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Insect Biochemistry and Molecular Biology 36 (2006) 674–682 Xenobiotic response in Drosophila melanogaster: Sex dependence of Gae¨lle Le Goffa,b,Ã, Fre´de´rique Hillioub, Blair D. Siegfriedc, Sam Boundya, Eric Wajnbergb, Luc Soferb, Pascaline Audantb, Richard H. ffrench-Constanta, Rene´ Feyereisenb aDepartment of Biology and Biochemistry, University of Bath, Bath BA2 7AY, UK bINRA and Universite´ de Nice-Sophia Antipolis, UMR 1112, 06903 Sophia Antipolis, France cDepartment of Entomology, University of Nebraska, Lincoln, Nebraska Received 28 March 2006; received in revised form 19 May 2006; accepted 22 May 2006 The effect of xenobiotics (phenobarbital and atrazine) on the expression of Drosophila melanogaster CYP genes encoding cytochromes P450, a gene family generally associated with detoxification, was analyzed by DNA microarray hybridization and verified by real-timeRT-PCR in adults of both sexes. Only a small subset of the 86 CYP genes was significantly induced by the xenobiotics. Eleven CYP genesand three glutathione S-transferases (GST) genes were significantly induced by phenobarbital, seven CYP and one GST gene wereinduced by atrazine. Cyp6d5, Cyp6w1, Cyp12d1 and the ecdysone-inducible Cyp6a2 were induced by both chemicals. The constitutiveexpression of several of the inducible genes (Cyp6a2, Cyp6a8, Cyp6d5, Cyp12d1) was higher in males than in females, and the inducedlevel similar in both sexes. Thus, the level of induction was consistently higher in females than in males. The female-specific andhormonally regulated yolk protein genes were significantly induced by phenobarbital in males and repressed by atrazine in females. Ourresults suggest that the numerous CYP genes of Drosophila respond selectively to xenobiotics, providing the fly with an adaptive responseto chemically adverse environments. The xenobiotic inducibility of some CYP genes previously associated with insecticide resistance inlaboratory-selected strains (Cyp6a2, Cyp6a8, Cyp12d1) suggests that deregulation of P450 gene expression may be a facile way to achieveresistance. Our study also suggests that xenobiotic-induced changes in P450 levels can affect insect fitness by interfering with hormonallyregulated networks.
r 2006 Elsevier Ltd. All rights reserved.
Keywords: Phenobarbital; Atrazine; DNA microarray; CYP gene; Glutathione S-transferase; Esterase; Induction; Resistance and 3-methylcholanthrene (Biochemicallydistinct P450 enzymes were revealed by these prototypical Multigene families encoding cytochromes P450, glu- inducers. Induction helped characterize most drug-meta- tathione S-transferases and esterases are thought to bolizing enzymes in vertebrates, before their total comple- provide animals means to fend off xenobiotic challenges ment was revealed by genome sequencing. In contrast, the from the environment, such as toxic plant and microbial large number of P450 genes in insects and their poor chemicals encountered in their food or drugs, pesticides representation in the initial EST collections ( and organic pollutants. The multiplicity of P450 enzymes begged the question of their function. Few genes was highlighted 40 years ago by the response of vertebrate encoding insect P450s, glutathione S-transferases (GST) or tissues to treatment by chemicals such as phenobarbital esterases have been specifically and directly linked to a rolein detoxification or insecticide resistance despite the over-whelming biochemical evidence of their role in these ÃCorresponding author. INRA and Universite´ de Nice-Sophia Anti- polis, UMR 1112, 06903 Sophia Antipolis, France. Tel.: +33 4 92 38 65 78; is therefore needed to characterize these genes. DNA 0965-1748/$ - see front matter r 2006 Elsevier Ltd. All rights reserved.
