Identification of Methylmercury Tolerance Gene Candidates in Drosophila
Identification of Methylmercury Tolerance Gene Candidates in Drosophila
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DOI：
10.1093/toxsci/kfq097
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发表时间：
2010-07-01
影响因子：
3.8
通讯作者：
Rand, Matthew D.
中科院分区：
文献类型：
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作者：
Mahapatra, Cecon T.;Bond, Jeffrey;Rand, Matthew D.
甲基汞（MeHg）是一种普遍存在的环境污染物，优先针对发育中的神经系统。人群中产前甲基汞暴露的可变结果表明，基因成分调节了甲基汞的毒性。因此，我们试图利用果蝇模型对MeHg耐受性状进行遗传和分子解剖，以确定基本的MeHg耐受基因。我们观察到在野生和实验室选择的MeHg耐受菌株中，MeHg耐受性状（对MeHg食物的发育）的常染色体显性。我们对存在和不存在甲基汞胁迫的耐（实验室选择）和不耐（对照）菌株的幼虫大脑进行了全基因组转录谱分析。四种条件（+/-选择和+/-MeHg）的成对转录组比较发现了“down-down-up”的表达特征，其中单独使用MeHg和单独使用选择导致更多的转录下调，而选择+ MeHg组合导致更多的转录上调。功能注释聚类分析显示单加氧酶/氧化还原酶富集，其中包括细胞色素P450 （CYP）家族成员。在耐受菌株中选择+ MeHg上调的10个CYPs中，CYP6g1表达量最高，对MeHg的响应最高，该等位基因先前在果蝇中被鉴定为二氯二苯三氯乙烷抗性等位基因。在所有基因中，选择+ MeHg对免疫途径调节的体液反应基因图兰朵A （TotA）的上调幅度最大。神经特异性转基因TotA过表达增强了蛹发育过程中的甲基汞耐受性。TotA和CYP基因作为MeHg耐受基因的鉴定是研究高等生物MeHg毒性和耐受中免疫信号通路和I期代谢途径保守功能的重要途径。
Methylmercury (MeHg) is a ubiquitous environmental contaminant that preferentially targets the developing nervous system. Variable outcomes of prenatal MeHg exposure within a population point to a genetic component that regulates MeHg toxicity. We therefore sought to identify fundamental MeHg tolerance genes using the Drosophila model for genetic and molecular dissection of a MeHg tolerance trait. We observe autosomal dominance in a MeHg tolerance trait (development on MeHg food) in both wild-derived and laboratory-selected MeHg-tolerant strains of flies. We performed whole-genome transcript profiling of larval brains of tolerant (laboratory selected) and nontolerant (control) strains in the presence and absence of MeHg stress. Pairwise transcriptome comparisons of four conditions (+/-selection and +/-MeHg) identified a "down-down-up" expression signature, whereby MeHg alone and selection alone resulted in a greater number of downregulated transcripts, and the combination of selection + MeHg resulted in a greater number of upregulated transcripts. Functional annotation cluster analyses showed enrichment for monooxygenases/oxidoreductases, which include cytochrome P450 (CYP) family members. Among the 10 CYPs upregulated with selection + MeHg in tolerant strains, CYP6g1, previously identified as the dichlorodiphenyl trichloroethane resistance allele in flies, was the most highly expressed and responsive to MeHg. Among all the genes, Turandot A (TotA), an immune pathway regulated humoral response gene, showed the greatest upregulation with selection + MeHg. Neural-specific transgenic overexpression of TotA enhanced MeHg tolerance during pupal development. Identification of TotA and CYP genes as MeHg tolerance genes is an inroad to investigating the conserved function of immune signaling and phase I metabolism pathways in MeHg toxicity and tolerance in higher organisms.