation (E7.5), and fetuses were harvested on E18.5. Resorbed fetuses, malformations, including neural tube defects (NTDs) increased in the VPA-treated group. Consistent with the clinical data, Mthfr677C>T mice also showed lower liver MTHFR enzymatic activity and elevated serum homocysteine (Hcy) levels. No abnormalities were observed in the saline-treated groups. Therefore, intraperitoneal injected VPA significantly increased the malformation rate of CT and TT heterozygote and homozygote mice, respectively, compared to that of CC mice (P < 0.05). In this study, an association between the 677 C > T polymorphism of MTHFR and susceptibility to VPA-induced teratogenesis in mice, especially in TT mice, was found. This may be related to changes in Hcy metabolism. Collectively, these data have important implications for exploring the different responses of individuals to drug-induced teratogenesis, which may help guide the adjustment of drug selection during pregnancy.
期刊介绍:
Drawing from a large number of disciplines, Reproductive Toxicology publishes timely, original research on the influence of chemical and physical agents on reproduction. Written by and for obstetricians, pediatricians, embryologists, teratologists, geneticists, toxicologists, andrologists, and others interested in detecting potential reproductive hazards, the journal is a forum for communication among researchers and practitioners. Articles focus on the application of in vitro, animal and clinical research to the practice of clinical medicine.
All aspects of reproduction are within the scope of Reproductive Toxicology, including the formation and maturation of male and female gametes, sexual function, the events surrounding the fusion of gametes and the development of the fertilized ovum, nourishment and transport of the conceptus within the genital tract, implantation, embryogenesis, intrauterine growth, placentation and placental function, parturition, lactation and neonatal survival. Adverse reproductive effects in males will be considered as significant as adverse effects occurring in females. To provide a balanced presentation of approaches, equal emphasis will be given to clinical and animal or in vitro work. Typical end points that will be studied by contributors include infertility, sexual dysfunction, spontaneous abortion, malformations, abnormal histogenesis, stillbirth, intrauterine growth retardation, prematurity, behavioral abnormalities, and perinatal mortality.