Abstract
Biological differences exist between strains of laboratory mice, and it is becoming increasingly evident that there are differences between substrains. In the C57BL/6 mouse, the primary substrains are called 6J and 6N. Previous studies have demonstrated that 6J and 6N mice differ in response to many experimental models of human disease. The aim of our study was to determine if differences exist between 6J and 6N mice in terms of their response to acute carbon tetrachloride (CCl4) exposure. Mice were given CCl4 once and were euthanized 12 to 96 h later. Relative to 6J mice, we found that 6N mice had increased liver injury but more rapid repair. This was because of the increased speed with which necrotic hepatocytes were removed in 6N mice and was directly related to increased recruitment of macrophages to the liver. In parallel, enhanced liver regeneration was observed in 6N relative to 6J mice. Hepatic stellate cell activation occurred earlier in 6N mice, but there was no difference in matrix metabolism between substrains. Taken together, these data demonstrate specific and significant differences in how the C57BL/6 substrains respond to acute CCl4, which has important implications for all mouse studies utilizing this model.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 187-205 |
| Number of pages | 19 |
| Journal | Gene expression |
| Volume | 17 |
| Issue number | 3 |
| DOIs | |
| State | Published - 2017 |
Funding
This work was supported by the National Institutes of Health (NIH), National Center for Research Resources (P20 RR021940), the National Institute of General Medical Sciences (P20 GM103549), the National Institute of Environmental Health Sciences "Training Program in Environmental Toxicology" (T32 ES007079), the National Institutes of Alcohol Abuse and Alcoholism (R00 AA17918), an NIH Clinical and Translational Science Award grant (UL1 TR000001, formerly UL1RR033179) awarded to the University of Kansas Medical Center (KUMC), and an internal Lied Basic Science Grant Program of the KUMC Research Institute. In addition, funds from the Center for Reproductive Health after Disease from the National Centers for Translational Research in Reproduction and Infertility (P50 HD076188) and the National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK098414) were used to complete the work in this study. A special thanks to the KUMC's Laboratory Animal Resource husbandry staff, veterinary technicians, veterinarians, Office of Animals Welfare, and Institutional Animal Care and Use Committee for the care of our animals. Thanks to the KUMC Pharmacology, Toxicology, and Therapeutics COBRE Cell Isolation Core for the preparation of primary hepatocytes from 6J and 6N mice. Thanks also to members of the KUMC Pharmacology, Toxicology, and Therapeutics Department, in particular Dr. Ben Woolbright (for helpful discussions and LDH assay training), Dr. Partha Kasturi (for the hormesis idea), and Dr. Yuxia Zhang (for the use of her Zeiss Axio Observer A.1 inverted microscope, Olympus DP71 camera, and cellSens imaging software).
Keywords
- Carbon tetrachloride
- Hepatic inflammation
- Hepatic injury
- Liver regeneration
ASJC Scopus subject areas
- Genetics
- Molecular Biology