Journal Article

Circadian Clock Regulates Response to Pesticides in <i>Drosophila</i> via Conserved <i>Pdp1</i> Pathway

Laura Michelle Beaver, Louisa Ada Hooven, Shawn Michael Butcher, Natraj Krishnan, Katherine Alice Sherman, Eileen Shin-Yeu Chow and Jadwiga Maria Giebultowicz

in Toxicological Sciences

Volume 115, issue 2, pages 513-520
Published in print June 2010 | ISSN: 1096-6080
Published online March 2010 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfq083
Circadian Clock Regulates Response to Pesticides in Drosophila via Conserved Pdp1 Pathway

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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 ϵ-isoform of the PAR-domain protein 1 (Pdp1ε) 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 Pdp1ε 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 α-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.

Keywords: circadian clock; Pdp1; permethrin; Cyp6g1; α-Esterase-7; DHR96

Journal Article.  4932 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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