Effects of male germ-cell stage on the frequency, nature, and spectrum of induced specific-locus mutations in the mouse.

By means of the mouse specific-locus test (SLT) with visible markers, which is capable of detecting intragenic mutations as well as larger lesions, about 20 mutagens have been studied comparatively across arrays of male germ-cell stages. In addition, a very large historical control, accumulated over decades, provides data on spontaneous mutations in males. Each mutagen has a characteristic germ-cell-stage sensitivity pattern. Although most chemicals yield their maximum numbers of mutations following exposure of spermatozoa and late spermatids, mutagens have now been identified that peak in each of the major stages of spermatogenesis and spermiogenesis, including those in which effects on recombination can also be induced. Stem-cell spermatogonia have yielded positive results with only five of 15 mutagenic chemicals. In postspermatogonial stages, all chemicals, as well as radiations, induce primarily large lesions (LL). By contrast, in spermatogonia (either stem-cell or differentiating) all chemicals except one (bleomycin) produce very few such lesions. The spectrum of relative mutation frequencies at the seven loci of the SLT is characteristic for treated germ-cell stage and mutagen. Treatments that induce primarily LL are characterized by a great preponderance of s (Ednrb)-locus mutations (possibly due to a paucity of haplo-insufficient genes in the surrounding region); and those that induce very few, if any, LL by a great preponderance of p-locus mutations. Spontaneous locus-spectra differ from both types of treatment-induced spectra; moreover, there are two distinct types of spontaneous spectra, depending on whether mutations occurred in mitotic cells or during the perigametic interval.