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Comparative toxicoproteogenomics of mouse and rat liver identifies TCDD-resistance genes

  • Organ Toxicity and Mechanisms
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Abstract

The aryl hydrocarbon receptor (AHR) mediates many toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). However, the AHR alone does not explain the widely different outcomes among organisms. To identify the other factors involved, we evaluated three transgenic mouse lines, each expressing a different rat AHR isoform (rWT, DEL, and INS) providing widely different resistance to TCDD toxicity, as well as C57BL/6 and DBA/2 mice which exhibit a ~ tenfold divergence in TCDD sensitivity (exposures of 5-1000 μg/kg TCDD). We supplement these with whole-genome sequencing, together with transcriptomic and proteomic analyses of the corresponding rat models, Long–Evans (L–E) and Han/Wistar (H/W) rats (having a ~ 1000-fold difference in their TCDD sensitivities; 100 μg/kg TCDD), to identify genes associated with TCDD-response phenotypes. Overall, we identified up to 50% of genes with altered mRNA abundance following TCDD exposure are associated with a single AHR isoform (33.8%, 11.7%, 5.2% and 0.3% of 3076 genes altered unique to rWT, DEL, C57BL/6 and INS respectively following 1000 μg/kg TCDD). Hepatic Pxdc1 was significantly repressed in all three TCDD-sensitive animal models (C57BL/6 and rWT mice, and L–E rat) after TCDD exposure. Three genes, including Cxxc5, Sugp1 and Hgfac, demonstrated different AHRE-1 (full) motif occurrences within their promoter regions between rat strains, as well as different patterns of mRNA abundance. Several hepatic proteins showed parallel up- or downward alterations with their RNAs, with three genes (SNRK, IGTP and IMPA2) showing consistent, strain-dependent changes. These data show the value of integrating genomic, transcriptomic and proteomic evidence across multi-species models in toxicologic studies.

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Data availability

The data sets supporting the results of this article are publicly available. All transcriptomic datasets are available from NCBI’s Gene Expression Omnibus (GEO; http://www.ncbi.nlm.nih.gov/geo/): C57BL/6 mouse data are available at accession GSE61038 (Lee et al. 2015); other mouse data are available from GSE127217 (EXP1) and GSE72270 (EXP2); rat transcriptomic data are available from accessions GSE31411 (Yao et al. 2012) and GSE13513 (Boutros et al. 2011). Combined transcriptomic data are additionally available from the TCDD. Transcriptomics (v2.2.5) package for the R statistical environment (Prokopec et al. 2017). The sequence data generated in this study have been submitted to the NCBI BioProject database (http://www.ncbi.nlm.nih.gov/bioproject/) under accession number PRJNA480994. Raw and processed LC–MS data are available from MassIVE under accession MSV000083870.

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Acknowledgements

The authors thank Hanbert Chen, Alexander Wu, Ashley Smith, Janne Korkalainen, Arja Moilanen, and Virpi Tiihonen for excellent technical assistance and support. Additional thanks to Marc Baumann and staff at the Meilahti Clinical & Basic Proteomics Core Facility. This work was supported by the Canadian Institutes of Health Research [grant number MOP-57903 to ABO and PCB], the Academy of Finland [grant number 123345 to RP], and with the support of the Ontario Institute for Cancer Research to PCB through funding provided by the Government of Ontario. PCB was supported by a Terry Fox Research Institute New Investigator Award and a Canadian Institutes of Health Research New Investigator Award.

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Author notes

  1. Stephenie D. Prokopec, Aileen Lu, and Sandy Che-Eun S. Lee are contributed equally to this work.

Authors and Affiliations

  1. Computational Biology, Ontario Institute for Cancer Research, Toronto, ON, M5G 0A3, Canada

    Stephenie D. Prokopec, Aileen Lu, Sandy Che-Eun S. Lee, Cindy Q. Yao, Ren X. Sun, John D. Watson, Richard de Borja & Paul C. Boutros

  2. Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, M5S 1A8, Canada

    Aileen Lu, Allan B. Okey & Paul C. Boutros

  3. Department of Biochemistry and Developmental Biology, Meilahti Clinical and Basic Proteomics Core Facility, University of Helsinki, FI-00790, Helsinki, Finland

    Rabah Soliymani

  4. Genome Technologies Program, Ontario Institute for Cancer Research, Toronto, ON, M5G 0A3, Canada

    Ada Wong, Michelle Sam, Philip Zuzarte & John D. McPherson

  5. Laboratory of Toxicology, National Institute for Health and Welfare, FI-70701, Kuopio, Finland

    Raimo Pohjanvirta

  6. Department of Food Hygiene and Environmental Health, University of Helsinki, FI-00790, Helsinki, Finland

    Raimo Pohjanvirta

  7. Department of Medical Biophysics, University of Toronto, Toronto, ON, M5G 1L7, Canada

    Paul C. Boutros

  8. Department of Human Genetics, University of California, Los Angeles, CA, 90095, USA

    Paul C. Boutros

  9. Department of Urology, University of California, Los Angeles, CA, 90095, USA

    Paul C. Boutros

  10. Institute for Precision Health, University of California, Los Angeles, CA, 90095, USA

    Paul C. Boutros

  11. Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, 90024, USA

    Paul C. Boutros

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  1. Stephenie D. Prokopec
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Contributions

JDW and SDP carried out the sample preparation for transcriptomic analyses. AW, MS and PZ were involved in library preparation and genome sequencing. RS performed proteomics work. AL, SDP, SL and RDB performed statistical and bioinformatics analyses. AL and SDP wrote the first draft of the manuscript. AL, CQY, SDP, RXS and RP generated tools and reagents. ABO, RP and PCB initiated the project. JDM, ABO, RP and PCB supervised the research. All authors approved the manuscript.

Corresponding authors

Correspondence to Allan B. Okey, Raimo Pohjanvirta or Paul C. Boutros.

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The authors declare that they have no conflict of interest.

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All study plans were approved by the Finnish National Animal Experiment Board (Eläinkoelautakunta, ELLA; permit code: ESLH-2008-07223/Ym-23). All animal handling and reporting comply with ARRIVE guidelines (Kilkenny et al. 2010).

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Prokopec, S.D., Lu, A., Lee, S.CE.S. et al. Comparative toxicoproteogenomics of mouse and rat liver identifies TCDD-resistance genes. Arch Toxicol 93, 2961–2978 (2019). https://doi.org/10.1007/s00204-019-02560-0

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