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

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

doi:10.1371/journal.pone.0176768

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.

Highlights

Pharmaceutical and non-pharmaceutical chemicals have been shown to produce liver tumors in mice, which function through non DNA reactive mechanisms [1]
We investigated the role that retroelement reactivation may play in compounddriven mouse specific carcinogenesis
We used the well-studied mouse nongenotoxic carcinogen WY-14,643. We show that this compound induced a general increase in LTR and LINE retroelements, two retroelement classes known to be highly active in mice and to induce the majority of all retroelement driven mutations in mice [12, 41]

Summary

Introduction

Pharmaceutical and non-pharmaceutical chemicals have been shown to produce liver tumors in mice, which function through non DNA reactive (nongenotoxic) mechanisms [1]. These nongenotoxic mechanisms are often species and tissue specific and most times do not translate to a human liability [2,3,4]. A positive signal for carcinogenicity in a 2-year carcinogenicity study in rodents often results in significant development program delays and costs to the program. The responsible regulatory agency has required additional. The specific roles of these authors are articulated in the ‘author contributions’ section

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