Repeated Developmental Exposure of Mice to Chlorpyrifos Oxon Is Associated with Paraoxonase 1 (PON1)-Modulated Effects on Cerebellar Gene Expression
Repeated Developmental Exposure of Mice to Chlorpyrifos Oxon Is Associated with Paraoxonase 1 (PON1)-Modulated Effects on Cerebellar Gene Expression
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DOI：
10.1093/toxsci/kfr157
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发表时间：
2011-09-01
影响因子：
3.8
通讯作者：
Furlong, Clement E.
中科院分区：
文献类型：
--
作者：
Cole, Toby B.;Beyer, Richard P.;Furlong, Clement E.
利用基因芯片技术研究了出生后反复暴露于毒死蜱（CPO）对转基因小鼠小脑基因表达的影响。高密度脂蛋白相关酶对氧磷酶1（PON 1）在毒死蜱（CPF）的解毒过程中起着重要作用。两个因素在调节CPO的毒性中是重要的，Q192 R PON 1多态性和PON 1血浆水平，其在出生时较低，在整个出生后发育中增加。在这些研究中使用的小鼠包括野生型（PON 1（+/+））、PON 1敲除（PON 1（-/-））和在PON 1（-/-）背景下表达人PON 1（Q192）或PON 1（R192）的两个转基因品系（tgHuPON 1（Q192）、tgHuPON 1（R192））。PON 1（R192）比PON 1（Q192）更有效地水解CPO。所有四种基因型暴露于CPO（0.35或0.50毫克/公斤/天），每天从出生后第4天（PND）PND 21显示出显着差异的基因表达PND 22与对照组相比。通路分析和基因集分析揭示了多种通路和基因集受到CPO暴露的显著影响，包括参与线粒体功能障碍、氧化应激、神经传递和神经系统发育的基因。基因型之间的比较揭示了特定的基因，基因集，和途径之间的差异影响tgHuPON 1（Q192）和tgHuPON 1（R192）小鼠和PON 1（-/-）和PON 1（+/+）小鼠之间的CPO暴露。在PON 1（-/-）和tgHuPON 1（Q192）小鼠出生后发育期间，重复暴露CPO也导致脑乙酰胆碱酯酶活性的剂量相关性降低，但在PON 1（+/+）或tgHuPON 1（R192）小鼠中没有。这些研究结果表明，PON 1状态在调节新生儿CPO暴露对发育中大脑的影响中起着关键作用。
Microarray analysis was used to examine effects of repeated postnatal exposure to chlorpyrifos oxon (CPO) on gene expression in the cerebellum of genetically modified mice. The high-density lipoprotein-associated enzyme paraoxonase 1 (PON1) plays a significant role in the detoxication of CPO, which is present in exposures and generated from chlorpyrifos (CPF) in vivo following exposure. Two factors are important in modulating toxicity of CPO, the Q192R PON1 polymorphism and PON1 plasma level, which is low at birth and increases throughout postnatal development. Mice used in these studies included wild type (PON1(+/+)), PON1 knockout (PON1(-/-)), and two transgenic lines (tgHuPON1(Q192), tgHuPON1(R192)) expressing either human PON1(Q192) or PON1(R192) on the PON1(-/-) background. PON1(R192) hydrolyzes CPO more efficiently than PON1(Q192). All four genotypes exposed to CPO (0.35 or 0.50 mg/kg/day) daily from postnatal day (PND) 4 to PND 21 showed significant differences in gene expression on PND 22 compared with controls. Pathway analysis and Gene Set Analysis revealed multiple pathways and gene sets significantly affected by CPO exposure, including genes involved in mitochondrial dysfunction, oxidative stress, neurotransmission, and nervous system development. Comparison between genotypes revealed specific genes, gene sets, and pathways differentially affected between tgHuPON1(Q192) and tgHuPON1(R192) mice and between PON1(-/-) and PON1(+/+) mice following CPO exposure. Repeated CPO exposure also resulted in a dose-related decrease in brain acetylcholinesterase activity during postnatal development in PON1(-/-) and tgHuPON1(Q192) mice but not in PON1(+/+) or tgHuPON1(R192) mice. These findings indicate that PON1 status plays a critical role in modulating the effects of neonatal CPO exposure in the developing brain.