Circadian Clock Regulates Response to Pesticides in Drosophila via Conserved Pdp1 Pathway

Abstract

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 (Pdp1epsilon) 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 Pdp1epsilon 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.

Loss of circadian clock accelerates aging in neurodegeneration-prone mutants

“…Circadian clocks are involved in the regulation of response to genotoxic stress and xenobiotics in both mice and fly (Antoch et al, 2008; Beaver et al, 2010; Gachon and Firsov, 2011). Therefore, increased neurodegeneration in arrhythmic sni 1 and sws 1 mutants may involve additional pathways beyond ROS homeostasis.…”

Esterase-based metabolic resistance to insecticides in heliothine and spodopteran pests

“…123,124) There are also data showing coordinate control of some esterase, P450 and GST genes mediated by circadian clock genes, with correlated effects on xenobiotic (including permethrin) detoxification. [124][125][126] It is clearly unlikely that circadian clock genes are directly involved in the resistance phenotypes we have reviewed. However these and the microarray data demonstrate that the expression of at least some genes with primary detoxification functions are embedded in larger regulatory networks.…”

“…However these and the microarray data demonstrate that the expression of at least some genes with primary detoxification functions are embedded in larger regulatory networks. Orthologues of the genes encoding transcription factors or receptors downstream of the Drosophila clock genes in the pathway which Beaver et al 125) have begun to elucidate may be candidate loci for the master regulator mutations.…”

Integrating Circadian Activity and Gene Expression Profiles to Predict Chronotoxicity of Drosophila suzukii Response to Insecticides

“…Since metabolic resistance of insecticides is believed to develop through upregulation of detoxification pathways [40], [44], the time of day when expression of detoxification genes and subsequent enzyme activities is at their minimum may correspond to the time when insects are most susceptible to insecticides. A study using D. melanogaster as a model concluded that there is indeed some correlation between the circadian timing of susceptibility to certain classes of pesticides to expression of circadian regulated Phase I and II detoxification enzymes [45], [46]. Assuming that detoxification of xenobiotics in D. suzukii is similar to that in D. melanogaster , other insects, and even mammals [46]–[49] in being under circadian clock control, it may be possible to identify a time period when D. suzukii is most susceptible to insecticides.…”

“…A study using D. melanogaster as a model concluded that there is indeed some correlation between the circadian timing of susceptibility to certain classes of pesticides to expression of circadian regulated Phase I and II detoxification enzymes [45], [46]. Assuming that detoxification of xenobiotics in D. suzukii is similar to that in D. melanogaster , other insects, and even mammals [46]–[49] in being under circadian clock control, it may be possible to identify a time period when D. suzukii is most susceptible to insecticides.…”