DNA modifications that do not cause gene mutations confer the potential for mutagenicity by combined treatment with food chemicals.


Division of Pathology, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-shi, Kawasaki-ku, Kanagawa, 210-9501, Japan; Faculty of Animal Health Technology, Yamazaki University of Animal Health Technology, 4-7-2, Minami-osawa, Hachihoji, Tokyo, 192-0364, Japan. Electronic address: [Email]


Cell proliferation plays a key role in fixing mutations induced by DNA damage. We clarified whether this phenomenon occurred after combined treatment with chemicals in food. The effects of antibiotic flumequine (FL), a residue of veterinary medicinal products in foodstuffs, on mutagenicity in the liver were examined in mice treated with estragole (ES), a natural food flavouring compound. Gpt delta mice were orally administered 10 or 100 mg/kg/day ES and simultaneously fed a diet containing 0.4% FL for 4 weeks. Proliferating cell nuclear antigen-positive cells and cell cycle-related genes were additively increased in the livers of combined treatment groups as compared with high-dose ES or FL groups. Mutant frequencies (MFs) in gpt after cotreatment with low-dose ES and FL were significantly increased, although treatment with ES alone increased MFs only in the high-dose group. Sult1a1 mRNA levels were unchanged after FL treatment. Liquid chromatography with tandem-mass spectrometry analysis showed that FL did not affect the amount of ES-specific DNA adducts in the livers, indicating that FL treatment did not influence metabolic pathways of ES. Thus, enhancement of the mutagenic potential of a chemical by chemical-induced cell proliferation may occur as a result of the combined effects of chemicals in food.


Cell proliferation,Combined effects,Estragole,Flumequine,Gene mutation,