doi: G. Le Goff et al. / Insect Biochemistry and Molecular Biology 36 (2006) 674–682 microarray hybridization is the method of choice to study genome-wide responses, as shown in Caenorhabditiselegans (). In Drosophila this Total RNA was extracted from 50–100 flies using Trizol technique has been used to identify responses to chemical Reagent (Invitrogen Life technologies). Three independent stressors such as paraquat, H2O2 and tunicamycin ( extractions were performed on three independent biologi- microarrays have been used to detect genes that areconstitutively overexpressed in insecticide-resistant strains from Drosophila and mosquitoes obtained from the field orselected further in the laboratory ; A cDNA microarray was constructed using expressed sequence tags (ESTs) of 1.8 kb average length and gene- specific tags of 0.4 kb average length obtained by PCR selectively represent all members of the detoxification gene amplification and plasmid cloning. This ‘‘Drosophila families and appropriate controls genes can provide a toxicology microarray’’ contained 319 genes that represent useful tool to identify inducible genes. all cytochromes P450, glutathione S-transferases, esterases, have used such a ‘‘detox chip’’ with 300 rat genes other genes of interest including attacin or Ftz-F1 and represented to study the effects of four known inducers, several housekeeping genes as controls. Each insert was phenobarbital, 3-methylcholanthrene, dexamethasone and amplified by PCR with flanking universal primers, purified clofibrate on rat liver gene expression. This study described and then spotted using the ChipWriterPro Virtek (BioRad) the inducer-specific pattern of transcriptional activation spotter at three independent locations on Corning Ultra- and confirmed the induction of CYP2B1, CYP2B2, GAPS slides (Corning). All information concerning the CYP2C6 as well as CYP3A12 and 3A2 by phenobarbital.
Induction of drug-metabolizing enzymes, and of cyto- chrome P450-mediated pesticide metabolism in particular,has been extensively studied in insects ().
2.4. cDNA preparation and microarray hybridization Induction of specific genes is now well documented (e.g.,CYP6A1; and induction of P450 genes cDNA were synthesized from 10 mg of total RNA and by a wide variety of chemicals is now amply demonstrated labelled with the dyes Cy3- dCTP and Cy5- dCTP (Amersham) using the Pronto! Universal Microarray response within the whole multigene families or the Hybridization Kit according to the manufacturer’s instruc- selectivity of the inducer has yet to be documented.
tions. Each RNA was labelled with Cy3 and Cy5 to Here we use a Drosophila melanogaster DNA microarray perform reverse-labelled replicate arrays (dye swap) be- of 319 genes covering in a redundant manner all CYP cause of bias in dye incorporation. One comparison genes, GST genes and esterase genes, to determine which consists of a total of six arrays corresponding to two dye- genes are affected in both males and females by treatment swap arrays for each of our three biological replicates. We of the flies with phenobarbital and atrazine, a prototypical realized a balanced-block design of 24 arrays to compare inducer and a widely used herbicide known to contaminate phenobarbital and atrazine treatments in which female and both terrestrial and aquatic habitats. Our results show that male were separately treated. Hybridizations were per- induction is sex- and inducer-specific and that xenobiotic formed at 42 1C for 14 h, followed by post-hybridization exposure can interfere with hormonally regulated physio- washes. Slides were scanned on a Genepix 4000b scanner and signal quantification was performed using the Genepixpro 4.1 software (Axon Instruments).
2.1. Drosophila stock and induction regime Data files from Genepix were converted using Express Converter software and normalized in Microarray Data All fly stocks were maintained at 21 1C on standard corn Analysis System (MIDAS), using two publicly available medium for a 12:12 h dark/light period. Oregon R flies were used as wild-type strain. Emerging flies were Three steps of normalization were performed in MIDAS, separated by sex and maintained on standard diet for (a) a low-intensity filter in which signal intensity o1000 72 h before induction. The flies were then placed on was removed; (b) a global lowess normalization was medium containing the inducer at 10 mM for phenobarbi- applied; (c) a flip dye consistency check, the Cy3 and Cy5 tal or 5 mM atrazine for 72 additional hours. These labels were swapped between controls versus treatments to concentrations were sublethal during the course of the account for potential differences in labelling efficiency. For experiment. After exposure, flies were frozen in liquid statistical analysis, each array intensity was log-trans- nitrogen for subsequent RNA extraction.
formed, centred by their average value and reduced by their G. Le Goff et al. / Insect Biochemistry and Molecular Biology 36 (2006) 674–682 standard deviation. The resulting data for each gene were treated versus control transcript levels expressed as fold analyzed with a type III two-way (i.e., sex  treatment) change for each treatment and for males and females.
analysis of variance (ANOVA) taking into account the Phenobarbital induced seven P450 genes and one GST presence of missing values. A gene was considered as gene in males. In females, phenobarbital induced ten P450 differentially expressed if 50% or more of its variance was and two GST genes and it down-regulated two P450 genes explained by the treatment effect with a corresponding and the a-Esterase 3 gene. Six P450 genes as well as GST P-value lower than 0.035. Data were removed when there D2 were induced by phenobarbital in both sexes. Atrazine was no consistency for a same gene represented on the induced four P450 genes, a GST gene and an esterase gene array by PCR products of different size, as this may have in males; it repressed one P450 gene, a GST and an esterase reflected a different degree of specificity.
gene. In females, atrazine induced six P450 genes. ThreeP450 genes were induced by atrazine in both sexes.
