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Archives of Toxicology

, Volume 89, Issue 2, pp 221–231 | Cite as

A day and night difference in the response of the hepatic transcriptome to cyclophosphamide treatment

  • Kirsten C. G. Van Dycke
  • Romana M. Nijman
  • Paul F. K. Wackers
  • Martijs J. Jonker
  • Wendy Rodenburg
  • Conny T. M. van Oostrom
  • Daniela C. F. Salvatori
  • Timo M. Breit
  • Harry van Steeg
  • Mirjam Luijten
  • Gijsbertus T. J. van der Horst
Molecular Toxicology

Abstract

Application of omics-based technologies is a widely used approach in research aiming to improve testing strategies for human health risk assessment. In most of these studies, however, temporal variations in gene expression caused by the circadian clock are a commonly neglected pitfall. In the present study, we investigated the impact of the circadian clock on the response of the hepatic transcriptome after exposure of mice to the chemotherapeutic agent cyclophosphamide (CP). Analysis of the data without considering clock progression revealed common responses in terms of regulated pathways between light and dark phase exposure, including DNA damage, oxidative stress, and a general immune response. The overall response, however, was stronger in mice exposed during the day. Use of time-matched controls, thereby eliminating non-CP-responsive circadian clock-controlled genes, showed that this difference in response was actually even more pronounced: CP-related responses were only identified in mice exposed during the day. Only minor differences were found in acute toxicity pathways, namely lymphocyte counts and kidney weights, indicating that gene expression is subject to time of day effects. This study is the first to highlight the impact of the circadian clock on the identification of toxic responses by omics approaches.

Keywords

Toxicogenomics Circadian clock Cyclophosphamide Mouse in vivo Chronotoxicity 

Notes

Acknowledgments

The work described was carried out under auspices of the Netherlands Toxicogenomics Centre (NTC) (http://www.toxicogenomics.nl) and received financial support from the Netherlands Genomics Initiative/Netherlands Organisation for Scientific Research (NGI/NWO Grant No. 050-060-510). The authors gratefully acknowledge the assistance of Edwin Zwart and thank Liset de la Fonteyne for immunological evaluations and for performing the micronucleus assay.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

204_2014_1257_MOESM1_ESM.pdf (1.1 mb)
Supplementary material 1 (PDF 1152 kb)

