In Vivo Mammalian Mutagenesis

Environmental Health Sciences

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Abstract

Somatic and germinal mutations can have a severe impact on the fitness of multicellular organisms and offspring. The ability to study the occurrence of mutations in higher organisms has been limited by available methods rendering it difficult to address important questions such a 1) kinetics of mutation induction in relation to organ specificity, 2) mutation induction during development, 3) systemic effect of somatic mutations of age-related degenerative diseases, and 4) tumor progression from pre-neoplastic to neoplastic growth in relation to genomic stability. PhiX174 with the well characterized am3 mutation is used as a transgene to evaluate substitutions at the A:T base pair. Using this system mutations that are fixed in the animal can be separated from the mutations that arise from ex vivo damage in the DNA. Most cells in neonatal mice will divide several times before the animal reaches adulthood. The mutational fixation of DNA damage requires at least semi-conservative DNA replications. A study is in progress to test if young animals are more effective in mutational fixation of DNA damage than adult animals.Four day-old and 90-old mice hemizygous for the phiX insert were injected i.p. with 50 mg/kg of ENU. The ENU-induced revertant frequency in the spleen of both sets of animals were the same whereas the liver from the mice treated at 4 days of age were dramatically increased, which indicate selective sensitivity of neonatal to mutagens.