The Experts below are selected from a list of 207 Experts worldwide ranked by ideXlab platform

U.h. Ehling - One of the best experts on this subject based on the ideXlab platform.

  • Induction of Specific-Locus and dominant lethal mutations in male mice by ifosfamide (Holoxan).
    Genetical research, 1998
    Co-Authors: U.h. Ehling, Jack Favor, Angelika Neuhäuser-klaus, I.-d. Adler
    Abstract:

    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. The spermatogenic Specificity of ifosfamide in mouse germ cells is similar to that of the structurally related cytostatic drugs cyclophosphamide and trofosfamide. Due to the post-spermatogonial germ cell Specificity of ifosfamide, the genetic risk is limited to a few weeks after exposure.

  • 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)
    Mutation research, 1997
    Co-Authors: U.h. Ehling, Jack Favor, I.-d. Adler, Angelika Neuhäuser-klaus
    Abstract:

    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.wt. induced dominant lethal mutations primarily in spermatocytes, whereas higher doses of BCNU induced dominant lethals in spermatids and spermatocytes. Following doses of 5 and 10 mg CCNU per kg b.wt. dominant lethals were induced in spermatids and spermatocytes similar to the results for higher doses of BCNU. Higher dose exposure to BCNU and CCNU was associated with dominant lethals expressed as pre-implantation loss (reduction in total number of implants). In addition, higher doses of CCNU showed a cytotoxic effect in differentiating spermatogonia. Both compounds induced Specific-Locus mutations in post-spermatogonial germ cell stages of mice. However, CCNU increased also the Specific-Locus mutation frequency in spermatogonia in two out of three experiments. We conclude in analogy with criteria developed by IARC, that BCNU and CCNU are potential human mutagens.

  • 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
    Mutation Research, 1997
    Co-Authors: Jack Favor, Andrea Wulff, U.h. Ehling, Angelika Neuhauserklaus, Albert A Van Zeeland
    Abstract:

    Abstract 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×C3H)F 1 mice were exposed to 4×10, 2×40, 4×20 or 4×40 mg ethylnitrosourea per kg body weight with 24 h between applications; 4×40 mg ethylnitrosourea per kg body weight with 72 h between dose applications; and 2×40, 4×20 and 4×40 mg ethylnitrosourea per kg body weight with 168 h between dose applications. For all experiments with 24-h intervals between dose applications, there was no effect due to dose fractionation on the observed mutation rates, indicating the time interval between dose applications to be shorter than the recovery time of the repair processes acting on ethylnitrosourea-induced DNA adducts. In contrast, a fractionation interval of 168 h was associated with a significant reduction in the observed mutation rate due to recovery of the repair process. However, although reduced, the observed mutation rates for fractionation intervals of 168 h were higher than the spontaneous Specific-Locus mutation rate. These observations contradict the expectation for a true threshold dose response. We interpret this discrepancy to be due to the differences in the predictions of a mathematical abstraction of experimental data and the complexities of the biological system being studied. Biologically plausible explanations of the discrepancy are presented.

  • Induction of Specific-Locus and dominant lethal mutations in male mice by n-propyl and isopropyl methanesulfonate
    Mutation Research, 1995
    Co-Authors: U.h. Ehling, Angelika Neuhäuser-klaus
    Abstract:

    Abstract n -Propyl methanesulfonate (nPMS) and isopropyl methanesulfonate (iPMS) induce dominant lethal and Specific-Locus mutations in male mice. The responses 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. In contrast, the induction of dominant lethal mutations by iPMS is dose dependent: a dose of 20 mg iPMS/kg body weight (bw) is active only in spermatocytes, while a dose of 100 mg/kg bw induces dominant lethal mutations in all postspermatogonial germ cell stages. One other striking difference in the biological effectiveness of both compounds is that iPMS induces a sterile phase in stem-cell spermatogonia, wheras nPMS treated males even at the highest dose are fully fertile.

  • Induction of Specific-Locus and dominant lethal mutations in male mice by trophosphamide
    Mutation Research, 1994
    Co-Authors: U.h. Ehling, Angelika Neuhäuser-klaus
    Abstract:

    Abstract 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.

