Archives of Toxicology

, Volume 91, Issue 4, pp 1763–1782 | Cite as

Strain differences in the proteome of dioxin-sensitive and dioxin-resistant mice treated with 2,3,7,8-tetrabromodibenzo-p-dioxin

  • Hoa Thanh Nguyen
  • Maria Claret Lauan Tsuchiya
  • Jean Yoo
  • Midori Iida
  • Tetsuro Agusa
  • Masashi Hirano
  • Eun-Young Kim
  • Tatsuhiko Miyazaki
  • Masato Nose
  • Hisato Iwata
Molecular Toxicology

Abstract

Dioxins cause various toxic effects through the aryl hydrocarbon receptor (AHR) in vertebrates, with dramatic species and strain differences in susceptibility. Although inbred mouse strains C3H/HeJ-lpr/lpr (C3H/lpr) and MRL/MpJ-lpr/lpr (MRL/lpr) are known as dioxin-sensitive and dioxin-resistant mice, respectively, the molecular mechanism underlying this difference remains unclear. The difference in the hepatic proteome of the two mouse strains treated with vehicle or 2,3,7,8-tetrabromodibenzo-p-dioxin (TBDD) was investigated by a proteomic approach of two-dimensional electrophoresis (2-DE) coupled with matrix-assisted laser desorption/ionization time-of-flight/time-of-flight tandem mass spectrometry (MALDI-TOF/TOF). To confirm the strain-difference in response to TBDD treatment, cytochrome P450 (CYP) 1A1 and 1A2 protein levels were measured in both strains. A dose of 10 µg/kg body weight of TBDD induced hepatic CYP1A1 and CYP1A2 expression in both strains, but the expression levels of both CYP1A proteins were higher in C3H/lpr mice than in MRL/lpr mice, supporting that C3H/lpr mice are more sensitive to dioxins than MRL/lpr mice. Proteins that were more induced or suppressed by TBDD treatment in C3H/lpr mice were successfully identified by 2-DE and MALDI-TOF/TOF, including proteins responsible for AHR activation through production of endogenous ligands such as aspartate aminotransferase, indolethylamine N-methyltransferase, and aldehyde dehydrogenases, as well as proteins reducing oxidative stress, such as superoxide dismutase and peroxiredoxins. Taken together, our results provide insights into the molecular mechanism underlying the high dioxin susceptibility of the C3H/lpr strain, in which AHR activation by TBDD is more prompted by the production of endogenous ligands, but the adaptation to oxidative stress is also acquired.

Keywords

Dioxin Susceptibility Proteome C3H/lpr MRL/lpr 

Supplementary material

204_2016_1834_MOESM1_ESM.pdf (536 kb)
Fig. S1 Effects of TBDD exposure on body and organ weights in C3H/lpr and MRL/lpr mice. (A) Body weight of C3H/lpr and MRL/lpr mice was measured before and after three days of treatment with corn oil (control) or TBDD. (B) Relative liver, spleen, kidney, and thymus weights in control and TBDD-treated C3H/lpr and MRL/lpr mice. Fig. S3 Enlarged regions of the 2-DE gel images showing the spots of GPRIN1 (A), PDHA1 (B), and ASS1 (C) isoforms differentially expressed by TBDD exposure. Fig. S4 C3H/lpr network found by Network Analyzer (Cytoscape). Nodes with higher degree are displayed as a larger circle, while shades of red to green colors represent high to low betweenness centrality values for the node.(PDF 537 kb)
204_2016_1834_MOESM2_ESM.pdf (390 kb)
Fig. S2 Representative Coomassie Brilliant Blue-stained 2-DE gel images of protein (350 µg) extracted from representative liver microsomal (A) and cytosolic (B) fractions in vehicle-treated C3H/lpr, TBDD-treated C3H/lpr, vehicle-treated MRL/lpr, and TBDD-treated MRL/lpr mice (PDF 391 kb)
204_2016_1834_MOESM3_ESM.xlsx (15 kb)
Supplementary material 3 (XLSX 15 kb)

