Dose-related gene expression changes in forebrain following acute, low-level chlorpyrifos exposure in neonatal rats.
Dose-related gene expression changes in forebrain following acute, low-level chlorpyrifos exposure in neonatal rats.
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DOI：
10.1016/j.taap.2010.07.026
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发表时间：
2010-10-15
影响因子：
3.8
通讯作者：
Pope C
中科院分区：
文献类型：
--
作者：
Ray A;Liu J;Ayoubi P;Pope C
毒死蜱（Chlorpyrifos，CPF）是一种广泛使用的有机磷杀虫剂，也是一种发育神经毒物。CPF的急性毒性是通过抑制乙酰胆碱酯酶（AChE）而引起的。我们的特点是剂量相关的（0.1，0.5，1和2毫克/公斤）基因表达谱和细胞信号通路的变化24小时后，在7天大的大鼠急性CPF暴露。微阵列实验表明，44，000个基因中约有9%在所研究的四种CPF剂量中的任何一种后差异表达（0.1、0.5、1.0和2.0 mg/kg CPF的546、505、522和3，066个基因）。使用K-均值聚类根据剂量相关表达模式对基因进行分组，同时使用Incidity Pathway Analysis®评估基因网络和典型途径。通过RT-PCR鉴定了20个簇，并验证了所选基因的差异表达。四个最大的簇（每个包含276-905个基因）构成了超过50%的所有差异表达的基因，并在暴露于最高剂量（2 mg/kg CPF）后表现出上调。受CPF影响的基因网络总数也随着CPF的最高剂量而急剧增加（0.1、0.5、1和2 mg/kg CPF为18、16、18和50）。仅在最高剂量组中前脑胆碱酯酶（ChE）活性显著降低（26%）。基于差异表达基因的剂量相关变化幅度、受影响的基因簇和信号网络的相对数量以及仅在2 mg/kg CPF下的前脑胆碱酯酶抑制，我们将随后的分析集中在该处理组上。确定了6条典型途径，它们受到2 mg/kg CPF的显著影响（MAPK、氧化应激、NF κ B、线粒体功能障碍、芳烃受体和肾上腺素能受体信号传导）。对差异表达基因的不同细胞功能的评估表明与嗅觉受体、细胞粘附/迁移、突触/突触传递和转录/翻译相关的变化。在所有四个CPF给药组中，九个基因受到不同影响。我们的结论是，最强大的，一致的变化，在新生儿前脑的差异基因表达在一系列的急性CPF剂量发生在暴露水平与OP毒性的经典标志物，乙酰胆碱酯酶抑制。多个细胞通路的中断，特别是细胞粘附，可能有助于这种农药的发育神经毒性潜力。
Chlorpyrifos (CPF) is a widely used organophosphorus insecticide (OP) and putative developmental neurotoxicant in humans. The acute toxicity of CPF is elicited by acetylcholinesterase (AChE) inhibition. We characterized dose-related (0.1, 0.5, 1 and 2 mg/kg) gene expression profiles and changes in cell signaling pathways 24 hr following acute CPF exposure in seven day-old rats. Microarray experiments indicated that approximately 9% of the 44,000 genes were differentially expressed following either one of the four CPF dosages studied (546, 505, 522, and 3,066 genes with 0.1, 0.5, 1.0 and 2.0 mg/kg CPF). Genes were grouped according to dose-related expression patterns using K-means clustering while gene networks and canonical pathways were evaluated using Ingenuity Pathway Analysis®. Twenty clusters were identified and differential expression of selected genes was verified by RT-PCR. The four largest clusters (each containing from 276–905 genes) constituted over 50% of all differentially expressed genes and exhibited up-regulation following exposure to the highest dosage (2 mg/kg CPF). The total number of gene networks affected by CPF also rose sharply with the highest dosage of CPF (18, 16, 18 and 50 with 0.1, 0.5, 1 and 2 mg/kg CPF). Forebrain cholinesterase (ChE) activity was significantly reduced (26%) only in the highest dosage group. Based on magnitude of dose-related changes in differentially expressed genes, relative numbers of gene clusters and signaling networks affected, and forebrain ChE inhibition only at 2 mg/kg CPF, we focused subsequent analyses on this treatment group. Six canonical pathways were identified that were significantly affected by 2 mg/kg CPF (MAPK, oxidative stress, NFKB, mitochondrial dysfunction, arylhydrocarbon receptor and adrenergic receptor signaling). Evaluation of different cellular functions of the differentially expressed genes suggested changes related to olfactory receptors, cell adhesion/migration, synapse/synaptic transmission and transcription/translation. Nine genes were differentially affected in all four CPF dosing groups. We conclude that the most robust, consistent changes in differential gene expression in neonatal forebrain across a range of acute CPF dosages occurred at an exposure level associated with the classical marker of OP toxicity, AChE inhibition. Disruption of multiple cellular pathways, in particular cell adhesion, may contribute to the developmental neurotoxicity potential of this pesticide.
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影响因子：
4.8
作者：
Boscher, Cecile;Mege, Rene-Marc
通讯作者：
Mege, Rene-Marc
DOI：
10.1038/sj.jea.7500307
发表时间：
2004-01-01
期刊：
JOURNAL OF EXPOSURE ANALYSIS AND ENVIRONMENTAL EPIDEMIOLOGY
影响因子：
--
作者：
Colt, JS;Lubin, J;Hartge, P
通讯作者：
Hartge, P
膜形成和稳定中的Ankyrin蛋白网络。
影响因子：
5.3
作者：
Cunha SR;Mohler PJ
通讯作者：
Mohler PJ
影响因子：
4.6
作者：
Barnes, Sarah H.;Price, Stephen R.;Guthrie, Sarah C.
通讯作者：
Guthrie, Sarah C.
影响因子：
3.8
作者：
Cheshenko, Ksenia;Brion, Francois;Eggen, Rik I. L.
通讯作者：
Eggen, Rik I. L.