F. J. De Serres - One of the best experts on this subject based on the ideXlab platform.

  • Quantitative and qualitative comparisons of spontaneous and radiation-induced Specific-Locus mutation in the ad-3 region of heterokaryon 12 of Neurospora crassa
    Mutation research, 1997
    Co-Authors: F. J. De Serres, H V Malling, Herman E. Brockman, Tong-man Ong
    Abstract:

    Abstract The data from forward-mutation experiments to obtain Specific-Locus mutations at two closely linked loci in the adenine-3 ( ad-3 ) region of heterokaryon 12 (H-12) of Neurospora crassa have been tabulated to determine the relative frequencies and mutational spectra of ad-3 mutants occurring spontaneously and those induced by 22 different chemical treatments. Previous studies have demonstrated that Specific-Locus mutations at these two loci result from 5 major genotypic classes, namely two classes of gene/point mutations ( ad-3A R and ad-3B R ), and 3 classes of multiLocus deletion mutations ([ ad-3A ] IR , [ ad-3B ] IR and [ ad-3A ad-3B ] IR ). In addition, prior studies have demonstrated that some chemical mutagens induced ad-3 mutants exclusively, or almost exclusively, by gene/point mutation and other chemical mutagens by gene/point mutation and multiLocus deletion mutation. In the latter cases, there was wide variation in the percentages of ad-3 mutants in these 5 major genotypic classes. Two comparative methods of analysis that also were used to compare spontaneous and chemical-induced ad-3 mutational spectra included χ 2 -tests on the numbers of ad-3 mutants resulting in the following two sets of ratios: (1) gene/point mutations and multiLocus deletion mutations; and (2) complementing and non-complementing ad-3B R mutants. Combination of the p -values from χ 2 -tests for these two methods of comparison demonstrated that all 22 chemicals induce a spectrum of ad-3 mutants that is qualitatively different from that occurring spontaneously. In addition, these same two methods of comparison have been used to compare the mutagenic effects of each of the 22 chemical treatments with each other. Combination of the data from these two methods of comparison has demonstrated that 93.1% (215/231) of the pairwise combinations of these 22 chemicals were different from each other. The implication of these experimental data on the induction of Specific-Locus mutations in somatic cells of Neurospora for genetic risk assessment exercises is discussed.

  • Quantitative and qualitative aspects of spontaneous Specific-Locus mutation in the ad-3 region of heterokaryon 12 of Neurospora crassa.
    Mutation Research, 1995
    Co-Authors: F. J. De Serres, H V Malling, Brooke B. Webber, Herman E. Brockman
    Abstract:

    Abstract The data from forward-mutation experiments to obtain Specific-Locus mutations at 2 closely linked loci in the adenine-3 (ad-3) region of heterokaryon 12 (H-12) of Neurospora crassa have been tabulated to determine the frequency of spontaneous ad-3 mutations and to determine the percentages resulting from each of the 2 major genotypic classes: gene/point mutations and multiLocus deletion mutations. Gene/point mutations at the ad-3B Locus (ad-3BR) have been characterized to determine the percentage showing allelic complementation to obtain a presumptive identification of the genetic alteration in each mutation at the molecular level. Data from experiments performed at 2 different laboratories have been compared to assess the interlaboratory reproducibility of quantitative data on H-12. No difference was found between the frequencies of spontaneous Specific-Locus mutations in the ad-3 region. Genetic analysis of 172 ad-3 mutants demonstrated that Specific-Locus mutations in the ad-3 region result from both gene/point mutations (82.0% [ 141 172 ]), and multiLocus deletion mutations (14.5% [ 25 172 ]). Heterokaryon tests for allelic complementation demonstrated that 52.5% ( 53 101 ) spontaneous ad-3BR mutants show allelic complementation, and result from single base-pair alterations. In addition, 100% ( 25 25 ) of the spontaneous multiLocus deletion mutations result from the 3 smallest sized genotypic subclasses. The implications of the present experimental data for the validation of the ad-3 Specific-Locus assay system in Neurospora are discussed.

