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

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.

Harnessing natural variation to identify cis regulators of sex-biased gene expression in a multi-strain mouse liver model

“…The male bias in Zfp809 expression seen in B6 but not CAST mouse liver could thus impart strain differences for genes where endogenous retroviral silencing is critical. Incomplete silencing of endogenous retroviral sequences contributes to strain differences in spontaneous and drug-induced liver tumorigenesis [86] but has not been explored in the context of sex differences. Trim24 is a suppressor of mouse hepatocellular carcinoma [87,88]; consequently, its elevated expression in female compared to male B6 mouse liver may contribute to the lower incidence of liver cancer in females [70,89].…”

Harnessing natural variation to identify cis regulators of sex-biased gene expression in a multi-strain mouse liver model

“…The male bias in Zfp809 expression seen in B6 but not CAST mouse liver could thus impart strain differences for genes where endogenous retroviral silencing is critical. Incomplete silencing of endogenous retroviral sequences contributes to strain differences in spontaneous and drug-induced liver tumorigenesis [85], but has not been explored in the context of sex differences. Trim24 is a suppressor of mouse hepatocellular carcinoma [86,87]; consequently, its elevated expression in female compared to male B6 mouse liver may contribute to the lower incidence of liver cancer in females [70,88].…”