Effect of temperature on mutation in cultured human skin fibroblasts

Because clothing enhances the gonadal temperature in the human male and because as a consequence of that the spontaneous mutation rate might be increased, a study was undertaken to determine the effect of temperature on mutation towards HPRT deficiency in human diploid skin fibroblasts. Culturing of the cells in HAT medium containing azaserine, to remove pre-existing mutants, was highly mutagenic. Some results suggested that azaserine acts as an indirect mutagen. The mutational process in the presence of azaserine was influenced by temperature, a rise in temperature from 33 to 37 degrees C leading to a more than 10-fold increase in mutation rate per cell generation. This temperature dependence, taken as a starting point for the estimation of the consequences of the rise in gonadal temperature, could be responsible for an increase of 135% in the incidence of a sex-linked lethal (Lesch-Nyhan) in the human population. Epidemiological data on the frequency of Lesch-Nyhan disease and on the ratio of paternal and maternal mutations leading to Lesch-Nyhan disease do not contradict the findings in the cultured cells.