  • Triethylenemelamine: induction of Specific-Locus mutations in the ad-3 region of heterokaryon 12 of Neurospora crassa.
    Mutation research, 1995
    Co-Authors: F. J. De Serres, H V Malling
    Abstract:

    The mutagenicity of the trifunctional alkylating (or cross-linking) agent TEM (triethylenemelamine or 2,4,6-tris(1-aziridinyl)-1,3,5-triazine) in the adenine-3 (ad-3) region was studied with a two-component heterokaryon (H-12) of Neurospora crassa. The objective was to characterize the genetic damage produced by this chemical to determine the spectrum of Specific-Locus mutations induced in a lower eukaryotic organism and to compare this spectrum with that induced in the mouse. Specific-Locus mutations in the ad-3 region of strain H-12 result from gene/point mutations, multiple-Locus mutations, and multiLocus deletion mutations at the closely linked ad-3A and ad-3B loci. These loci control two sequential biochemical reactions in the purine biosynthetic pathway. A 0.1 M solution of TEM was used to treat conidial suspensions of H-12 for 20, 40, 80, 120, or 170 min to obtain dose-response curves for (1) inactivation of conidia, and (2) the induction of Specific-Locus mutations in the ad-3 region. These experiments demonstrated that TEM is a strong mutagen (maximum forward-mutation frequency between 100 and 1000 ad-3 mutations per 10(6) survivors) for the induction of Specific-Locus mutations in the ad-3 region. Both biochemical and classical genetic tests were used to characterize the TEM-induced ad-3 mutations from each of the five treatment groups to distinguish between the different genotypic classes and subclasses. The overall data base from these genetic studies demonstrates that TEM-induced ad-3 mutations result predominantly (95.5% [769/805]) from gene/point mutations at the ad-3A and ad-3B loci, and from a low percentage (4.5% [36/805) of multiLocus deletion mutations. In addition, TEM induces an unusually high frequency of multiple-Locus mutations with sites of recessive lethal damage closely linked with the ad-3 region. Comparison of the dose-response curves for the major classes and subclasses of TEM-induced ad-3 mutations demonstrates (1) that gene/point mutations and multiLocus deletion mutations increase as the 1.4 power of TEM treatment time, and (2) that the two classes of TEM-induced multiple-Locus ad-3 mutations consisting of gene/point mutations with separate sites of recessive lethal damage increase at about the 1.96 power of TEM treatment time. When the data from the present Specific-Locus studies are compared with those in the mouse, we find, insofar as such comparisons are possible, that a similar spectrum of Specific-Locus mutations has been induced by TEM in each assay system.

  • Ethylene oxide: induction of Specific-Locus mutations in the ad-3 region of heterokaryon 12 of Neurospora crassa and implications for genetic risk assessment of human exposure in the workplace
    Mutation research, 1995
    Co-Authors: F. J. De Serres, Herman E. Brockman
    Abstract:

