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题名: 基于基因组和蛋白组学技术研究卡马西平对稀有鮈鲫的毒性及毒理作用机制
作者: 王妙
学位类别: 硕士
答辩日期: 2014-11
授予单位: 中国科学院研究生院
授予地点: 北京
导师: 查金苗
关键词: 卡马西平,稀有鮈鲫,功能基因芯片,蛋白组学技术,毒性及毒理作用机制,Carbamazepine (CBZ), Chinese rare minnow (Gobiocypris rarus), functional gene microarray, proteomics technology, toxicity and toxicology
其他题名: Toxicity and Toxicology of Carbamazepine on Chinese Rare Minnow (Gobiocypris rarus) Based on Genomic and Proteomic Technology
学位专业: 环境工程
中文摘要:     卡马西平是一种典型的抗癫痫药物,广泛存在于各类水体环境中,对水生生物具有潜在的影响,然而卡马西平对于鱼类特别是我国土著鱼类稀有鮈鲫毒性及毒理作用机制还不清楚。本研究旨在结合基因毒理组学和蛋白组学技术研究卡马西平对稀有鮈鲫的毒性及毒理作用机制,为卡马西平环境风险评估提供科学数据及技术支撑。
    基于稀有鮈鲫定制功能芯片技术,初步筛选出与内分泌干扰效应相关基因,通过定量PCR技术验证了定制功能芯片可靠性;体征指数、病理学观察、血液固醇指标以及下丘脑-垂体-性腺作用轴相关基因表达图谱,确认了卡马西平能对非靶标生物稀有鮈鲫产生雌激素效应,且在雌雄鱼体内的作用机制存在差异。
    基于稀有鮈鲫定制功能芯片筛查结果,发现了RAS原癌基因家族基因rab5c、原癌基因myc以及翻译控制肿瘤蛋白基因tpt1表达,初步判定了卡马西平具有潜在的致癌作用。克隆了Ras信号通路中的n-ras、k-ras、pik3cd、raf1以及pin1基因,并对基因进行比对和系统进化分析,且获得了在肝脏、鳃、肾脏、脑和性腺中表达谱,为进一步开展致癌作用机制研究提供了分子生物学基础。
    基于蛋白组学技术,筛选了15个与癌症相关的蛋白;基于信号通路分析,初步探明卡马西平对于稀有鮈鲫致癌作用机制:在雄鱼中卡马西平激活Ras信号通路,导致致癌效应的产生;而雌鱼中卡马西平引起P53介导的细胞凋亡,表明卡马西平对雌鱼和雄鱼中的作用机制存在差异。
英文摘要:     Carbamazepine (CBZ), an anticonvulsant and mood stabilizer, ubiquitously distributes in aquatic environment, which could cause adverse effects on aquatic biota. However, the toxicity and toxicology of CBZ on fish, especially China’s indigenous fish Chinese rare minnow (Gobiocypris rarus), is not clear. In this study, genomics and proteomics technology were combined and employed to study the toxicity and toxicology of CBZ on Chinese rare minnow, which can provide the scientific data and technical support for the environmental risk assessment of CBZ.
    Based on functional gene microarray, some hypothalamic-pituitary-gonad (HPG) axis-related genes were screened and the reliability of functional gene microarray was verified by the PCR quantitative technology. Combining somatic indices, pathological changes, steroid hormone levels and expression profiles of the hypothalamus-pituitary-gonad axis related genes, CBZ was verified to have endocrine interference effect on non-target organisms-Chinese rare minnow. In addition, the results demonstrated that CBZ had different effect mechanisms on male and female fishes.
    Based on the results of functional gene microarray, rab5c, myc and tpt1 were detected to be significantly changed, which tentatively indicated that CBZ could induce carcinogenic risk. The partial cDNA sequences of n-ras, k-ras, pik3cd, raf1 and pin1, which are involved in Ras signal pathway, were cloned, sequenced and sequence analyzed. The expression profiles on the liver, gills, kidney, brain and gonad of Chinese rare minnow were obtained . These results offered molecular biological basis for further carcinogenic mechanism research.
    Based on proteomic technology, 15 proteins related to cancer/tumor were observed to be significantly changed at protein level after CBZ exposure. Preliminary carcinogenic mechanism of CBZ on Chinese rare minnow was obtained. In the male fish, CBZ led to carcinogenic effect by influencing the calcium ion signaling, Ras signaling pathway and protein folding, while in the female fish, CBZ induced apoptosis process by impacting P53 signaling pathway.
内容类型: 学位论文
URI标识: http://ir.rcees.ac.cn/handle/311016/34436
Appears in Collections:环境水质学国家重点实验室_学位论文

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Recommended Citation:
王妙. 基于基因组和蛋白组学技术研究卡马西平对稀有鮈鲫的毒性及毒理作用机制[D]. 北京. 中国科学院研究生院. 2014.
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