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

Timothy M Coskran1, Zhijie Jiang2, James E Klaunig3

  • 1Drug Safety Research & Development, Pfizer Inc., Groton, Connecticut, United States of America.

Plos One
|May 5, 2017
PubMed

Insights

Species-specific liver tumors in mice may be driven by endogenous retroelements. Resistant mouse strains with robust immune responses may prevent tumor formation by clearing cells with activated retroelements.

Area of Science:

  • Toxicology
  • Genetics
  • Immunology

Background:

  • Species-specific chemical carcinogens pose a challenge in understanding tumor development.
  • The nongenotoxic rodent hepatic carcinogen WY-14,643 activates peroxisome proliferator-activated receptor alpha (PPARα).
  • Endogenous retroelements and immune responses are implicated in species-specific tumorigenicity.

Purpose of the Study:

  • To investigate the role of endogenous retroelements and immune responses in WY-14,643-induced liver tumorigenicity in mice.
  • To compare the effects of WY-14,643 in high (C3H/HeJ) and low (C57BL/6) liver tumor susceptible mouse strains.

Main Methods:

  • Treatment of male mice from C3H/HeJ and C57BL/6 strains with WY-14,643.
  • Analysis of endogenous retroelement expression (LTR and LINE elements).
  • Assessment of retroviral defense gene expression and immune-mediated viral defense.

Main Results:

  • WY-14,643 increased endogenous retroelement expression in both mouse strains.
  • Retroviral defense gene expression was elevated, particularly in the resistant C57BL/6 strain.
  • C57BL/6 mice exhibited enhanced basal and WY-14,643-induced immune-mediated viral defense.
  • The sensitive C3H/HeJ strain showed gene signatures of DNA recombination following WY-14,643 treatment.

Conclusions:

  • High endogenous retroelement activity in mice contributes to species-specific liver tumorigenicity.
  • A competent immune system in resistant strains like C57BL/6 can prevent tumors by eliminating cells with activated retroelements.
  • WY-14,643-induced DNA recombination in sensitive strains may facilitate tumor development.

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