References

  1. Ao K, Suzuki T, Murai H et al (2009) Comparison of immunotoxicity among tetrachloro-, pentachloro-, tetrabromo- and pentabromo-dibenzo-p-dioxins in mice. Toxicology 256:25–31. doi:10.1016/j.tox.2008.10.024 CrossRefPubMedGoogle Scholar
  2. Birnbaum LS, Staskal DF, Diliberto JJ (2003) Health effects of polybrominated dibenzo-p-dioxins (PBDDs) and dibenzofurans (PBDFs). Environ Int 29:855–860. doi:10.1016/S0160-4120(03)00106-5 CrossRefPubMedGoogle Scholar
  3. Bittinger MA, Nguyen LP, Bradfield CA (2003) Aspartate aminotransferase generates proagonists of the aryl hydrocarbon receptor. Mol Pharmacol 64:550–556. doi:10.1124/mol.64.3.550 CrossRefPubMedGoogle Scholar
  4. Boutros PC, Moffat ID, Franc MA et al (2004) Dioxin-responsive AHRE-II gene battery: identification by phylogenetic footprinting. Biochem Biophys Res Commun 321:707–715. doi:10.1016/j.bbrc.2004.06.177 CrossRefPubMedGoogle Scholar
  5. Boverhof DR, Burgoon LD, Tashiro C et al (2005) Temporal and dose-dependent hepatic gene expression patterns in mice provide new insights into TCDD-Mediated hepatotoxicity. Toxicol Sci Off J Soc Toxicol 85:1048–1063. doi:10.1093/toxsci/kfi162 CrossRefGoogle Scholar
  6. Boverhof DR, Burgoon LD, Tashiro C et al (2006) Comparative toxicogenomic analysis of the hepatotoxic effects of TCDD in Sprague Dawley rats and C57BL/6 mice. Toxicol Sci Off J Soc Toxicol 94:398–416. doi:10.1093/toxsci/kfl100 CrossRefGoogle Scholar
  7. Cho S-W, Suzuki K, Miura Y et al (2015) Novel role of hnRNP-A2/B1 in modulating aryl hydrocarbon receptor ligand sensitivity. Arch Toxicol 89:2027–2038. doi:10.1007/s00204-014-1352-1 CrossRefPubMedGoogle Scholar
  8. Chorley BN, Campbell MR, Wang X, et al (2012) Identification of novel NRF2-regulated genes by ChIP-Seq: influence on retinoid X receptor alpha. Nucleic Acids Res 40(15):7416–7429CrossRefPubMedPubMedCentralGoogle Scholar
  9. Davidson WF, Giese T, Fredrickson TN (1998) Spontaneous development of plasmacytoid tumors in mice with defective fas–fas ligand interactions. J Exp Med 187:1825–1838CrossRefPubMedPubMedCentralGoogle Scholar
  10. Denison MS, Heath-Pagliuso S (1998) The Ah receptor: a regulator of the biochemical and toxicological actions of structurally diverse chemicals. Bull Environ Contam Toxicol 61:557–568CrossRefPubMedGoogle Scholar
  11. Denison MS, Nagy SR (2003) Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals. Annu Rev Pharmacol Toxicol 43:309–334. doi:10.1146/annurev.pharmtox.43.100901.135828 CrossRefPubMedGoogle Scholar
  12. Denison MS, Fisher JM, Whitlock JP (1988) The DNA recognition site for the dioxin-Ah receptor complex. Nucleotide sequence and functional analysis. J Biol Chem 263:17221–17224PubMedGoogle Scholar
  13. Dere E, Boverhof DR, Burgoon LD, Zacharewski TR (2006) In vivo–in vitro toxicogenomic comparison of TCDD-elicited gene expression in Hepa1c1c7 mouse hepatoma cells and C57BL/6 hepatic tissue. BMC Genom 7:80. doi:10.1186/1471-2164-7-80 CrossRefGoogle Scholar
  14. Doncheva NT, Assenov Y, Domingues FS, Albrecht M (2012) Topological analysis and interactive visualization of biological networks and protein structures. Nat Protoc 7:670–685. doi:10.1038/nprot.2012.004 CrossRefPubMedGoogle Scholar
