TY - JOUR
T1 - Induction of endogenous retroelements as a potential mechanism for mouse-specific drug-induced carcinogenicity
AU - Coskran, Timothy M.
AU - Jiang, Zhijie
AU - Klaunig, James E.
AU - Mager, Dixie L.
AU - Obert, Leslie
AU - Robertson, Andrew
AU - Tsinoremas, Nicholas
AU - Wang, Zemin
AU - Gosink, Mark
PY - 2017/5
Y1 - 2017/5
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85019088881&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85019088881&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0176768
DO - 10.1371/journal.pone.0176768
M3 - Article
C2 - 28472135
AN - SCOPUS:85019088881
VL - 12
JO - PLoS One
JF - PLoS One
SN - 1932-6203
IS - 5
M1 - e0176768
ER -