Only three P450 genes, Cyp6a2, Cyp6w1, Cyp12d1, were induced by both chemicals and in both sexes. The other Total RNA (1 mg) was reverse-transcribed using the genes had sex- and/or chemical-selective responses. Sur- iScript cDNA Synthesis Kit (BioRad). QPCR reactions prisingly, the three yolk protein (Yp) genes that were part were carried out on an Opticon monitor 2 (BioRad) using of the set of control genes on the array were found to be the Absolute QPCR SYBR green Mix (ABgene). The PCR strongly induced by phenobarbital in males and were conditions were as follows: 95 1C for 15 min to activate the upregulated from virtually undetectable levels in untreated hot-start DNA polymerase, followed by 40 cycles of 95 1C flies. Atrazine down-regulated these same genes in females for 30 s, 65 1C for 30 s and 72 1C for 30 s. Each reaction was (). Further, the Ftz-f1 nuclear receptor gene was performed in triplicate and the mean of three independent significantly down-regulated in females by atrazine. Cyto- biological replicates was calculated. All results were chrome b5, a redox partner in some microsomal P450 normalized to the RpL17 mRNA level and calculated reactions, was induced in males and repressed in females by Microarray results were confirmed by qRT-PCR for Cyp6a2, Cyp6d5, Cyp6g1, Cyp6w1, Cyp12d1 and also forCyp6a8 that was not included in the microarray experi- Adult flies of both sexes were exposed to phenobarbital ments for technical reasons. The results ) and atrazine in their food, and changes in the transcript highlight the significant sex-dependent differences in abundance for P450, GST and esterase genes assayed using induction with low basal levels in females and more microarray hybridization. list the genes that spectacular induction than in males. The strong induction were significantly up- or down-regulated and the ratio of of yolk protein genes was confirmed by qRT-PCR ().
Table 1Genes differentially expressed in females flies after phenobarbital treatment (ANOVA) G. Le Goff et al. / Insect Biochemistry and Molecular Biology 36 (2006) 674–682 Table 2Genes differentially expressed in male flies after phenobarbital treatment (ANOVA) Table 3Genes differentially expressed in male flies after atrazine treatment (ANOVA) Table 4Genes differentially expressed in female flies after atrazine treatment (ANOVA) formly responsive to xenobiotics. Only five P450 genes, andone GST gene, were induced by the two chemicals used in Our results show that the Drosophila genes coding for this study, whereas another handful of genes showed a the ‘‘drug-metabolizing enzymes’’ (DME) are not uni- more selective pattern of transcriptional variation. Even G. Le Goff et al. / Insect Biochemistry and Molecular Biology 36 (2006) 674–682 Fig. 3. Effects of phenobarbital on yolk protein mRNA levels in adultmales of Drosophila. Validations of microarray data by qPCR. Datapresented are the ratio of YP to Rpl17.
Fig. 1. Effects of phenobarbital on CYP mRNA levels in male and femaleDrosophila. Validations of microarray data by qPCR. Data presented are a threshold of approximately 90% DNA identity ( whereas cDNA/PCR-based arrays candistinguish P450 genes up to 80% DNA identity ). We therefore used qRT-PCR normalizedagainst Rpl17 expression to confirm the results of themicroarrays. The results obtained are consistent with eachother, although qRT-PCR is, as expected, a more sensitivetool. The use of a microarray dedicated to a subset of geneshas already proven useful in detecting transcriptionalchanges that are associated with insecticide resistance inDrosophila ) andin the mosquito Anopheles gambiae ).