  15. Ema M, Ohe N, Suzuki M et al (1994) Dioxin binding activities of polymorphic forms of mouse and human arylhydrocarbon receptors. J Biol Chem 269:27337–27343PubMedGoogle Scholar
  16. Enright AJ, Dongen SV, Ouzounis CA (2002) An efficient algorithm for large-scale detection of protein families. Nucleic Acids Res 30:1575–1584. doi:10.1093/nar/30.7.1575 CrossRefPubMedPubMedCentralGoogle Scholar
  17. Esser C, Rannug A, Stockinger B (2009) The aryl hydrocarbon receptor in immunity. Trends Immunol 30:447–454. doi:10.1016/j.it.2009.06.005 CrossRefPubMedGoogle Scholar
  18. Fernandez-Salguero PM, Hilbert DM, Rudikoff S et al (1996) Aryl-hydrocarbon receptor-deficient mice are resistant to 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced toxicity. Toxicol Appl Pharmacol 140:173–179. doi:10.1006/taap.1996.0210 CrossRefPubMedGoogle Scholar
  19. Furumatsu K, Nishiumi S, Kawano Y, et al (2011) A role of the aryl hydrocarbon receptor in attenuation of colitis. Dig Dis Sci 56(9):2532–2544CrossRefPubMedGoogle Scholar
  20. Guengerich FP (1982) Microsomal enzymes involved in toxicology: analysis and separation. In: Hayes AW (ed) Principles and methods of toxicology. Raven Press, New York, pp 609–634Google Scholar
  21. Hornung MW, Zabel EW, Peterson RE (1996) Toxic equivalency factors of polybrominated dibenzo-p-dioxin, dibenzofuran, biphenyl, and polyhalogenated diphenyl ether congeners based on rainbow trout early life stage mortality. Toxicol Appl Pharmacol 140:227–234. doi:10.1006/taap.1996.0217 CrossRefPubMedGoogle Scholar
  22. Itoh K, Chiba T, Takahashi S, et al (1997) An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem Biophys Res Commun 236(2):313–322CrossRefPubMedGoogle Scholar
  23. Iwata H, Yoshinari K, Negishi M, Stegeman JJ (2002) Species-specific responses of constitutively active receptor (CAR)-CYP2B coupling: lack of CYP2B inducer-responsive nuclear translocation of CAR in marine teleost, scup (Stenotomus chrysops). Comp Biochem Physiol Toxicol Pharmacol CBP 131:501–510CrossRefGoogle Scholar
  24. Jeong J, Kim Y, Kyung Seong J, Lee K-J (2012) Comprehensive identification of novel post-translational modifications in cellular peroxiredoxin 6. Proteomics 12:1452–1462. doi:10.1002/pmic.201100558 CrossRefPubMedGoogle Scholar
  25. Jiang T, Tian F, Zheng H et al (2014) Nrf2 suppresses lupus nephritis through inhibition of oxidative injury and the NF-κB-mediated inflammatory response. Kidney Int 85:333–343. doi:10.1038/ki.2013.343 CrossRefPubMedGoogle Scholar
  26. Kawakami T, Ishimura R, Nohara K et al (2006) Differential susceptibilities of Holtzman and Sprague-Dawley rats to fetal death and placental dysfunction induced by 2,3,7,8-teterachlorodibenzo-p-dioxin (TCDD) despite the identical primary structure of the aryl hydrocarbon receptor. Toxicol Appl Pharmacol 212:224–236. doi:10.1016/j.taap.2005.08.007 CrossRefPubMedGoogle Scholar
  27. Mandal PK (2005) Dioxin: a review of its environmental effects and its aryl hydrocarbon receptor biology. J Comp Physiol [B] 175:221–230. doi:10.1007/s00360-005-0483-3 CrossRefGoogle Scholar