References

  1. Akhtar RA, Reddy AB, Maywood ES et al (2002) Circadian cycling of the mouse liver transcriptome, as revealed by cDNA microarray, is driven by the suprachiasmatic nucleus. Curr Biol CB 12(7):540–550CrossRefGoogle Scholar
  2. Anton E (1993) Differential sensitivity of DBA/2 and C57BL/6 mice to cyclophosphamide. J Appl Toxicol JAT 13(6):423–427CrossRefGoogle Scholar
  3. Balsalobre A, Damiola F, Schibler U (1998) A serum shock induces circadian gene expression in mammalian tissue culture cells. Cell 93(6):929–937PubMedCrossRefGoogle Scholar
  4. Blumenthal RD, Waskewich C, Goldenberg DM, Lew W, Flefleh C, Burton J (2001) Chronotherapy and chronotoxicity of the cyclooxygenase-2 inhibitor, celecoxib, in athymic mice bearing human breast cancer xenografts. Clin Cancer Res 7(10):3178–3185PubMedGoogle Scholar
  5. Bozek K, Relogio A, Kielbasa SM et al (2009) Regulation of clock-controlled genes in mammals. PLoS ONE 4(3):e4882. doi: 10.1371/journal.pone.0004882 PubMedCentralPubMedCrossRefGoogle Scholar
  6. Colvin OM (1999) An overview of cyclophosphamide development and clinical applications. Curr Pharm Des 5(8):555–560PubMedGoogle Scholar
  7. Cui X, Hwang JT, Qiu J, Blades NJ, Churchill GA (2005) Improved statistical tests for differential gene expression by shrinking variance components estimates. Biostatistics 6(1):59–75. doi: 10.1093/biostatistics/kxh018 PubMedCrossRefGoogle Scholar
  8. de Leeuw WC, Rauwerda H, Jonker MJ, Breit TM (2008) Salvaging Affymetrix probes after probe-level re-annotation. BMC Res Notes 1:66. doi: 10.1186/1756-0500-1-661756-0500-1-66 PubMedCentralPubMedCrossRefGoogle Scholar
  9. DeLeve LD (1996) Cellular target of cyclophosphamide toxicity in the murine liver: role of glutathione and site of metabolic activation. Hepatology 24(4):830–837. doi: 10.1002/hep.510240414 PubMedCrossRefGoogle Scholar
  10. Destici E, Oklejewicz M, Nijman R, Tamanini F, van der Horst GT (2009) Impact of the circadian clock on in vitro genotoxic risk assessment assays. Mutat Res 680(1–2):87–94. doi: 10.1016/j.mrgentox.2009.09.001 PubMedCrossRefGoogle Scholar
  11. Emadi A, Jones RJ, Brodsky RA (2009) Cyclophosphamide and cancer: golden anniversary. Nat Rev Clin Oncol 6(11):638–647. doi: 10.1038/nrclinonc.2009.146 PubMedCrossRefGoogle Scholar
  12. Gachon F, Olela FF, Schaad O, Descombes P, Schibler U (2006) The circadian PAR-domain basic leucine zipper transcription factors DBP, TEF, and HLF modulate basal and inducible xenobiotic detoxification. Cell Metab 4(1):25–36. doi: 10.1016/j.cmet.2006.04.015 PubMedCrossRefGoogle Scholar
  13. Gorbacheva VY, Kondratov RV, Zhang R et al (2005) Circadian sensitivity to the chemotherapeutic agent cyclophosphamide depends on the functional status of the CLOCK/BMAL1 transactivation complex. Proc Natl Acad Sci USA 102(9):3407–3412. doi: 10.1073/pnas.0409897102 PubMedCentralPubMedCrossRefGoogle Scholar
  14. Granda TG, Filipski E, D’Attino RM et al (2001) Experimental chronotherapy of mouse mammary adenocarcinoma MA13/C with docetaxel and doxorubicin as single agents and in combination. Cancer Res 61(5):1996–2001PubMedGoogle Scholar
  15. Grechez-Cassiau A, Rayet B, Guillaumond F, Teboul M, Delaunay F (2008) The circadian clock component BMAL1 is a critical regulator of p21WAF1/CIP1 expression and hepatocyte proliferation. J Biol Chem 283(8):4535–4542. doi: 10.1074/jbc.M705576200 PubMedCrossRefGoogle Scholar
  16. Hales BF (1982) Comparison of the mutagenicity and teratogenicity of cyclophosphamide and its active metabolites, 4-hydroxycyclophosphamide, phosphoramide mustard, and acrolein. Cancer Res 42(8):3016–3021PubMedGoogle Scholar
  17. Hill DL, Laster WR Jr, Struck RF (1972) Enzymatic metabolism of cyclophosphamide and nicotine and production of a toxic cyclophosphamide metabolite. Cancer Res 32(4):658–665PubMedGoogle Scholar
  18. Hughes ME, Hogenesch JB, Kornacker K (2010) JTK_CYCLE: an efficient nonparametric algorithm for detecting rhythmic components in genome-scale data sets. J Biol Rhythms 25(5):372–380. doi: 10.1177/0748730410379711 PubMedCentralPubMedCrossRefGoogle Scholar
  19. Hussain A, Shadma W, Maksood A, Ansari SH (2013) Protective effects of Picrorhiza kurroa on cyclophosphamide-induced immunosuppression in mice. Pharmacognosy Res 5(1):30–35. doi: 10.4103/0974-8490.105646 PubMedCentralPubMedCrossRefGoogle Scholar