    Abstract Ethylene oxide (ETO) is an important industrial intermediate used extensively in the production of ethylene glycol, as a fumigant, and as a sterilant of choice for various medical devices. The mutagenicity of ETO was studied for the induction of Specific-Locus mutations in the adenine-3 ( ad-3 ) region of a two-component heterokaryon (H-12) of Neurospora crassa . The objectives of these studies with ETO were to rank its mutagenic potency and to compare its mutational spectrum for induced Specific-Locus mutations with other chemical mutagens in this lower eukaryotic organism. Specific-Locus mutations in the ad-3 region of heterokaryon H-12 result from gene/point mutations at the closely linked ad-3A and ad-3B loci, multiLocus deletion mutations and multiple-Locus mutations. These major genotypic classes are similar to the types of Specific-Locus mutations that can be detected in higher organisms. Conidial suspensions of H-12 were treated with five different concentrations of ETO (0.1–0.35%) for 3 h at 25°C. Control and ETO-treated conidial suspensions were used to obtain dose-response curves for inactivation as well as the overall induction of ad-3 forward mutations using a non-selective method based on pigment accumulation rather than a requirement for adenine. The results from these experiments are: (1) the slope of the dose-response curve for ETO-induced Specific-Locus mutations in the ad-3 region is 1.49±0.07, and (2) the maximum forward-mutation frequency fell between 10 and 100 ad-3 mutations per 10 6 survivors; therefore, ETO is a moderate mutagen . Classical genetic tests were used to characterize the ETO-induced ad-3 mutations from each of two treatments (0.25 and 0.35%). The overall data base demonstrates that ETO-induced ad-3 mutations result from a high percentage (96.9%) of gene/point mutations at the ad-3A and ad-3B loci, as well as from a low percentage (3.1%) of multiLocus deletion mutations. The mutagenic activity of ETO is compared with the mutagenic Specificity of other chemical mutagens and carcinogens in the ad-3 forward-mutation assay in Neurospora. The utilization of the Neurospora Specific-Locus data on ETO and those from experiments in the mouse and Drosophila, by others, is discussed for genetic risk assessment of germ-cell effects resulting from human exposure to ETO in the workplace.

  • Genetic risk assessment and Specific-Locus mutations in the ad-3 region of Neurospora crassa.
    Environmental Health Perspectives, 1994
    Co-Authors: F. J. De Serres
    Abstract:

    Data from experiments on the induction of Specific-Locus mutations in model systems are used in genetic risk assessment to estimate potential adverse effects in the human population. In such assessments with radiation or chemical mutagens, the following information is required: a) spontaneous and induced forward-mutation frequencies, b) dose-response curves for the overall induction of Specific-Locus mutations, c) genetic characterization of spontaneous and induced mutations, and d) dose-response curves for the different genotypic classes. Specific-Locus assays in most eukaryote assay systems provide only portions of the information required for such assessments. In recognition of the need for more detailed information for risk assessment, a model system has been developed for Specific-Locus assays in Neurospora crassa. The adenine-3 (ad-3) Specific-Locus assay was modeled after the two-gene morphological Specific-Locus assay in the dilute-short-ear region of the mouse and detects forward-mutations at two closely linked loci: ad-3A and ad-3B. A computerized data management program has made it possible to obtain precise dose-response curves not only for the overall induction of ad-3 mutations, but also for various genotypic subclasses. In addition, computerized statistical programs have been developed to compare dose-response curves. These methods of analysis have shown that the overall dose-response curve for Specific-Locus mutations in the ad-3 region is a composite of many different genotypic subclasses. In addition, these subclasses may have very different induction kinetics from those of the overall dose-response curve for ad-3 mutations.

Jack Favor - One of the best experts on this subject based on the ideXlab platform.

  • Induction of Specific-Locus and dominant lethal mutations in male mice by ifosfamide (Holoxan).
    Genetical research, 1998
    Co-Authors: U.h. Ehling, Jack Favor, Angelika Neuhäuser-klaus, I.-d. Adler
    Abstract:

    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. The spermatogenic Specificity of ifosfamide in mouse germ cells is similar to that of the structurally related cytostatic drugs cyclophosphamide and trofosfamide. Due to the post-spermatogonial germ cell Specificity of ifosfamide, the genetic risk is limited to a few weeks after exposure.

  • the mutagenic activity of ethylnitrosourea at low doses in spermatogonia of the mouse as assessed by the Specific Locus test
    Mutation Research, 1998
    Co-Authors: Jack Favor
    Abstract:

    Abstract Ethylnitrosourea is the most efficient chemical mutagen in spermatogonial stem cells of the mouse and its mutagenic activity has been intensively studied. The pertinent Specific-Locus mutation test results for a discussion of low dose–effect studies have been summarized and indicate: (1) A threshold dose response best characterizes the relationship between dose and mutation rate. (2) The reduced effectiveness of ethylnitrosourea in the low dose range is likely due to a saturable repair process. (3) The recovery of the saturable repair process as assessed in fractionated dose experiments is long (ca. 168 h). The dynamics of stem cell spermatogonia suggests a long time interval before the cell population passes through at least one cell division and this may be relevant to an interpretation of the fractionation effects. (4) There is a slight but important discrepancy between the predicted and observed mutagenic activity of ethylnitrosourea in the low dose range. This is interpreted to be due to the differences between a mathematical abstraction and the biological realities of the system being studied.

