Wlodarczyk Bogdan J, Cabrera Robert M, Hill Denise S, Bozinov Daniel, Zhu Huiping, Finnell Richard H
Center for Environmental and Genetic Medicine, Institute of Biosciences and Technology, Texas A&M University System Health Science Center, Houston, 77030, USA.
Neurotoxicology. 2006 Jul;27(4):547-57. doi: 10.1016/j.neuro.2006.02.005. Epub 2006 Apr 18.
Arsenic injected intraperitoneally (i.p.) during early organogenesis to small pregnant laboratory rodents (mouse, rat, and hamster) induces several congenital defects in the progeny. Among those abnormalities consistently and predominantly observed are exencephaly and encephalocele. These severe defects of the central nervous system originate from a corrupted process of neurulation and are better known as neural tube defects (NTDs). In order to understand the mechanism of arsenate-induced NTDs, we designed studies in which highly sensitive Folr2 nullizygous mice were injected intraperitoneally with sodium arsenate at the beginning of the neural tube formation process. This specific knockout mouse and the arsenic exposure conditions were chosen as they were known to provide a high incidence of exencephaly in exposed embryos. We have applied gene expression technology to the anterior neural tube. This allowed us to study arsenic-induced changes in patterns of gene expression that may contribute to the development of neural tube defects in these mice. Using extensive data analysis approaches including hierarchical clustering and gene ontology analysis, we identified several candidate genes as well as important ontology groups that may be responsible for arsenic's teratogenicity. Changes in the expression of several genes in response to arsenic treatment in our model had previously been demonstrated by other investigators to also induce NTDs in murine model systems. These include: engrailed 1 (En-1), platelet derived growth factor receptor alpha (Pdgfralpha) and ephrinA7 (EphA7). We also found several gene ontology groups that could be implicated in arsenic's underlying teratogenicity: morphogenesis, oxidative phosporylation, redox response, and regulation of I-kappaB kinase/NF-kappaB cascade. Additionally, we revealed new target genes which may be responsible for arsenic disrupted oxidative phosphorylation.
在器官形成早期，向怀孕的小型实验啮齿动物（小鼠、大鼠和仓鼠）腹腔内注射砷会导致后代出现多种先天性缺陷。在这些持续且主要观察到的异常中，包括无脑畸形和脑膨出。这些严重的中枢神经系统缺陷源于神经胚形成过程的破坏，也就是更为人所知的神经管缺陷（NTDs）。为了理解砷酸盐诱导神经管缺陷的机制，我们设计了研究，在神经管形成过程开始时，给高度敏感的Folr2基因敲除小鼠腹腔内注射砷酸钠。选择这种特定的基因敲除小鼠和砷暴露条件，是因为已知它们会使暴露胚胎中无脑畸形的发生率很高。我们将基因表达技术应用于前神经管。这使我们能够研究砷诱导的基因表达模式变化，这些变化可能导致这些小鼠神经管缺陷的发生。通过使用包括层次聚类和基因本体分析在内的广泛数据分析方法，我们确定了几个可能与砷的致畸性有关的候选基因以及重要的本体组。在我们的模型中，其他研究人员先前已证明，几种基因对砷处理的表达变化也会在小鼠模型系统中诱导神经管缺陷。这些基因包括：engrailed 1（En-1）、血小板衍生生长因子受体α（Pdgfralpha）和ephrinA7（EphA7）。我们还发现了几个可能与砷潜在致畸性有关的基因本体组：形态发生、氧化磷酸化、氧化还原反应以及I-κB激酶/NF-κB级联反应的调节。此外，我们还揭示了可能是砷破坏氧化磷酸化作用的新靶基因。
