Department of Anatomy and Neurobiology, College of Medicine, University of Vermont, Burlington, Vermont 05405, USA.
Toxicol Sci. 2010 Jul;116(1):225-38. doi: 10.1093/toxsci/kfq097. Epub 2010 Apr 7.
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.
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。人群中产前接触 MeHg 后出现的不同结果表明，存在调节 MeHg 毒性的遗传成分。因此，我们使用果蝇模型来寻找基本的 MeHg 耐受基因，以对 MeHg 耐受特性进行遗传和分子剖析。
我们观察到，在源自野生和经 MeHg 耐受选择的果蝇品系中，MeHg 耐受特性（在 MeHg 食物上的发育）具有常染色体显性遗传。我们在存在和不存在 MeHg 应激的情况下，对耐受（经实验室选择）和非耐受（对照）品系的幼虫大脑进行了全基因组转录谱分析。
在四种条件（+/–选择和+/–MeHg）下进行的成对转录组比较，确定了一个“down-down-up”表达特征，即 MeHg 单独和选择单独导致更多的下调转录本，而选择+MeHg 的组合导致更多的上调转录本。功能注释聚类分析显示，单加氧酶/氧化还原酶富集，包括细胞色素 P450（CYP）家族成员。在耐受品系中，与选择+MeHg 一起上调的 10 个 CYP 中，CYP6g1 是上调最多的，也是对 MeHg 最敏感的，此前被鉴定为果蝇中的滴滴涕抗性等位基因。在所有基因中，Turandot A（TotA），一种免疫途径调节的体液反应基因，在与选择+MeHg 一起表达时上调最为显著。
神经特异性过表达 TotA 在蛹发育期间增强了 MeHg 耐受性。将 TotA 和 CYP 基因鉴定为 MeHg 耐受基因，是研究免疫信号和 I 相代谢途径在高等生物 MeHg 毒性和耐受中的保守功能的一个切入点。
