Induction of endogenous retroelements as a potential mechanism for mouse-specific drug-induced carcinogenicity

Timothy M. Coskran, Zhijie Jiang, James E. Klaunig, Dixie L. Mager, Leslie Obert, Andrew Robertson, Nicholas Tsinoremas, Zemin Wang, Mark Gosink

Research output: Contribution to journalArticle

Abstract

A number of chemical compounds have been shown to induce liver tumors in mice but not in other species. While several mechanisms for this species-specific tumorigenicity have been proposed, no definitive mechanism has been established. We examined the effects of the nongenotoxic rodent hepatic carcinogen, WY-14,643, in male mice from a high liver tumor susceptible strain (C3H/HeJ), and from a low tumor susceptible strain (C57BL/6). WY- 14,643, a PPARα activator induced widespread increases in the expression of some endogenous retroelements, namely members of LTR and LINE elements in both strains. The expression of a number of known retroviral defense genes was also elevated. We also demonstrated that basal immune-mediated viral defense was elevated in C57BL/6 mice (the resistant strain) and that WY-14,643 further activated those immuno-defense processes. We propose that the previously reported >100X activity of retroelements in mice drives mouse-specific tumorigenicity. We also propose that C57BL/6's competent immune to retroviral activation allows it to remove cells before the activation of these elements can result in significant chromosomal insertions and mutation. Finally, we showed that WY-14,643 treatment induced gene signatures of DNA recombination in the sensitive C3H/HeJ strain.

Original languageEnglish (US)
Article numbere0176768
JournalPloS one
Volume12
Issue number5
DOIs
StatePublished - May 2017

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Coskran, T. M., Jiang, Z., Klaunig, J. E., Mager, D. L., Obert, L., Robertson, A., Tsinoremas, N., Wang, Z., & Gosink, M. (2017). Induction of endogenous retroelements as a potential mechanism for mouse-specific drug-induced carcinogenicity. PloS one, 12(5), [e0176768]. https://doi.org/10.1371/journal.pone.0176768