  28. Mimura J, Yamashita K, Nakamura K et al (1997) Loss of teratogenic response to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in mice lacking the Ah (dioxin) receptor. Genes Cells Devoted Mol Cell Mech 2:645–654CrossRefGoogle Scholar
  29. Moffat ID, Boutros PC, Chen H et al (2010) Aryl hydrocarbon receptor (AHR)-regulated transcriptomic changes in rats sensitive or resistant to major dioxin toxicities. BMC Genom 11:263. doi:10.1186/1471-2164-11-263 CrossRefGoogle Scholar
  30. Nakahama T, Kimura A, Nguyen NT, et al (2011) Aryl hydrocarbon receptor deficiency in T cells suppresses the development of collagen-induced arthritis. Proc Natl Acad Sci USA 108(34):14222–14227CrossRefPubMedPubMedCentralGoogle Scholar
  31. Nebert DW, Roe AL, Dieter MZ et al (2000) Role of the aromatic hydrocarbon receptor and [Ah] gene battery in the oxidative stress response, cell cycle control, and apoptosis. Biochem Pharmacol 59:65–85CrossRefPubMedGoogle Scholar
  32. Nishihara M, Terada M, Kamogawa J et al (1999) Genetic basis of autoimmune sialadenitis in MRL/lpr lupus-prone mice: additive and hierarchical properties of polygenic inheritance. Arthritis Rheum 42:2616–2623. doi:10.1002/1529-0131(199912)42:12<2616:AID-ANR16>3.0.CO;2-O CrossRefPubMedGoogle Scholar
  33. Nordgren M, Fransen M (2014) Peroxisomal metabolism and oxidative stress. Biochimie 98:56–62. doi:10.1016/j.biochi.2013.07.026 CrossRefPubMedGoogle Scholar
  34. Nose M (2007) A proposal concept of a polygene network in systemic vasculitis: lessons from MRL mouse models. Allergol Int 56:79–86. doi:10.2332/allergolint.R-04-140 CrossRefPubMedGoogle Scholar
  35. Nose M, Nishimura M, Kyogoku M (1989) Analysis of granulomatous arteritis in MRL/Mp autoimmune disease mice bearing lymphoproliferative genes. The use of mouse genetics to dissociate the development of arteritis and glomerulonephritis. Am J Pathol 135:271–280PubMedPubMedCentralGoogle Scholar
  36. Oberemm A, Meckert C, Brandenburger L et al (2005) Differential signatures of protein expression in marmoset liver and thymus induced by single-dose TCDD treatment. Toxicology 206:33–48. doi:10.1016/j.tox.2004.06.061 CrossRefPubMedGoogle Scholar
  37. Okey AB, Vella LM, Harper PA (1989) Detection and characterization of a low affinity form of cytosolic Ah receptor in livers of mice nonresponsive to induction of cytochrome P1-450 by 3-methylcholanthrene. Mol Pharmacol 35:823–830PubMedGoogle Scholar
  38. Omura T, Sato R (1964) The carbon monoxide-binding pigment of liver microsomes. I. Evidence for its hemoprotein nature. J Biol Chem 239:2370–2378PubMedGoogle Scholar
  39. Pastorelli R, Carpi D, Campagna R et al (2006) Differential expression profiling of the hepatic proteome in a rat model of dioxin resistance: correlation with genomic and transcriptomic analyses. Mol Cell Proteom MCP 5:882–894. doi:10.1074/mcp.M500415-MCP200 CrossRefGoogle Scholar
  40. Poland A, Glover E (1990) Characterization and strain distribution pattern of the murine Ah receptor specified by the Ahd and Ahb-3 alleles. Mol Pharmacol 38:306–312PubMedGoogle Scholar
  41. Poland A, Palen D, Glover E (1994) Analysis of the four alleles of the murine aryl hydrocarbon receptor. Mol Pharmacol 46:915–921PubMedGoogle Scholar