  20. Irizarry RA, Hobbs B, Collin F et al (2003) Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics 4(2):249–264. doi: 10.1093/biostatistics/4.2.2494/2/249 PubMedCrossRefGoogle Scholar
  21. Kern JC, Kehrer JP (2002) Acrolein-induced cell death: a caspase-influenced decision between apoptosis and oncosis/necrosis. Chem Biol Interact 139(1):79–95PubMedCrossRefGoogle Scholar
  22. King PD, Perry MC (2001) Hepatotoxicity of chemotherapy. Oncologist 6(2):162–176PubMedCrossRefGoogle Scholar
  23. Ko CH, Takahashi JS (2006) Molecular components of the mammalian circadian clock. Hum Mol Genet 15 Spec No 2:R271-7. doi: 10.1093/hmg/ddl207
  24. Kumaki Y, Ukai-Tadenuma M, Uno KD et al (2008) Analysis and synthesis of high-amplitude Cis-elements in the mammalian circadian clock. Proc Natl Acad Sci USA 105(39):14946–14951. doi: 10.1073/pnas.0802636105 PubMedCentralPubMedCrossRefGoogle Scholar
  25. Lee C, Etchegaray JP, Cagampang FR, Loudon AS, Reppert SM (2001) Posttranslational mechanisms regulate the mammalian circadian clock. Cell 107(7):855–867PubMedCrossRefGoogle Scholar
  26. Levi F, Schibler U (2007) Circadian rhythms: mechanisms and therapeutic implications. Annu Rev Pharmacol Toxicol 47:593–628. doi: 10.1146/annurev.pharmtox.47.120505.105208 PubMedCrossRefGoogle Scholar
  27. Levi F, Okyar A, Dulong S, Innominato PF, Clairambault J (2010) Circadian timing in cancer treatments. Annu Rev Pharmacol Toxicol 50:377–421. doi: 10.1146/annurev.pharmtox.48.113006.094626 PubMedCrossRefGoogle Scholar
  28. Levi F, Karaboue A, Gorden L et al (2011) Cetuximab and circadian chronomodulated chemotherapy as salvage treatment for metastatic colorectal cancer (mCRC): safety, efficacy and improved secondary surgical resectability. Cancer Chemother Pharmacol 67(2):339–348. doi: 10.1007/s00280-010-1327-8 PubMedCrossRefGoogle Scholar
  29. Lowrey PL, Takahashi JS (2011) Genetics of circadian rhythms in Mammalian model organisms. Adv Genet 74:175–230. doi: 10.1016/B978-0-12-387690-4.00006-4 PubMedCentralPubMedCrossRefGoogle Scholar
  30. Ludeman SM (1999) The chemistry of the metabolites of cyclophosphamide. Curr Pharm Des 5(8):627–643PubMedGoogle Scholar
  31. Lushnikova EL, Molodykh OP, Nepomnyashchikh LM, Bakulina AA, Sorokina YA (2011) Ultrastructurural picture of cyclophosphamide-induced damage to the liver. Bull Exp Biol Med 151(6):751–756PubMedCrossRefGoogle Scholar
  32. Miller BH, McDearmon EL, Panda S et al (2007) Circadian and CLOCK-controlled regulation of the mouse transcriptome and cell proliferation. Proc Natl Acad Sci USA 104(9):3342–3347. doi: 10.1073/pnas.0611724104 PubMedCentralPubMedCrossRefGoogle Scholar
  33. Mohawk JA, Green CB, Takahashi JS (2012) Central and peripheral circadian clocks in mammals. Annu Rev Neurosci 35:445–462. doi: 10.1146/annurev-neuro-060909-153128 PubMedCentralPubMedCrossRefGoogle Scholar
  34. Mootha VK, Lindgren CM, Eriksson KF et al (2003) PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet 34(3):267–273. doi: 10.1038/ng1180 PubMedCrossRefGoogle Scholar
  35. Mullenders J, Fabius AW, Madiredjo M, Bernards R, Beijersbergen RL (2009) A large scale shRNA barcode screen identifies the circadian clock component ARNTL as putative regulator of the p53 tumor suppressor pathway. PLoS ONE 4(3):e4798. doi: 10.1371/journal.pone.0004798 PubMedCentralPubMedCrossRefGoogle Scholar
  36. OECD Test No. 474: Mammalian Erythrocyte Micronucleus Test. OECD PublishingGoogle Scholar
  37. Ohdo S (2010) Chronopharmaceutics: pharmaceutics focused on biological rhythm. Biol Pharm Bull 33(2):159–167PubMedCrossRefGoogle Scholar
  38. Panda S, Antoch MP, Miller BH et al (2002) Coordinated transcription of key pathways in the mouse by the circadian clock. Cell 109(3):307–320PubMedCrossRefGoogle Scholar
  39. Paschos GK, Baggs JE, Hogenesch JB, FitzGerald GA (2010) The role of clock genes in pharmacology. Annu Rev Pharmacol Toxicol 50:187–214. doi: 10.1146/annurev.pharmtox.010909.105621 PubMedCrossRefGoogle Scholar
  40. Pizarro A, Hayer K, Lahens NF, Hogenesch JB (2013) CircaDB: a database of mammalian circadian gene expression profiles. Nucleic Acids Res 41(Database issue):D1009-13. doi: 10.1093/nar/gks1161
