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Detection of DNA Damage Induced in Vivo following Exposure of Rats to Carcinogens

Pathology and Toxicology Research Unit, The Upjohn Company, Kalamazoo, Michigan 49001

An alkaline elution assay previously used to detect single-strand breaks in DNA of cultured mammalian cells has been modified to allow the analysis of DNA damage in various organs of rats following exposure to chemical carcinogens. Prior to exposure, the DNA of neonatal animals was labeled with [³H]thymidine. DNA damage was assessed in liver, lung, thymus, brain, kidney, stomach, duodenum, colon, bone marrow, and mammary gland. Dimethylnitrosamine, diethylnitrosamine, 4-nitroquinoline 1-oxide, 2-acetylaminofluorene, N-hydroxyacetylaminofluorene, aflatoxin B₁, 1,2-dimethylhydrazine, azoxymethane, benzidine-HCI, and 7,12-dimethylbenz(a)anthracene induced the greatest extent of DNA damage in target organs for carcinogenicity. In vivo exposure to several direct-acting alkylating agents, including N-methyl-N'-nitro-N-nitrosoguanidine, N-methyl-N-nitrosourea, N-ethyl-N-nitrosourea, methyl methanesulfonate, and ethyl methanesulfonate, caused significant DNA damage in target and non-target tissues. Dose-related increases in the DNA elution patterns were observed. DNA repair time, as measured by the return to a normal elution pattern, varied from as little as 24 hr for 4-nitroquinoline 1-oxide to as long as 7 days for dimethylnitrosamine. The in vivo DNA damage-alkaline elution assay offers a rapid and reliable assay for assessment of the ability of a compound to induce DNA damage.

¹ To whom requests for reprints should be addressed.

Received 6/23/77. Accepted 3/ 1/78.

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