  42. Quintana FJ, Basso AS, Iglesias AH et al (2008) Control of T(reg) and T(H)17 cell differentiation by the aryl hydrocarbon receptor. Nature 453:65–71. doi:10.1038/nature06880 CrossRefPubMedGoogle Scholar
  43. Richard DM, Dawes MA, Mathias CW et al (2009) L-Tryptophan: basic metabolic functions, behavioral research and therapeutic indications. Int J Tryptophan Res 2:45–60PubMedGoogle Scholar
  44. Sarioglu H, Brandner S, Haberger M et al (2008) Analysis of 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced proteome changes in 5L rat hepatoma cells reveals novel targets of dioxin action including the mitochondrial apoptosis regulator VDAC2. Mol Cell Proteom MCP 7:394–410. doi:10.1074/mcp.M700258-MCP200 CrossRefGoogle Scholar
  45. Schlezinger JJ, White RD, Stegeman JJ (1999) Oxidative activation of cytochrome P-450 1A (CYP1A) stimulated by 3,3′,4,4′-tetrachlorobiphenyl: production of reactive oxygen by vertebrate CYP1As. Mol Pharmacol 56:588–597. doi:10.1124/mol.56.3.588 PubMedGoogle Scholar
  46. Schlezinger JJ, William DJ. Struntz, Goldstone JV, Stegeman JJ (2006) Uncoupling of cytochrome P450 1A and stimulation of reactive oxygen species production by co-planar polychlorinated biphenyl congeners. Aquat Toxicol 77(4):422–432CrossRefPubMedGoogle Scholar
  47. Schrader M, Fahimi HD (2006) Peroxisomes and oxidative stress. Biochim Biophys Acta BBA—Mol Cell Res 1763:1755–1766. doi:10.1016/j.bbamcr.2006.09.006 CrossRefGoogle Scholar
  48. Smirnova A, Wincent E, Vikström Bergander L et al (2016) Evidence for new light-independent pathways for generation of the endogenous aryl hydrocarbon receptor agonist FICZ. Chem Res Toxicol 29:75–86. doi:10.1021/acs.chemrestox.5b00416 CrossRefPubMedGoogle Scholar
  49. Smith AG, Clothier B, Robinson S et al (1998) Interaction between iron metabolism and 2,3,7,8-tetrachlorodibenzo-p-dioxin in mice with variants of the Ahr gene: a hepatic oxidative mechanism. Mol Pharmacol 53:52–61. doi:10.1124/mol.53.1.52 PubMedGoogle Scholar
  50. Snel B, Lehmann G, Bork P, Huynen MA (2000) STRING: a web-server to retrieve and display the repeatedly occurring neighbourhood of a gene. Nucleic Acids Res 28:3442–3444CrossRefPubMedPubMedCentralGoogle Scholar
  51. Starkov AA, Fiskum G (2001) Myxothiazol induces H(2)O(2) production from mitochondrial respiratory chain. Biochem Biophys Res Commun 281:645–650. doi:10.1006/bbrc.2001.4409 CrossRefPubMedGoogle Scholar
  52. Steiner G, Skriner K, Smolen JS (1996) Autoantibodies to the A/B proteins of the heterogeneous nuclear ribonucleoprotein complex: novel tools for the diagnosis of rheumatic diseases. Int Arch Allergy Immunol 111:314–319CrossRefPubMedGoogle Scholar
  53. Sturla SJ, Boobis AR, FitzGerald RE et al (2014) Systems toxicology: from basic research to risk assessment. Chem Res Toxicol 27:314–329. doi:10.1021/tx400410s CrossRefPubMedPubMedCentralGoogle Scholar
  54. Szklarczyk D, Franceschini A, Wyder S et al (2015) STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res 43:D447–D452. doi:10.1093/nar/gku1003 CrossRefPubMedGoogle Scholar
  55. Takamura T, Harama D, Matsuoka S, et al (2010) Activation of the aryl hydrocarbon receptor pathway may ameliorate dextran sodium sulfate-induced colitis in mice. Immunol Cell Biol 88 (6):685–689CrossRefPubMedGoogle Scholar
