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Polyamines modulate carcinogen‐induced mutagenesis in vivo
Author(s) -
Wallon U. Margaretha,
O'Brien Thomas G.
Publication year - 2005
Publication title -
environmental and molecular mutagenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1
H-Index - 87
eISSN - 1098-2280
pISSN - 0893-6692
DOI - 10.1002/em.20086
Subject(s) - transgene , genetically modified mouse , polyamine , mutant , mutagenesis , microbiology and biotechnology , carcinogen , ornithine decarboxylase , carcinogenesis , biology , in vivo , biochemistry , chemistry , enzyme , genetics , gene
Abstract Elevated polyamine levels as a consequence of targeted overexpression of ornithine decarboxylase (ODC) to murine skin enhance susceptibility to tumorigenesis in this tissue. A possible mechanism for the enhanced susceptibility phenotype is an increased sensitivity of tissues with elevated polyamine levels to the mutagenic action of carcinogens. To test this hypothesis, a transgenic mouse model containing the Big Blue transgene and also expressing a K6/ODC transgene was developed. Incorporation of the K6/ODC transgene into the Big Blue model did not affect the spontaneous lacI mutant frequency in either skin or epidermis of the double‐transgenic mice. After skin treatment with single doses of either 7,12‐dimethylbenz[ a ]anthracene or N ‐methyl‐ N ′‐nitro‐ N ‐nitrosoguanidine, however, the mutant frequency was significantly increased in the skin of double‐transgenic Big Blue;K6/ODC mice compared to Big Blue controls. The increases in mutant frequency were clearly due to ODC transgene activity, since treatment of mice with the ODC inhibitor, α‐difluoromethylornithine, completely abolished the difference in mutant frequencies between double‐transgenic and Big Blue mice. These results demonstrate that intracellular polyamine levels modulate mutation induction following carcinogen exposure. Environ. Mol. Mutagen., 2005. © 2004 Wiley‐Liss, Inc.