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Effects of carcinogenic agents upon different mechanisms for intragenic recombination in mammalian cells
T Helleday1, C Arnaudeau, D Jenssen
1Department of Genetic and Cellular Toxicology, Wallenberg Laboratory, Stockholm University, Sweden. helleday@genetics.su.se
Abstract:
A growing body of carcinogens are known to affect genetic recombination in mammalian cells and to thereby interfere with the process of carcinogenesis. In order to screen for recombinogenic effects of chemical and physical agents a variety of in vitro assay systems utilizing mammalian cells have been developed. However, the effects of potential carcinogens differ in these different systems. In order to investigate this phenomenon further, we have employed two different assay procedures, involving spontaneous duplication mutants in mammalian cells, which respond to homologous or non-homologous recombination. Four carcinogens were investigated, i.e. Aroclor 1221, benzene, methylmethanesulphonate (MMS) and thiourea, as were gamma- and UV-irradiation. With the exception of thiourea all of these factors resulted in elevated frequencies of homologous recombination. On the other hand, only UV-irradiation affected the rate of non-homologous recombination. These results indicate that substrate length and/or the recombination mechanism may influence the recombinogenic response of mammalian fibroblasts to carcinogenic factors. Thus, procedures for recombinogenic effects of carcinogens should consider the different pathways of recombination occurring in mammalian cells.
Insights
Carcinogens can impact genetic recombination in mammalian cells, influencing cancer development. Different assay systems reveal that carcinogens affect homologous recombination more broadly than non-homologous recombination.
Area of Science:
- Genetics
- Toxicology
- Cell Biology
Background:
- Carcinogens are known to influence genetic recombination in mammalian cells, potentially affecting carcinogenesis.
- Existing in vitro assay systems for screening carcinogens have shown variable results.
- The differential response of these systems necessitates further investigation into carcinogen effects on recombination.
Purpose of the Study:
- To investigate the phenomenon of differing carcinogen effects across various mammalian cell assay systems.
- To compare the recombinogenic effects of specific chemical and physical agents on homologous versus non-homologous recombination pathways.
Main Methods:
- Utilized two distinct in vitro assay procedures in mammalian cells.
- Assayed spontaneous duplication mutants sensitive to either homologous or non-homologous recombination.
- Tested four carcinogens: Aroclor 1221, benzene, methyl methanesulphonate (MMS), and thiourea, alongside gamma- and UV-irradiation.
Main Results:
- Aroclor 1221, benzene, methyl methanesulphonate (MMS), and gamma- and UV-irradiation elevated homologous recombination frequencies.
- Thiourea did not significantly affect homologous recombination.
- Only UV-irradiation demonstrably increased non-homologous recombination rates.
Conclusions:
- Mammalian cell recombination pathways and substrate characteristics influence responses to carcinogenic factors.
- Assay procedures for detecting carcinogen recombinogenicity must account for distinct mammalian recombination mechanisms.
- Understanding these differences is crucial for accurate carcinogen screening and risk assessment.