Benzo[a]pyrene effects on glycine N-methyltransferase mRNA expression and enzyme activity in Fundulus heteroclitus embryos.
Benzo[a]pyrene effects on glycine N-methyltransferase mRNA expression and enzyme activity in Fundulus heteroclitus embryos.
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DOI：
10.1016/j.aquatox.2010.02.004
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发表时间：
2010-06-10
影响因子：
4.5
通讯作者：
Willett, Kristine L.
中科院分区：
文献类型：
--
作者：
Fang, Xiefan;Dong, Wu;Thornton, Cammi;Willett, Kristine L.
苯并[a]芘（BaP）是一种普遍存在的环境多环芳烃（PAH）污染物，是一种致癌物和发育毒物。我们推测BaP的一些发育毒性可能是通过对甘氨酸n -甲基转移酶（GNMT）的作用介导的。GNMT是蛋氨酸和叶酸循环的介质，其同四聚体形式将一个甲基从s -腺苷基蛋氨酸（SAM）转化为甘氨酸，形成s -腺苷基同型半胱氨酸（SAH）和肌氨酸。由GNMT调节的SAM稳态与DNA甲基化的调节密切相关，GNMT表达的改变与肝脏病变有关。GNMT的同二聚体形式被认为是4S多环芳烃结合蛋白。为了进一步研究BaP与GNMT的相互作用，将异交底泥胚胎暴露于10和100 μg/L的水性BaP中，检测GNMT mRNA的表达和酶活性。全株原位杂交显示，BaP可提高7、10和14个dpf异交胚胎肝脏区GNMT mRNA的表达。与mRNA诱导相比，体内BaP暴露降低了4、10和14个dpf胚胎的GNMT酶活性。然而，与BaP一起体外培养的成虫肝细胞质并没有引起酶活性的降低。综上所述，BaP暴露改变了GNMT的表达，这可能是BaP介导的胚胎毒性和DNA甲基化变化的新靶点途径。
Benzo[a]pyrene (BaP) is a ubiquitous environmental polycyclic aromatic hydrocarbon (PAH) contaminant that is both a carcinogen and a developmental toxicant. We hypothesize that some of BaP’s developmental toxicity may be mediated by effects on glycine N-methyltransferase (GNMT). GNMT is a mediator in the methionine and folate cycles, and the homotetrameric form enzymatically transfers a methyl group from S-adenosylmethionine (SAM) to glycine forming S-adenosylhomocysteine (SAH) and sarcosine. SAM homeostasis, as regulated by GNMT, is critically involved in regulation of DNA methylation, and altered GNMT expression is associated with liver pathologies. The homodimeric form of GNMT has been suggested as the 4S PAH-binding protein. To further study BaP-GNMT interactions, Fundulus heteroclitus embryos were exposed to waterborne BaP at 10 and 100 μg/L and both GNMT mRNA expression and enzyme activity were determined. Whole mount in situ hybridization showed GNMT mRNA expression was increased by BaP in the liver region of 7, 10 and 14 dpf F. heteroclitus embryos. In contrast to mRNA induction, in vivo BaP exposure decreased GNMT enzyme activity in 4, 10 and 14 dpf embryos. However, in vitro incubations of adult F. heteroclitus liver cytosol with BaP did not cause decreased enzyme activity. In conclusion, BaP exposure altered GNMT expression, which may represent a new target pathway for BaP-mediated embryonic toxicities and DNA methylation changes.
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