  • 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)
    Mutation research, 1997
    Co-Authors: U.h. Ehling, Jack Favor, I.-d. Adler, Angelika Neuhäuser-klaus
    Abstract:

    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.wt. induced dominant lethal mutations primarily in spermatocytes, whereas higher doses of BCNU induced dominant lethals in spermatids and spermatocytes. Following doses of 5 and 10 mg CCNU per kg b.wt. dominant lethals were induced in spermatids and spermatocytes similar to the results for higher doses of BCNU. Higher dose exposure to BCNU and CCNU was associated with dominant lethals expressed as pre-implantation loss (reduction in total number of implants). In addition, higher doses of CCNU showed a cytotoxic effect in differentiating spermatogonia. Both compounds induced Specific-Locus mutations in post-spermatogonial germ cell stages of mice. However, CCNU increased also the Specific-Locus mutation frequency in spermatogonia in two out of three experiments. We conclude in analogy with criteria developed by IARC, that BCNU and CCNU are potential human mutagens.

  • 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
    Mutation Research, 1997
    Co-Authors: Jack Favor, Andrea Wulff, U.h. Ehling, Angelika Neuhauserklaus, Albert A Van Zeeland
    Abstract:

    Abstract 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×C3H)F 1 mice were exposed to 4×10, 2×40, 4×20 or 4×40 mg ethylnitrosourea per kg body weight with 24 h between applications; 4×40 mg ethylnitrosourea per kg body weight with 72 h between dose applications; and 2×40, 4×20 and 4×40 mg ethylnitrosourea per kg body weight with 168 h between dose applications. For all experiments with 24-h intervals between dose applications, there was no effect due to dose fractionation on the observed mutation rates, indicating the time interval between dose applications to be shorter than the recovery time of the repair processes acting on ethylnitrosourea-induced DNA adducts. In contrast, a fractionation interval of 168 h was associated with a significant reduction in the observed mutation rate due to recovery of the repair process. However, although reduced, the observed mutation rates for fractionation intervals of 168 h were higher than the spontaneous Specific-Locus mutation rate. These observations contradict the expectation for a true threshold dose response. We interpret this discrepancy to be due to the differences in the predictions of a mathematical abstraction of experimental data and the complexities of the biological system being studied. Biologically plausible explanations of the discrepancy are presented.

  • the induction of forward and reverse Specific Locus mutations and dominant cataract mutations in spermatogonia of treated strain dba 2 mice by ethylnitrosourea
    Mutation Research, 1991
    Co-Authors: Jack Favor, Angelika Neuhauserklaus, U.h. Ehling
    Abstract:

    Abstract 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. However, ENU was less effective in treated DBA/2 mice than in the standard experimental protocol employing treated hybrid (102 × C3H)F1 male mice. This observed difference for a direct-acting mutagen such as ENU may result from differences in the detoxification of ENU or from differences in the DNA-repair capabilities of strain DBA/2. The first documented reverse mutation of the b allele is reported. The reversion was shown to be due to an AT to GC transition. To date, in addition to the reverse mutation of the b allele, 5 independent ENU-induced mutations recovered in germ cells of the mouse have been molecularly characterized and all have been shown to be base substitutions at an AT site. This is in contrast to the expected mechanism of ENU mutation induction due to O6-ethylguanine adduct formation which results in a GC to AT base-pair substitution and emphasizes the complexities of mutagenesis in germ cells of mammals.

Angelika Neuhäuser-klaus - One of the best experts on this subject based on the ideXlab platform.

Liane B Russell - One of the best experts on this subject based on the ideXlab platform.

