Differential sensitivities of spermatogonial and postspermatogonial cell stages of the mouse to induction of unscheduled DNA synthesis by ethyl- and methyl-nitrosourea.

An autoradiographic procedure was used to measure unscheduled DNA synthesis (UDS, DNA repair synthesis) in spermatogonial and postspermatogonial cell stages of mice after treatment with two doses of N-ethyl-N-nitrosourea (ENU) and N-methyl-N-nitrosourea (MNU). Significant levels of UDS were measured in type A spermatogonia, meiotic spermatocytes, round spermatids, and early elongating spermatids but not in mature spermatids. The extent of UDS varied according to the germ cell stage and the dose.

Induction of specific-locus and dominant lethal mutations in male mice by ifosfamide (Holoxan).

Ifosfamide induced dominant lethal mutations in spermatozoa of mice at doses of 200 and 300 mg/kg and in spermatids and spermatocytes at 600 mg/kg. The highest dose also induced specific-locus mutations in post-spermatogonial germ-cell stages of mice but not in spermatogonial stem cells. The nature of the induced mutations suggests they are intergenic.

Induction of specific-locus and dominant lethal mutations in male mice by 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU).

1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) induced dominant lethal and specific-locus mutations in male mice. For both compounds the germ cell stage sensitive to the induction of dominant lethal mutations was dose dependent. A dose of 5 mg BCNU per kg b.

The effect of the interval between dose applications on the observed specific-locus mutation rate in the mouse following fractionated treatments of spermatogonia with ethylnitrosourea.

Our earlier analyses have suggested an apparent threshold dose-response for ethylnitrosourea-induced specific-locus mutations in treated spermatogonia of the mouse to be due to a saturable repair process. In the current study a series of fractionated-treatment experiments was carried out in which male (102 x C3H)F1 mice were exposed to 4 x 10, 2 x 40. 4 x 20 or 4 x 40 mg ethylnitrosourea per kg body weight with 24 h between applications; 4 x 40 mg ethylnitrosourea per kg body weight with 72 h between dose applications; and 2 x 40, 4 x 20 and 4 x 40 mg ethylnitrosourea per kg body weight with 168 h between dose applications.

Synthesis report of the step project detection of germ cell mutagens.

The project 'Detection of Germ Cell Mutagens' was designed with three major goals: (1) Detection and characterization of germ-cell mutagens; (2) standardization and validation of new germ-cell tests; and (3) development of a data base on germ-cell mutagenicity. All three goals were achieved. The classical germ-cell tests were applied to characterize the genetic effects of acrylamide (AA), 1,3-butadiene (BD), trophosphamide (TP) and urethane (UR).

Acrylamide: a review of its genotoxicity and an assessment of heritable genetic risk.

An updated review of the genotoxicity studies with acrylamide is provided. Then, using data from the studies generating quantitative information concerning heritability of genetic effects, an assessment of the heritable genetic risk presented by acrylamide is presented. The review offers a discussion of the reactions and possible mechanisms of genotoxic action by acrylamide and its epoxide metabolite glycidamide.

Germ line specific factors in chemical mutagenesis.

Chemical mutagenesis test results have not revealed evidence of germ line specific mutagens. However, conventional assays have indicated that there are male-female differences in mutagenic response, as well as quantitative/qualitative differences in induced mutations which depend upon the particular cell stage exposed. Many factors inherent in the germ line can be speculated to influence chemical transport to, and interaction with, target cell populations to result in mutagenic outcomes.

Induction of specific-locus and dominant lethal mutations in male mice by n-propyl and isopropyl methanesulfonate.

n-Propyl methanesulfonate (nPMS) and isopropyl methanesulfonate (iPMS) induce dominant lethal and specific-locus mutations in male mice. The response of the various spermatogenic stages to the induction of mutations differ markedly for nPMS and iPMS. Independent of the effective dose range the induction of dominant lethal mutations by nPMS is limited to spermatozoa and spermatids.

Induction of specific-locus and dominant lethal mutations in male mice by trophosphamide.

Trophosphamide induced dominant lethal and specific-locus mutations in spermatozoa and spermatids of mice. The induction pattern of specific-locus and dominant lethal mutations shows two maxima in the mating intervals 1-4 and 9-16 days post treatment. The nature of induced mutations is suggested to be intergenic.

Induction of specific-locus and dominant lethal mutations in male mice by 1-methyl-1-nitrosourea (MNU).

