Induction of endogenous retroelements as a potential mechanism for mouse-specific drug-induced carcinogenicity.
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 carci...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2017-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC5417610?pdf=render |
| _version_ | 1818324116755709952 |
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| author | Timothy M Coskran Zhijie Jiang James E Klaunig Dixie L Mager Leslie Obert Andrew Robertson Nicholas Tsinoremas Zemin Wang Mark Gosink |
| author_facet | Timothy M Coskran Zhijie Jiang James E Klaunig Dixie L Mager Leslie Obert Andrew Robertson Nicholas Tsinoremas Zemin Wang Mark Gosink |
| author_sort | Timothy M Coskran |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-13T11:23:29Z |
| format | Article |
| id | doaj.art-77f70d26f5cc49d79b7be814cb53e00a |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-13T11:23:29Z |
| publishDate | 2017-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-77f70d26f5cc49d79b7be814cb53e00a2022-12-21T23:48:22ZengPublic Library of Science (PLoS)PLoS ONE1932-62032017-01-01125e017676810.1371/journal.pone.0176768Induction of endogenous retroelements as a potential mechanism for mouse-specific drug-induced carcinogenicity.Timothy M CoskranZhijie JiangJames E KlaunigDixie L MagerLeslie ObertAndrew RobertsonNicholas TsinoremasZemin WangMark GosinkA 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.http://europepmc.org/articles/PMC5417610?pdf=render |
| spellingShingle | Timothy M Coskran Zhijie Jiang James E Klaunig Dixie L Mager Leslie Obert Andrew Robertson Nicholas Tsinoremas Zemin Wang Mark Gosink Induction of endogenous retroelements as a potential mechanism for mouse-specific drug-induced carcinogenicity. PLoS ONE |
| title | Induction of endogenous retroelements as a potential mechanism for mouse-specific drug-induced carcinogenicity. |
| title_full | Induction of endogenous retroelements as a potential mechanism for mouse-specific drug-induced carcinogenicity. |
| title_fullStr | Induction of endogenous retroelements as a potential mechanism for mouse-specific drug-induced carcinogenicity. |
| title_full_unstemmed | Induction of endogenous retroelements as a potential mechanism for mouse-specific drug-induced carcinogenicity. |
| title_short | Induction of endogenous retroelements as a potential mechanism for mouse-specific drug-induced carcinogenicity. |
| title_sort | induction of endogenous retroelements as a potential mechanism for mouse specific drug induced carcinogenicity |
| url | http://europepmc.org/articles/PMC5417610?pdf=render |
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