Toxicity and genotoxicity of N-nitrosodimethylamine and N-nitrosodiethylamine in mice after repeated administration
Objectives Repeated administration of N-nitrosodimethylamine(NDMA)and N-nitrosodiethylamine(NDEA)in C57BL/6J mice for seven consecutive days was observed until 28 days after the first administration,and the main toxic target organs and genotoxic risk of both were evaluated.Methods A solvent control group(0.5％sodium carboxymethyl cellulose),a test group(0.75,1.50,3.00 mg·kg-1 NDMA or 3.25,7.50,15.00 mg·kg-1 NDEA,respectively)and a positive control group(200 mg·kg-1 ethyl mesylate;40 mg·kg-1 N-ethyl-n-nitrosourea).The solvent control group and the test group were given ig once a day for seven consecutive days,and the positive control group was given ig once a day for three consecutive days.Comet tests in mouse liver,kidney,and peripheral blood were performed after the final dose,and the average percentage of Tail DNA and Tail Moment in liver,kidney,and blood cells of each animal were calculated.After observation(D28),mouse Pig-a gene mutation test was carried out to calculate the mutation rate of reticulocyte(RETCD24-)and total erythrocyte(RBCCD24-).The expression of 8-hydroxydeoxyguanosine(8-OHdG),DNA damage genes(ATM,gH2AX,Nbn,Prkdc,Trp)and liver drug enzyme genes(CYP2E1,CYP2A6)in liver,kidney and lung were studied after the final administration and recovery period.Results When the dose of NDMA was 3 mg·kg-1 all the animals died.After continuous administration for four days,the body weight of mice in the NDEA 15 mg·kg-1 group significantly decreased compared to the solvent control group(P＜0.001).There were differences in organ coefficient,blood biochemical index and histopathology between NDMA and NDEA and the solvent control group(P＜0.05,0.01,and 0.001),suggesting that NDMA and NDEA had certain toxicity to liver and kidney.The results of comet test in liver and kidney of NDMA and NDEA mice were positive,and RETCD24-in Pig-a gene mutation test of high-dose NDEA group was positive.The content of 8-OHdG in liver,kidney and lung of NDMA and NDEA groups was significantly increased(P＜0.05,0.001),and there were significant differences in DNA damage and liver drug enzyme gene expression(P＜0.05,0.001).Conclusion NDMA produced hepatotoxicity at a dose of 1.5 mgkg-1,and mutagenic and DNA damage in liver and kidney cells at a dose of 0.75 mg·kg-1,respectively.NDEA can produce hepatotoxicity at a dose of 15 mg·kg-1,and lead to mutagen and DNA damage in liver and kidney cells.It has been proved that the results of 8-OHdG and DNA damage genes are related to the genotoxicity results of NDMA and NDEA.
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万方数据
维普