  41. Rehman MU, Tahir M, Ali F et al (2012) Cyclophosphamide-induced nephrotoxicity, genotoxicity, and damage in kidney genomic DNA of Swiss albino mice: the protective effect of Ellagic acid. Mol Cell Biochem 365(1–2):119–127. doi: 10.1007/s11010-012-1250-x PubMedCrossRefGoogle Scholar
  42. Reppert SM, Weaver DR (2001) Molecular analysis of mammalian circadian rhythms. Annu Rev Physiol 63:647–676. doi: 10.1146/annurev.physiol.63.1.64763/1/647 PubMedCrossRefGoogle Scholar
  43. Reppert SM, Weaver DR (2002) Coordination of circadian timing in mammals. Nature 418(6901):935–941. doi: 10.1038/nature00965 PubMedCrossRefGoogle Scholar
  44. Sancar A, Lindsey-Boltz LA, Kang TH, Reardon JT, Lee JH, Ozturk N (2010) Circadian clock control of the cellular response to DNA damage. FEBS Lett 584(12):2618–2625. doi: 10.1016/j.febslet.2010.03.017 PubMedCentralPubMedCrossRefGoogle Scholar
  45. Smyth GK (2004) Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol 3(3). doi: 10.2202/1544-6115.1027
  46. Storch KF, Lipan O, Leykin I et al (2002) Extensive and divergent circadian gene expression in liver and heart. Nature 417(6884):78–83. doi: 10.1038/nature744 PubMedCrossRefGoogle Scholar
  47. Storey JD, Tibshirani R (2003) Statistical significance for genomewide studies. Proc Natl Acad Sci USA 100(16):9440–9445. doi: 10.1073/pnas.1530509100 PubMedCentralPubMedCrossRefGoogle Scholar
  48. Subramanian A, Tamayo P, Mootha VK et al (2005) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA 102(43):15545–15550. doi: 10.1073/pnas.0506580102 PubMedCentralPubMedCrossRefGoogle Scholar
  49. Tonk EC, de Groot DM, Penninks AH et al (2010) Developmental immunotoxicity of methylmercury: the relative sensitivity of developmental and immune parameters. Toxicol Sci 117(2):325–335. doi: 10.1093/toxsci/kfq223 PubMedCrossRefGoogle Scholar
  50. Tripathi DN, Jena GB (2008) Ebselen attenuates cyclophosphamide-induced oxidative stress and DNA damage in mice. Free Radical Res 42(11–12):966–977. doi: 10.1080/10715760802566558 CrossRefGoogle Scholar
  51. Ueda HR, Chen W, Adachi A et al (2002) A transcription factor response element for gene expression during circadian night. Nature 418(6897):534–539. doi: 10.1038/nature00906 PubMedCrossRefGoogle Scholar
  52. Weaver DR (1998) The suprachiasmatic nucleus: a 25-year retrospective. J Biol Rhythms 13(2):100–112PubMedCrossRefGoogle Scholar
  53. Welsh DK, Takahashi JS, Kay SA (2010) Suprachiasmatic nucleus: cell autonomy and network properties. Annu Rev Physiol 72:551–577. doi: 10.1146/annurev-physiol-021909-135919 PubMedCentralPubMedCrossRefGoogle Scholar
  54. Wolfinger RD, Gibson G, Wolfinger ED et al (2001) Assessing gene significance from cDNA microarray expression data via mixed models. J Comput Biol 8(6):625–637. doi: 10.1089/106652701753307520 PubMedCrossRefGoogle Scholar
  55. Yan J, Wang H, Liu Y, Shao C (2008) Analysis of gene regulatory networks in the mammalian circadian rhythm. PLoS Comput Biol 4(10):e1000193. doi: 10.1371/journal.pcbi.1000193 PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Kirsten C. G. Van Dycke
    • 1
    • 2
  • Romana M. Nijman
    • 2
  • Paul F. K. Wackers
    • 1
    • 2
    • 3
  • Martijs J. Jonker
    • 3
    • 4
  • Wendy Rodenburg
    • 1
  • Conny T. M. van Oostrom
    • 1
  • Daniela C. F. Salvatori
    • 5
  • Timo M. Breit
    • 3
    • 4
  • Harry van Steeg
    • 1
    • 6
  • Mirjam Luijten
    • 1
    • 6
  • Gijsbertus T. J. van der Horst
    • 1
    • 2
  1. 1.Centre for Health ProtectionNational Institute for Public Health and the Environment (RIVM)BilthovenThe Netherlands
  2. 2.Department of Genetics, Center for Biomedical GeneticsErasmus University Medical CenterRotterdamThe Netherlands
  3. 3.MicroArray Department and Integrative Bioinformatics Unit, Swammerdam Institute for Life Sciences, Faculty of ScienceUniversity of AmsterdamAmsterdamThe Netherlands
  4. 4.Netherlands Bioinformatics Centre (NBIC)NijmegenThe Netherlands
  5. 5.Central Animal FacilityLeiden University Medical CenterLeidenThe Netherlands
  6. 6.Department of ToxicogeneticsLeiden University Medical CenterLeidenThe Netherlands

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