THE FAILURE OF THE POTENT MUTAGENIC CHEMICAL, 

 ETHYL METHANE SULPHONATE, TO SHORTEN THE 



LIFE-SPAN OF MICE 



PETER ALEXANDER and Miss D. I. CONNELL 



Chester Beatty Research Institute, Institute of Cancer Research, London, 



England 



SUMMARY 



Mice of the CBA strain were injected with large doses of the very powerful mutagenic 

 agent, ethyl methane sulphonate (EMS). The treatment had no effect on the average life- 

 span although it did elicit a high incidence of tumours late in Ufe. This observation 

 suggests that the pronounced life-span shortening seen in comparable experiments after 

 treatment with X-rays and the bifunctional alkylating agents, myleran and chloram- 

 bucil cannot be attributed to the induction of somatic mutations since, by analogy with 

 data from Drosophila, the dose of EMS used will induce many more mutations than the 

 three treatments which shortened the life-span of mice. We conclude that a non-genetic 

 cause must be sought for the reduction of life expectancy which occurs in CBA mice 

 after large doses of X-rays and which under the irradiation regime used is not due to a 

 carcinogenic or leukaemogenic action. The fact that all the life-span shortening agents 

 known are cytotoxic to dividing cells suggests that late disorders may be due to incom- 

 plete repair of the massive cell death which occurs at the time of treatment in organs 

 where mitosis is high. Delayed cell death in organs with low mitotic rate may be another 

 important factor. The deduction that somatic mutations have no part in radiation life- 

 span shortening refers only to the particular situation studied. 



The hypothesis has frequently been put forward that the life-span shortening 

 produced by ionizing radiations is a consequence of the induction of somatic 

 mutations which impair some normal physiological functions of cells and, in 

 particular, of differentiated cells. Our earlier observation (Alexander and 

 Connell, 1960) that two chemicals which are mutagenic, myleran (CH3SO2 . 

 . (0112)40 . SO2CH3) and the nitrogen mustard, chlorambucil (CO OH . 

 (CH2)3 . C6H4 . N(CH2CH2C1)2) brought about a shortening of life-span 

 might be considered as support for a mutation mechanism. These chemicals 

 are, however, bifunctional alkylating agents and as such are truly radio- 

 mimetic (Haddow, 1955). In particular, these two substances resemble 

 radiations in killing rapidly dividing cells within a few days. They also 

 produce in cells, not undergoing division at the time of treatment, delayed 

 lesions which cause death when the cells enter division weeks or months later. 

 This is seen, for example, in the kidney and liver. Consequently, the finding 

 that myleran and chlorambucil shorten life-span does not eliminate mechanisms 



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