Although whole genome arrays such as Affymetrix chipscan detect changes in more genes (e.g. ),practical considerations such as costs limit the number ofhybridizations and hence the statistical resolving power ofthese arrays. Thus, ‘‘detox chips’’ probably should becomea benchmark in the routine diagnosis of transcriptional Fig. 2. Effects of atrazine on CYP mRNA expression in male and female changes in the detoxification pathways of any organism Drosophila. Validations of microarray data by qPCR. Data presented are with a fully sequenced genome. Such thematic arrays have already proven their utility in vertebrate toxicology() and plant physiology ( though our arrays cover by design only a small proportion of all Drosophila genes, the results clearly identify a subset Several of the genes shown to be transcriptionally of genes that respond to xenobiotics and support the regulated by phenobarbital or atrazine have been reported usefulness of such thematic microarrays. Our study reveals before to be associated with metabolic resistance to that some of the genes regulated by xenobiotics have been associated with insecticide resistance or shown to be involved in resistance. Further we show that there is a strong sex bias in the induction, and that treatment by xenobiotics also disrupts the normal expression of genes known to be involved in endocrine processes.
Some of these genes are also inducible by other chemicals, The selective detection of transcriptional differences of such as DDT (). Insecticide resistance is closely related members of large gene families can be a generally attributed to constitutive overexpression of these difficult task, that was addressed for P450s in our study by the use of multiple DNA features of different sizes for each mutations in Cyp6a2 enable DDT metabolism. There are gene on the array, as well as by additional techniques, such other well-documented cases of xenobiotic-inducible genes as qRT-PCR. Affymetrix chips can distinguish genes up to that are constitutively overexpressed in insecticide-resistant G. Le Goff et al. / Insect Biochemistry and Molecular Biology 36 (2006) 674–682 strains, particularly CYP6A1 and CYP6D1 in the house fly (review in ). Is this relationship between constitutive expression of a P450 gene was reported induction and resistance coincidental or is there an underlying mechanism that ought to be studied in greater study shows that transcriptional regulation by xenobiotics detail? Early work, predominantly on housefly P450, had shown that resistant flies had biochemically distinct P450s, Phenobarbital is one of the most commonly used higher constitutive levels of P450, and different induction inducers of cytochromes P450, known to be effective in patterns. In some resistant strains induction is even greater animals as well as plants, and even in bacteria ( ). For insects, induction of a P450-dependent enzyme resistant strains, P450 levels are similar to induced levels of their susceptible counterparts (or even higher) and little or no further induction can be observed ().
ago. Molecular studies in several insect species have now Different inducers can also be distinguished in this way, identified many phenobarbital-inducible genes (review in some effective in a particular strain and others not species, several P450 genes were inducible as CYP6A1, CYP12A1 and CYP6D1 in the housefly, but here we metabolic resistance and induction were associated with provide a complete view of the pleiotropic effect of the production of different forms of glutathione S- phenobarbital induction on the CYP family in adult fruit flies. Regulatory elements responsible for the phenobarbi- induction in resistant flies was likely due to (P450) gene tal response of the Cyp6a2 and Cyp6a8 genes of Drosophila amplification, but they rejected induction as a factor in the development of resistance in the field. It was suggested that the same regulatory (trans-acting) gene may be involved in phenobarbital-inducible genes should facilitate this mole- both induction and biochemical resistance ), and further proposed that a receptor involved Atrazine is another known inducer of P450. Atrazine in xenobiotic induction may be altered in resistant insects.
induces P450-dependent activities and a CYP4-related However, despite growing evidence that overexpression of P450 gene in the aquatic larvae of the midge Chironomus some P450 genes in resistant strains can involve trans- induction of P450 activities has also been reported in induction has remained tenuous. Genetic analysis in Drosophila indicates that expressions of Cyp6a2 and induced pentoxyresorufin O-dealkylation activity in rats, as Cyp6a8 are controlled in trans by a negative regulator well as CYP2B on western blots, in a manner similar to mutations alter the normal regulatory network involved in Drosophila, we have shown that atrazine has a pattern of the induction of a P450 gene, this could result in higher induction that is similar, but not identical to phenobarbi- constitutive expression of the gene and hence resistance.
tal, and that is characterized by the induction of several The link between resistance and induction would thus be GST genes in males. This indicates a degree of selectivity, coincidental. Nonetheless, genes that are readily inducible but also an underlying complexity of the induction by xenobiotics have this regulatory mechanism in addition response. A large-scale screen of gene expression in the to their normal tissue, sex and developmental regulation.
