Detection of dominant lethal mutation in mice after repeated low-dose administration of 6-mercaptopurine

Area of Science:

• Toxicology
• Genetics
• Pharmacology

Background:

• 6-mercaptopurine (6-MP) is a base analog used in various treatments.
• Assessing the genotoxic potential of drugs, including dominant lethality, is crucial for safety evaluation.
• Repeated low-dose administration requires specific toxicological investigation.

Purpose of the Study:

• To investigate the potential for dominant lethality induction by repeated low-dose 6-mercaptopurine (6-MP) administration in mice.
• To evaluate the dose-dependent toxicity of 6-MP in male mice.
• To assess strain-specific differences in susceptibility to 6-MP-induced dominant lethality.

Main Methods:

• Male CD-1 mice were administered 6-MP (12.5, 25.0, or 50.0 mg/kg/day) or vehicle/triethylenemelamine (TEM) for 8 weeks.
• Treated males were cohoused with untreated females of CD-1 and (C3H x C57BL/10)F1 strains.
• Implant data from females were analyzed for dominant lethal mutations.

Main Results:

• High-dose 6-MP (50 mg/kg/day) resulted in 93% mortality and significant weight loss in male mice.
• Reduced body weight was observed in males treated with 25 mg/kg/day 6-MP.
• A statistically significant increase in dead implantations was found in CD-1 females mated with 6-MP treated males, but not in (C3H x C57BL/10)F1 females.

Conclusions:

• Repeated low-dose 6-MP can induce dominant lethality in a strain-dependent manner.
• Significant toxicity and mortality were observed at higher doses of 6-MP.
• The study highlights the importance of considering genetic background in genotoxicity assessments.