  • Effects of Male Germ-Cell Stage on the Frequency, Nature, and Spectrum of Induced Specific-Locus Mutations in the Mouse
    Genetica, 2004
    Co-Authors: Liane B Russell
    Abstract:

    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.

  • Spontaneous mutations recovered as mosaics in the mouse Specific-Locus test
    Proceedings of the National Academy of Sciences of the United States of America, 1996
    Co-Authors: Liane B Russell, W. L. Russell
    Abstract:

    The Specific-Locus test (SLT) detects new mutants among mice heterozygous for seven recessive visible markers. Spontaneous mutations can be manifested not only as singleton whole-body mutants in controls (for which we report new data), but as mosaics—either visible (manifesting mottled coat color) in the scored generation (G2) or masked, among the wild-type parental generation (G1). Masked G1 mosaics reveal themselves by producing clusters of whole-body mutants in G2. We provide evidence that most, if not all, mosaics detected in the SLT (both radiation and control progenies) result from a single-strand spontaneous mutation subsequent to the last premeiotic mitosis and before the first postmeiotic one of a parental genome—the “perigametic interval.” Such events in the genomes of the G1 and G0 result, respectively, in visible and masked 50:50 mosaics. Per cell cycle, the spontaneous mutation rate in the perigametic interval is much higher than that in pregamete mitotic divisions. A clearly different Locus spectrum further supports the hypothesis of different origin, and casts further doubt on the validity of the doubling-dose risk-estimation method. Because mosaics cannot have arisen in mitotic germ cells, and are not induced by radiation exposure in the perigametic interval, they should not be included in calculations of radiation-induced germ-line mutation rates. For per-generation calculations, inclusion of mosaics yields a spontaneous frequency 1.7 times that calculated from singletons alone for mutations contributed by males; including both sexes, the multiple is 2.2.

  • Chlorambucil and bleomycin induce mutations in the Specific-Locus test in female mice.
    Mutation Research, 1996
    Co-Authors: Liane B Russell, P R Hunsicker, Michael D. Shelby
    Abstract:

    Abstract Specific-Locus studies have shown chlorambucil (CHL) and bleomycin (BLE) to be mutagenic in mouse oocytes, almost doubling the number of chemicals previously known to induce mutations in females. The overall CHL-induced mutation rate in oocytes is, however, one order of magnitude below that for male meiotic and postmeiotic stages, and only 1 50 that for early spermatids. For BLE, no Specific-Locus data for males are available for comparison, but the chemical had earlier been found negative for dominant-lethal induction in males. Both BLE and CHL were significantly mutagenic only in mature and maturing oocytes. In keeping with an earlier report, BLE produced a high incidence of dominant lethals in these stages. CHL failed to induce dominant lethals, indicating that for mature and maturing oocytes, in contrast with results for males, sensitivity to dominant-lethal mutations is not a prerequisite for induction of Specific-Locus mutations. Exposure of immature oocytes to either BLE or CHL produced neither dominant lethals nor significant induction of Specific-Locus mutations; however, CHL gave evidence of killing immature oocytes. By contrast, BLE, which has been considered a radiomimetic chemical, does not appear to kill immature oocytes and thus differs markedly from radiation exposures equivalent for dominant-lethal induction. Therefore, the failure to recover Specific-Locus mutations cannot be ascribed to cell selection resulting from oocyte killing, as has sometimes been done for radiation. Adding results on the nature of the CHL- and BLE-induced mutations to prior information, the estimated minimum proportion of large DNA lesions induced in oocytes by chemicals becomes 35.3%, significantly different from the corresponding figure (∼ 70%) for radiations. For chemical treatments, the oocyte proportion is highly significantly above the 3.6% induced in spermatogonia, but only on the borderline of statistically significant difference from that induced in postspermatogonial stages.