  56. Thimmulappa RK, Mai KH, Srisuma S, et al (2002) Identification of Nrf2-regulated genes induced by the chemopreventive agent sulforaphane by oligonucleotide microarray. Cancer Res 62:5196–5203PubMedGoogle Scholar
  57. van den Berg M, Denison MS, Birnbaum LS et al (2013) Polybrominated dibenzo-p-dioxins, dibenzofurans, and biphenyls: inclusion in the toxicity equivalency factor concept for dioxin-like compounds. Toxicol Sci Off J Soc Toxicol 133:197–208. doi:10.1093/toxsci/kft070 CrossRefGoogle Scholar
  58. Viluksela M, Unkila M, Pohjanvirta R et al (1999) Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on liver phosphoenolpyruvate carboxykinase (PEPCK) activity, glucose homeostasis and plasma amino acid concentrations in the most TCDD-susceptible and the most TCDD-resistant rat strains. Arch Toxicol 73:323–336. doi:10.1007/s002040050626 CrossRefPubMedGoogle Scholar
  59. Vorderstrasse BA, Steppan LB, Silverstone AE, Kerkvliet NI (2001) Aryl hydrocarbon receptor-deficient mice generate normal immune responses to model antigens and are resistant to TCDD-induced immune suppression. Toxicol Appl Pharmacol 171:157–164. doi:10.1006/taap.2000.9122 CrossRefPubMedGoogle Scholar
  60. Wang J, Duncan D, Shi Z, Zhang B (2013) WEB-based GEne SeT analysis toolkit (WebGestalt): update 2013. Nucleic Acids Res 41:W77–W83. doi:10.1093/nar/gkt439 CrossRefPubMedPubMedCentralGoogle Scholar
  61. Watanabe-Fukunaga R, Brannan CI, Copeland NG et al (1992) Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature 356:314–317. doi:10.1038/356314a0 CrossRefPubMedGoogle Scholar
  62. WHO/ICPS (1998) Polybrominated dibenzo-p-dioxins and dibenzofuransGoogle Scholar
  63. Zelante T, Iannitti RG, Cunha C et al (2013) Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. Immunity 39:372–385. doi:10.1016/j.immuni.2013.08.003 CrossRefPubMedGoogle Scholar
  64. Zhang N (2011) The role of endogenous aryl hydrocarbon receptor signaling in cardiovascular physiology. J Cardiovasc Dis Res 2:91–95. doi:10.4103/0975-3583.83033 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Hoa Thanh Nguyen
    • 1
  • Maria Claret Lauan Tsuchiya
    • 1
    • 2
  • Jean Yoo
    • 1
  • Midori Iida
    • 3
  • Tetsuro Agusa
    • 1
    • 4
  • Masashi Hirano
    • 1
  • Eun-Young Kim
    • 5
  • Tatsuhiko Miyazaki
    • 6
  • Masato Nose
    • 7
  • Hisato Iwata
    • 1
  1. 1.Laboratory of Environmental Toxicology, Center for Marine Environmental Studies (CMES)Ehime UniversityMatsuyamaJapan
  2. 2.Institute of Biological SciencesUniversity of the Philippines Los BañosLagunaPhilippines
  3. 3.Graduate School of Computer Science and System EngineeringKyushu Institute of TechnologyIizukaJapan
  4. 4.Graduate School of Environmental and Symbiotic SciencesPrefectural University of KumamotoKumamotoJapan
  5. 5.Department of Life and Nanopharmaceutical Science and Department of BiologyKyung Hee UniversitySeoulKorea
  6. 6.Gifu University HospitalGifuJapan
  7. 7.Institute for Promotion of Advanced Science and TechnologyEhime UniversityMatsuyamaJapan

Personalised recommendations