1-Methyl-1-nitrosourea (MNU) induced specific-locus mutations in mice in all spermatogenic stages except spermatozoa. After intraperitoneal injection of 70 mg/kg body weight of MNU a high yield of specific-locus mutations was observed in spermatids (21.8 x 10(-5) mutations per locus per gamete).

The induction of forward and reverse specific-locus mutations and dominant cataract mutations in spermatogonia of treated strain DBA/2 mice by ethylnitrosourea.

The mutagenic effectiveness of ethylnitrosurea (ENU) was assessed in treated spermatogonia of DBA/2 mice. In a total of 17,515 offspring examined following 160 mg ENU/kg body weight treatment of parental males, 26 forward specific-locus mutations, 2 reverse specific-locus mutations and 9 dominant cataract mutations were recovered. ENU increased the mutation rate to all 3 genetic endpoints.

Induction of specific-locus and dominant lethal mutations in male mice by busulfan.

The chemotherapeutic agent busulfan was tested for the induction of dominant lethal and specific-locus mutations in male mice. A dose of 5 mg/kg b.w.

Mutations in the F1 generation of mice.

The occurrence of induced dominant genetic damage can be measured by comparing mutation frequencies in first generation descendants from treated and untreated populations, but for many characters, it is difficult to distinguish between the effects of newly occurring genetic damage and the within-strain variation. This problem has been solved for skeletal abnormalities and for dominant cataract mutations. The skeleton was chosen because it is formed over an extended period of development and is, therefore, presumably subject to modification by gene action expressed during a wide range of time.

A dose-response analysis of ethylnitrosourea-induced recessive specific-locus mutations in treated spermatogonia of the mouse.

A dose-response analysis was carried out with 2 independent data sets available for ethylnitrosourea-induced specific-locus mutations in spermatogonia of the mouse. It was assumed that the occurrence of mutation is binomially distributed and maximum-likelihood procedures were employed to determine the appropriateness of 4 alternative models, Linear, Linear-Quadratic, Power, and Threshold, in describing the dependence of the binomial parameter on dose. For both data sets, the Threshold model yielded a far superior fit and the threshold dose was estimated to be between 34 and 39 mg/kg.

Induction of specific-locus and dominant lethal mutations in male mice in the low dose range by methyl methanesulfonate (MMS).

Methyl methanesulfonate (MMS) induces specific-locus and dominant lethal mutations in spermatozoa and spermatids of mice. A dose of 15 mg/kg b.w.

The frequency of dominant cataract and recessive specific-locus mutations and mutation mosaics in F1 mice derived from post-spermatogonial treatment with ethylnitrosourea.

The frequency of dominant cataract and recessive specific-locus mutations and mutation mosaics was determined in F1 mice derived from post-spermatogonial germ-cell stage treatment with 2 X 80, 160 or 250 mg/kg ethylnitrosourea. A total of 5 dominant cataract mutations, 3 dominant cataract mutation mosaics, 1 specific-locus mutation and 9 specific-locus mutation mosaics were recovered in 15,542 screened F1 offspring. Results indicate that ethylnitrosourea treatment increases the mutation rate of dominant cataract and recessive specific-locus alleles in post-spermatogonial germ-cell stages of the mouse and that the mutations occur mainly as mosaics.

Induction of specific-locus mutations in male mice by ethyl methanesulfonate (EMS).

Using a sequential mating procedure, the induction of specific-locus mutations by ethyl methanesulfonate (EMS) was reinvestigated in male mice. Doses of 175 mg/kg b.w.

Induction of specific-locus and dominant lethal mutations in male mice by chlormethine.

Chlormethine (WHO), a nitrogen mustard (2,2'-dichloro-N-methyldiethylamine), induces dominant lethal and specific-locus mutations in spermatozoa and spermatids of mice.

[Quantification of chemical genetic risk].

Associated with technical advances of our civilization is the possibility of an increase of radiation- and chemically induced germ-cell mutations in man. This would result in an increase in the frequency of genetic diseases and would be detrimental to future generations. It is the duty of our generation to keep this risk as low as possible.

Germ cell mutations in mice.

The most extensive set of information on the factors affecting mutation induction by chemical mutagens in mice has been obtained by use of the dominant lethal assay and the specific locus method. Dominant lethal mutations are caused by chromosomal aberrations, and they occur shortly before or after implantation. The specific locus method can be used to detect a variety of mutational events, ranging from intralocus changes to multilocus deletions.