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Using Drosophila melanogaster to identify chemotherapy toxicity genes.

ABSTRACT: The severity of the toxic side effects of chemotherapy shows a great deal of interindividual variability, and much of this variation is likely genetically based. Simple DNA tests predictive of toxic side effects could revolutionize the way chemotherapy is carried out. Due to the challenges in identifying polymorphisms that affect toxicity in humans, we use Drosophila fecundity following oral exposure to carboplatin, gemcitabine and mitomycin C as a model system to identify naturally occurring DNA variants predictive of toxicity. We use the Drosophila Synthetic Population Resource (DSPR), a panel of recombinant inbred lines derived from a multiparent advanced intercross, to map quantitative trait loci affecting chemotoxicity. We identify two QTL each for carboplatin and gemcitabine toxicity and none for mitomycin. One QTL is associated with fly orthologs of a priori human carboplatin candidate genes ABCC2 and MSH2, and a second QTL is associated with fly orthologs of human gemcitabine candidate genes RRM2 and RRM2B. The third, a carboplatin QTL, is associated with a posteriori human orthologs from solute carrier family 7A, INPP4A&B, and NALCN. The fourth, a gemcitabine QTL that also affects methotrexate toxicity, is associated with human ortholog GPx4. Mapped QTL each explain a significant fraction of variation in toxicity, yet individual SNPs and transposable elements in the candidate gene regions fail to singly explain QTL peaks. Furthermore, estimates of founder haplotype effects are consistent with genes harboring several segregating functional alleles. We find little evidence for nonsynonymous SNPs explaining mapped QTL; thus it seems likely that standing variation in toxicity is due to regulatory alleles.

SUBMITTER: King EG

PROVIDER: S-EPMC4174942 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Using Drosophila melanogaster to identify chemotherapy toxicity genes.

King Elizabeth G EG Kislukhin Galina G Walters Kelli N KN Long Anthony D AD

Genetics 20140901 1

The severity of the toxic side effects of chemotherapy shows a great deal of interindividual variability, and much of this variation is likely genetically based. Simple DNA tests predictive of toxic side effects could revolutionize the way chemotherapy is carried out. Due to the challenges in identifying polymorphisms that affect toxicity in humans, we use Drosophila fecundity following oral exposure to carboplatin, gemcitabine and mitomycin C as a model system to identify naturally occurring DN ...[more]

PMID: 25236447

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Project description:Graphical abstract Highlights • Contact to Dithiothreitol (DTT), a widely used antioxidant, is lethal to the fruit fly Drosophila melanogaster.• At low concentrations, DTT contact induces the expression of some apoptosis genes.• In parallel, DTT triggers the expression of a cuticle barrier gene.• Expression of some genes involved in detoxification is intensified with increasing DTT concentrations.• Toxicity of DTT to the exnvironment should be tested. The thiol-containing compound Dithiothreitol (DTT) has been shown to be toxic to cultured cells by inducing the generation of reactive oxygen species that ultimately cause cell death. However, its effects on multicellular organisms and the environment have not been investigated yet in detail. In this work, we tested the toxicity of DTT to the model insect Drosophila melanogaster. We show that DTT is lethal to D. melanogaster by topical application but not through feeding. DTT treatment triggers the transcription of the canonical apoptosis regulators grim, hid and rpr at low amounts. The amplitude of this induction declines with elevating DTT amounts. By live microscopy, we observe apoptotic cells especially in the gut of DTT treated flies. In parallel, low DTT amounts also activate the expression of the cuticle barrier component gene snsl. This indicates that a physical defence response is launched upon DTT contact. This combined measure is seemingly successful in preventing fly death. The expression of a number of known detoxification genes including cyp6a2, cyp6a8, cyp12d1 and GstD2 is also enhanced through DTT contact. The degree of upregulation of these genes is proportional to the applied DTT amounts. Despite this effort, flies exposed to high amounts of DTT eventually die. Together, D. melanogaster is able to sense DTT toxicity and adjust the defence response successfully at least at low concentrations. This is the first time to analyse the molecular consequences of DTT exposure in a multicellular organism. Our work provides a new model to discuss the physiological response of animals against thiol toxins and to resurvey the effect of redox agents on the environment.

Project description:Organophosphate pesticides used in agriculture can pose health risks to humans and wildlife. We hypothesized that dietary supplementation with Lactobacillus, a genus of commensal bacteria, would reduce absorption and toxicity of consumed organophosphate pesticides (parathion and chlorpyrifos [CP]). Several Lactobacillus species were screened for toleration of 100 ppm of CP or parathion in MRS broth based on 24-h growth curves. Certain Lactobacillus strains were unable to reach stationary-phase culture maxima and displayed an abnormal culture morphology in response to pesticide. Further characterization of commonly used, pesticide-tolerant and pesticide-susceptible, probiotic Lactobacillus rhamnosus strain GG (LGG) and L. rhamnosus strain GR-1 (LGR-1), respectively, revealed that both strains could significantly sequester organophosphate pesticides from solution after 24-h coincubations. This effect was independent of metabolic activity, as L. rhamnosus GG did not hydrolyze CP and no difference in organophosphate sequestration was observed between live and heat-killed strains. Furthermore, LGR-1 and LGG reduced the absorption of 100 ?M parathion or CP in a Caco-2 Transwell model of the small intestine epithelium. To determine the effect of sequestration on acute toxicity, newly eclosed Drosophila melanogaster flies were exposed to food containing 10 ?M CP with or without supplementation with live LGG. Supplementation with LGG simultaneously, but not with administration of CP 3 days prior (prophylactically), mitigated CP-induced mortality. In summary, the results suggest that L. rhamnosus may be useful for reducing toxic organophosphate pesticide exposure via passive binding. These findings could be transferable to clinical and livestock applications due to affordability and practical ability to supplement products with food-grade bacteria.The consequences of environmental pesticide pollution due to widespread usage in agriculture and soil leaching are becoming a major societal concern. Although the long-term effects of low-dose pesticide exposure for humans and wildlife remain largely unknown, logic suggests that these chemicals are not aligned with ecosystem health. This observation is most strongly supported by the agricultural losses associated with honeybee population declines, known as colony collapse disorder, in which pesticide usage is a likely trigger. Lactobacilli are bacteria used as beneficial microorganisms in fermented foods and have shown potentials to sequester and degrade environmental toxins. This study demonstrated that commonly used probiotic strains of lactobacilli could sequester, but not metabolize, organophosphate pesticides (parathion and chlorpyrifos). This Lactobacillus-mediated sequestration was associated with decreased intestinal absorption and insect toxicity in appropriate models. These findings hold promise for supplementing human, livestock, or apiary foods with probiotic microorganisms to reduce organophosphate pesticide exposure.

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Using Drosophila melanogaster to identify chemotherapy toxicity genes.

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Using Drosophila melanogaster to identify chemotherapy toxicity genes.

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