Induction of micronuclei and karyotype aberrations during in vivo mouse skin carcinogenesis.
The induction of chromosome and/or genome mutations during the first steps of skin carcinogenesis was followed in male NMRI mice, treated with a 'two-stage' [9,10-dimethyl-1,2-benzanthracene (DMBA) + phorbol-12-myristate-13-acetate (TPA)], or a 'three-stage' [DMBA+methyl methanesulphonate (MMS) + phorbol-12-retinoate-13-acetate (RPA)] protocol. The scoring of micronuclei (MN) in basal and suprabasal keratinocytes allows a relatively fast in vivo estimation of clastogenic and aneugenic effects of various compounds and treatments. Relevant stages were then further analysed by karyotyping the in vivo treated keratinocytes that were allowed to divide during short in vitro cultivation. DMBA used as initiator in both protocols was able to induce MN. The well-known clastogen MMS had an acute but transient effect on MN induction when used alone or as convertor in the three-stage protocol. Neither the propagator RPA, nor the 'full-promotor' TPA, which can carry out conversion as well as propagation, induced statistically significant numbers of MN when applied on mouse skin. Combined treatments, DMBA+MMS and MMS+RPA, showed higher MN frequencies than when MMS treatments were given alone. The full carcinogenic protocols showed significant frequencies of MN but the time points of appearance differed, indicating that the accumulation of aberrations could be more important than the order of appearance. Karyotypic analysis of those stages where the MN assay detected genome and/or chromosome aberrations revealed no specific loss of chromosomes that might be directly related to the carcinogenic process. When chromosome loss and aberrations were both taken into consideration together, chromosomes 7 and 11 and surely 9, 17 and 18 were more frequently involved than others.
Haesen
S
S
Laboratory of Antropogenetics, Free University Brussels, Belgium.
Timmermans
M
M
Kirsch-Volders
M
M
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000008:administration & dosage / Q000633:toxicity; D000818:Animals; D002869:Chromosome Aberrations; D004334:Drug Administration Schedule; D004347:Drug Interactions; D007621:Karyotyping; D008297:Male; D008741:Methyl Methanesulfonate / Q000008:administration & dosage / Q000633:toxicity; D051379:Mice; D008815:Mice, Inbred Strains; D048629:Micronuclei, Chromosome-Defective / Q000187:drug effects / Q000473:pathology*; D015162:Micronucleus Tests; D012867:Skin / Q000187:drug effects* / Q000473:pathology; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology*; D013755:Tetradecanoylphorbol Acetate / Q000008:administration & dosage / Q000633:toxicity
D015127:9,10-Dimethyl-1,2-benzanthracene; D008741:Methyl Methanesulfonate; D013755:Tetradecanoylphorbol Acetate