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

Stephenie D. Prokopec, Aileen Lu, Sandy Che Eun S. Lee, Cindy Q. Yao, Ren X. Sun, John D. Watson, Rabah Soliymani, Richard de Borja, Ada Wong, Michelle Sam, Philip Zuzarte, John D. McPherson, Allan B. Okey, Raimo Pohjanvirta, Paul C. Boutros

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2961-2978
Number of pages18
JournalArchives of Toxicology
Volume93
Issue number10
DOIs
StatePublished - Oct 1 2019
Externally publishedYes

Keywords

  • AhR
  • Model organisms
  • Proteomics
  • TCDD
  • Transcriptomics
  • Whole-genome sequencing

ASJC Scopus subject areas

  • Toxicology
  • Health, Toxicology and Mutagenesis

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