  • Frequency and nature of Specific-Locus mutations induced in female mice by radiations and chemicals: a review
    Mutation research, 1992
    Co-Authors: Liane B Russell, W. L. Russell
    Abstract:

    Abstract The inducibility of heritable mutations in female mammals has been measured in the mouse Specific-Locus test (SLT). For radiation-induced mutations, a large body of data has been accumulated that includes information about biological and physical factors that influence mutation yields. However, relatively few SLT studies in females have been conducted with chemicals to date. A single estimate of the spontanous mutation rate in oocytes, 6 536,207 , has been derived as the most appropriate one to subtract from experimental rates. This rate is highly significantly below the spontaneous mutation rate in males. Mutations recovered from females mutagenized at any time after about the 12th day post-conception are induced in non-dividing cells. In adult females, most oocytes are arrested in small follicles; maturation from this stage to ovulation takes several weeks. High-dose-rate radiations are more mutagenic in mature and maturing oocytes than in spermatogonia of the male; on the other hand, no clearly induced mutations have been recovered from irradiated arrested oocytes. Efficient repair processes have been invoked to explain the latter finding as well as the upward-curving dose-effect relation for acute irradiation, and the fact that dose protraction drastically reduces mutation yield from mature and maturing oocytes. The dose-protraction effect is much greater than that found in spermatogonia. Radiation-induced mutation rates in embryonic, fetal, and newborn females are overall lower than those in the mature and maturing oocytes of adults. A dose-protraction effect has also been demonstrated at an early developmental stage when the nuclear morphology of mouse oocytes most resembles that of the human. Of only 5 chemicals so far explored for their effect in oocytes, 2 (ethylnitrosourea, ENU, and triethylenemelamine, TEM), and possibly a third (procarbazine hydrochloride, PRC), are mutagenic — with at least one of these (ENU) mutagenic in arrested as well as maturing oocytes. However, the mutation rate is, in each case, lower than for treated male germ cells. By contrast, ENU-induced mutation yield for the maternal genome of the zygote is an order of magnitude higher than that for the zygote's paternal genome or for spermatogonia. A high proportion of mutants derived from chemical treatment of oocytes (including the oocyte genome in zygotes) are mosaics, probably owing to lesions affecting only 1 strand of the DNA. A characteristic of Specific-Locus mutations induced in oocytes is that they include a considerably higher percentage of large (multi-Locus) lesions (LLs) than do mutations induced in spermatogonia. For each germ-cell type, the frequency of LLs appears lower for the chemicals so far tested than for radiations.

  • Induction of Specific-Locus mutations in male germ cells of the mouse by acrylamide monomer
    Mutation research, 1991
    Co-Authors: Liane B Russell, Patricia R. Hunsicker, N.l.a. Cacheiro, Walderico M. Generoso
    Abstract:

    Abstract Acrylamide monomer (AA), injected into male mice at the maximum tolerated dose of 5× 50 mg/kg (24-h intervals), significantly increased the Specific-Locus mutation rate in certain poststem-cell stages of spermatogenesis, but not in spermatogonial stem cells. Germ-cell stages in which the treatment induced dominant lethals — namely, exposed spermatozoa and late spermatids (number of surviving offspring only 3% and 27%, respectively, of those in concurrent controls) — jointly yielded the highest frequency of Specific-Locus mutations. AA thus conforms to Pattern 1 in our earlier classification of chemicals according to the spermatogenic stage at which they elicit maximum response (Russell et al., 1990). No Specific-Locus mutations were observed among 17,112 offspring derived from exposed spermatogonial stem cells, a result which rules out (at the 5% significance level) an induced mutation rate greater than 2.3 times the historical control rate. A sustained high productivity in matings made for severalmonths following week 3 indicates that there is no significant spermatogonial killing and that cell selection is presumably not the explanation for the negative result. On the basis of genetic and/or cytogenetic evidence, the mutations induced postmeiotically by AA were ‘large lesions’ (multi-Locus), while one of 2 recovered from exposure of differentiating spermatogonia is probably a small lesion. An earlier survery of mammalian mutagenesis results led us to conclude that, regardless of the classification of a chemical according to the stage at which it elicits its maximum response, the nature of mutations is determined by the germ-cell stage in which they are induced (Russell et al., 1990). The AA results on lesion size and on distribution of mutations among the loci fit the general pattern.