The alkaline single cell electrophoresis assay with eight mouse organs: results with 22 mono-functional alkylating agents (including 9 dialkyl N-nitrosoamines) and 10 DNA crosslinkers

The genotoxicity of 22 mono-functional alkylating agents (including 9 dialk yl N-nitrosoamines) and 10 DNA crosslinkers selected from IARC (Internation al Agency for Research on Cancer) groups 1, 2A, and 2B was evaluated in eig ht mouse organs with the alkaline single cell gel electrophoresis (SCGE) (c omet) assay. Groups of four mice were treated once intraperitoneally at the dose at which micronucleus tests had been conducted, and the stomach, colo n, liver, kidney, bladder, lung, brain, and bone marrow were sampled 3, 8, and/or 24 h later. All chemicals were positive in the SCGE assay in at leas t one organ. Of the 22 mono-functional alkylating agents, over 50% were pos itive in all organs except the brain and bone marrow. The two subsets of mo no-functional alkylating agents differed in their bone marrow genotoxicity: only 1 of the 9 dialkyl N-nitrosoamines was positive in bone marrow as opp osed to 8 of the 13 other alkylating agents, reflecting the fact that dialk yl N-nitrosoamines are poor micronucleus inducers in hematopoietic cells. T he two groups of mono-functional alkylating agents also differ in hepatic c arcinogenicity in spite of the fact that they are similar in hepatic genoto xicity. While dialkyl N-nitrosoamines produce tumors primarily in mouse liv er, only one (styrene-7,8-oxide) out of 10 of the other type of mono-functi onal alkylating agents is a mouse hepatic carcinogen. Taking into considera tion our previous results showing high concordance between hepatic genotoxi city and carcinogenicity for aromatic amines and azo compounds, a possible explanation for the discrepancy might be that chemicals that require metabo lic activation show high concordance between genotoxicity and carcinogenici ty in the liver. A high percent of the 10 DNA crosslinkers were positive in the SCGE assay in the gastrointestinal mucosa, but less than 50% were posi tive in the liver and lung. In this study, we allowed 10 min alkali-unwindi ng to obtain low,md stable control values. Considering that DNA crosslinkin g lesions can be detected as lowering of not only positive but also negativ e control values, low control values by short alkali-treatment might make i t difficult to detect DNA crosslinking lesions. In conclusion, although bot h mono-functional alkylating agents and DNA crosslinkers are genotoxic in m ouse multiple organs, the genotoxicity of DNA crosslinkers can be detected in the gastrointestinal organs even though they were given intraperitoneall y followed by the short alkali-treatment. (C) 2000 Published by Elsevier Sc ience B.V. All rights reserved.