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 IwataEmail author
Molecular Toxicology


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.


Dioxin Susceptibility Proteome C3H/lpr MRL/lpr 



This work was supported by Grants-in-Aid for Scientific Research (S) [No. 26220103] and Joint Research Project under the Japan–Korea Basic Scientific Cooperation Program for FY 2016 from Japan Society for the Promotion of Science (JSPS), which were given to Hisato Iwata. This study was also supported by the Ministry of Education, Culture, Sports, Science and Technology, Japan (MEXT), to a project on Joint Usage/Research Center—Leading Academia in Marine and Environmental Research (LaMer). Funding support was also given to E-Y. Kim from the National Research Foundation of Korea (NRF) grant funded by the Korea government (Ministry of Education, Science and Technology) [2016K2A9A2A08003746 and 2016R1A2B4007714].

Compliance with ethical standards

Conflict of interest

There is no conflict of interest.

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)


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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
    Email author
  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

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