Circadian Clock Regulates Response to Pesticides in Drosophila via Conserved Pdp1 Pathway
Circadian Clock Regulates Response to Pesticides in Drosophila via Conserved Pdp1 Pathway
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DOI：
10.1093/toxsci/kfq083
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发表时间：
2010-06-01
影响因子：
3.8
通讯作者：
Giebultowicz, Jadwiga Maria
中科院分区：
文献类型：
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作者：
Beaver, Laura Michelle;Hooven, Louisa Ada;Giebultowicz, Jadwiga Maria
生物钟产生的日常节律调节着许多生命功能，包括对外来化合物的反应。在黑腹果蝇中，生物钟由周期（cyc）和时钟（Clk）编码的积极元素和周期（per）和永恒（tim）基因编码的消极元素组成。par结构域蛋白1 （Pdp1 epsilon）转录因子的epsilon亚型受正向时钟元件控制，并调节日常运动活动节律。Pdp1靶基因尚未确定，其参与其他时钟输出通路尚不清楚。哺乳动物中Pdp1的同源基因参与了外源代谢的调节；因此，我们想知道Pdp1在果蝇中是否也有类似的作用。使用杀虫剂作为模型毒物，我们确定ppdp1 epsilon的破坏增加了杀虫剂引起的苍蝇死亡率。缺乏cyc的果蝇也显示出更高的死亡率，而per和tim的中断则没有影响。观察到昼夜和pdp1依赖性的异种代谢酶Cyp6a2， Cyp6g1和α -酯酶-7的表达差异，这可能导致解毒受损。DHR96是组成型雄烷受体和孕烷X受体的同源物，参与农药应答，当Pdp1被抑制时，DHR96的表达降低。综上所述，我们的数据揭示了一条从生物钟正臂通过Pdp1到解毒效应基因的途径，证明了昼夜节律系统在调节外源毒性方面的保守作用。
Daily rhythms generated by the circadian clock regulate many life functions, including responses to xenobiotic compounds. In Drosophila melanogaster, the circadian clock consists of positive elements encoded by cycle (cyc) and Clock (Clk) and negative elements encoded by period (per) and timeless (tim) genes. The epsilon-isoform of the PAR-domain protein 1 (Pdp1 epsilon) transcription factor is controlled by positive clock elements and regulates daily locomotor activity rhythms. Pdp1 target genes have not been identified, and its involvement in other clock output pathways is not known. Mammalian orthologs of Pdp1 have been implicated in the regulation of xenobiotic metabolism; therefore, we asked whether Pdp1 has a similar role in the fly. Using pesticides as model toxicants, we determined that disruption of Pdp1 epsilon increased pesticide-induced mortality in flies. Flies deficient for cyc also showed increased mortality, while disruption of per and tim had no effect. Day/night and Pdp1-dependent differences in the expression of xenobiotic-metabolizing enzymes Cyp6a2, Cyp6g1, and alpha-Esterase-7 were observed and likely contribute to impaired detoxification. DHR96, a homolog of constitutive androstane receptor and pregnane X receptor, is involved in pesticide response, and DHR96 expression decreased when Pdp1 was suppressed. Taken together, our data uncover a pathway from the positive arm of the circadian clock through Pdp1 to detoxification effector genes, demonstrating a conserved role of the circadian system in modulating xenobiotic toxicity.