nematode C. elegans revealed that CYP31A1 and A3 are Thus, they offer a broader target for mutational events inducible by both phenobarbital and atrazine whereas (point mutations, duplications, transposable element inser- CYP35A5 and 35C1 are induced by atrazine but not by tions, etc.) and may be more likely to be involved in resistance. Xenobiotic inducibility of a drug-metabolizing more chemicals will uncover the xenobiotic regulation of enzyme may therefore represent a risk factor for the different genes, and that a picture will emerge of over- lapping specificities of induction of P450 genes and/or Some of the sex differences in gene expression may be attributable to sex-linked differences in metabolism and Closely related genes showed a differential response to disposition of the inducers. In fact, little is known of the two inducing compounds: for instance, Cyp6a19 was phenobarbital or atrazine metabolism in insects (see repressed by phenobarbital in females, but Cyp6a2, 9, 17 and Cyp6a23 were induced, whereas other CYP6 genes exposure to the relatively high dose of inducer should were not affected. Some genes may represent ‘‘stress- minimize pharmacokinetic effects in favor of the pharma- responsive genes’’ such as Cyp28a5. This gene was induced by phenobarbital in both sexes, and by atrazine in males, Sex-dependent gene expression in Drosophila is well and this gene is also induced by paraquat, H2O2 and function of the genes transcriptionally regulated by G. Le Goff et al. / Insect Biochemistry and Molecular Biology 36 (2006) 674–682 phenobarbital or atrazine is largely unknown. Cyp6a2 is an document whether xenobiotic treatments actually modify abundant P450, enriched about 8-fold in Malpighian hormone levels. Xanthotoxin inducibility of the CYP6B1 gene in the black swallowtail, Papilio polyxenes is dependent on a xenobiotic response element in the gene promoter. Drosophila transcription factors related to the by many ESTs and the latter was first identified in olfactory vertebrate aryl hydrocarbon receptor appear to modulate organs (). Cyp12d1 is of special interest expression of the CYP6B1 promoter, but a ligand- because it encodes a mitochondrial P450, whereas the other dependent factor is not yet been identified ( genes encode microsomal P450s. The related CYP12A1 of The interactions between physiological signals and the housefly is also inducible by phenobarbital, and xenobiotics are necessary to allow the organism to integrate information from its environment and adapt to CYP12-like P450s of insects are thus a special type of it. The role of the so-called drug-metabolizing enzymes in inducible, environmental response genes, unlike the ster- this interplay is becoming clearer (reviewed by oid-metabolizing mitochondrial P450s of vertebrates and ). Our experiments start to shed some light on the known effects of P450 inducers on insect fitness as Little is known of the physiological substrates of the phenobarbital treatment was shown to delay development induced enzymes but Cyp6a2 was previously shown to be and reduce fecundity in flies by a mechanism that has metabolize JH III and related sesquiterpenoids ( more precisely the subset of xenobiotic-inducible genes and Cyp18a1 was initially cloned as a result of within the families encoding drug-metabolizing enzymes.
Tests on larvae as well as adults with a greater variety of Lobster CYP45, a CYP6/9-like P450 is induced by xenobiotics are thus warranted. The hypothesis that phenobarbital and by 20-hydroxyecdysone ( inducibility is a risk factor for resistance as discussed Similarly, CYP330A1 (a member of the CYP2 clan as CYP18) is inducible by ecdysteroids and by phenobarbitalin the crab Carcinus maenas whereas CYP4C39 is notThese genes are thus possible cross- over points between endocrine and xenobiotic signals.
Interestingly, the bFTZ-F1nuclear receptor, down-regu- We thank Charles Robin, Department of Genetics, lated by atrazine in female flies, is known to regulate University of Melbourne for clones of most of the GSTs ecdysteroid titers in Drosophila by controlling the expres- and esterase genes used on our array, Claire Conrad and sion of the dib and phm genes (). The dib Marcel Amichot for a set of P450 gene-specific tags, and and phm genes (Cyp302a1 and Cyp306a1) are expressed at Nathalie Tijet and Christian Helvig for their initial work levels too low to be detected in our whole-body sampling procedure. Nonetheless, the observation that yolk proteingene expression is down-regulated by atrazine as well asbFTZ-F1 is highly suggestive of endocrine disruption, because ecdysteroids normally induce yolk protein synth- Agosin, M., Scaramelli, N., Gil, L., Letelier, M.E., 1969. Some properties esis in female flies. Endocrine disruption is also suggested of the microsomal system metabolizing DDT in Triatoma infestans.
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