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L B Russell

Publications and source records attributed to L B Russell.

At least 109 records · Page 6Linked to original sources
PubMed1988

Genetic analysis and developmental regulation of testis-specific RNA expression of Mos, Abl, actin and Hox-1.4.

The pattern of Mos proto-oncogene RNA expression in the gonads of the sterile mouse mutants, dominant spotting (W), sex reversal (Sxr), testicular feminization (Tfm), hypogonadal (hpg), quaking (qk), two t-haplotypes, three X-autosomal translocations, and the YPOS strain, is consistent with its presence in haploid spermatids in the testes and in oocytes in the ovaries. In the male-sterile mouse mutants the pattern of expression of the testis-specific transcripts for Abl, actin, and the mouse homeobox Hox-1.4 genes is identical to that observed for Mos. However, during the postnatal onset of normal spermatogenesis we detected differences in the time of the appearance of the four transcripts. We detected Hox-1.4 transcripts at day 20, Mos at day 25, and Abl and actin at day 30, demonstrating a specific regulation of expression of each of these genes during haploid spermatid maturation in the mouse. Furthermore, comparison of Mos, Abl and actin RNA expression in mouse and rat testes revealed species-specific variations in the regulation of gene expression.

Actins↗
PubMed1987

Study of the base analog 6-mercaptopurine in the mouse specific-locus test.

The base analog 6-mercaptopurine (6MP) was studied in the mouse specific-locus test in various male germ-cell stages. The overall finding of 3 mutations in 65,376 offspring rules out (at the 5% significance level) an induced mutation rate greater than 1.22 times the historical control rate. For spermatogonial stem cells alone, the multiple ruled out is 3.7; and for postspermatogonial stages, it is 0.7. For late differentiating spermatogonia and preleptotene spermatocytes, stages that had earlier been found sensitive to dominant-lethal induction (a result confirmed in the present experiment), the results (0 mutations in 5214 offspring) do not rule out a positive effect; they indicate only that the induced rate is unlikely to be greater than 9.8 times the historical control rate. There is evidence that 6MP (or an active metabolite) reaches all germ-cell stages of concern. Because spermatogonial stem cells are not killed, the negative mutation mutation-rate results cannot be attributed to cell selection.

Animals↗
PubMed1987

Tests for urethane induction of germ-cell mutations and germ-cell killing in the mouse.

Urethane, a chemical that has given varied results in mutagenesis assays, was tested in the mouse specific-locus test, and its effect on germ-cell survival was explored. Altogether 32,828 offspring were observed from successive weekly matings of males exposed to the maximum tolerated i.p. dose of 1750 mg urethane/kg. The combined data rule out (at the 5% significance level) an induced mutation rate greater than 1.7 times the historical control rate. For spermatogonial stem cells alone, the multiple ruled out is 3.2, and for poststem-cell stages, 3.5. Litter sizes from successive conceptions made in any of the first 7 weeks give no indication of induced dominant lethality, confirming results of past dominant-lethal assays. That urethane (or an active metabolite) reaches germ cells is indicated by SCE induction in spermatogonia demonstrated by other investigators. Cytotoxic effects in spermatogonia are suggested by our finding of a slight reduction in numbers of certain types of spermatogonia in seminiferous tubule cross-sections and of a borderline decrease in the number of litters conceived during the 8th and 9th posttreatment weeks. The negative results for induction of gene mutations as well as clastogenic damage are at variance with Nomura's reports of dominant effects (F1 cancers and malformations) produced by urethane.

Animals↗
PubMed1987

Characterization of a panel of somatic cell hybrids for regional mapping of the mouse X chromosome.

A panel of five hybrid cell lines containing mouse X chromosomes with various deletions has been obtained by fusing splenocytes from male mice carrying one of a series of reciprocal X-autosome translocations with the azaguanine-resistant Chinese hamster cell line CH3g. These hybrids have been extensively characterized by using the allozymes hypoxanthine/guanine phosphoribosyltransferase (encoded by the Hprt locus) and alpha-galactosidase (Ags) and a series of 11 X-chromosome-specific DNA probes whose localization had been previously established by linkage studies. Such studies have established the genetic breakpoints of the T(X;12)13Rl and T(X;2)14Rl X-autosome translocations on the X chromosome and provided additional information as to the X-chromosome genetic breakpoints of the T(X;16)16H, T(X;4)7Rl, and T(X;7)6Rl translocations. The data establish clearly that both the T(X;4)7Rl and T(X;12)13Rl X-chromosome breakpoints are proximal to Hprt, the breakpoint of the former being more centromeric, lying as it does in the 9-centimorgan interval between the ornithine transcarbamoylase (Otc) and DXPas7 (M2C) loci. Similarly, it is now clear that the T(X;16)16H X-autosome translocation breakpoint lies distal to the DXPas8 (St14-1) locus, narrowing the X-chromosome breakpoint down to a region flanked proximally by this marker and representing, as expected from previous data, the distal quarter of the Hprt-Ta subchromosomal span. These five hybrid cell lines provide, with the previously characterized EBS4 hybrid cell line, a nested series of seven mapping intervals distributed along the length of the mouse X chromosome. Their characterization not only allows further correlation of the genetic and cytological X-chromosome maps but also should permit the rapid identification of DNA probes specific for particular regions of the mouse X chromosome.

Animals↗
PubMed1987

Allelic variation within the Emv-15 locus defines genomic sequences closely linked to the agouti locus on mouse chromosome 2.

Gene(s) at the agouti locus act within the microenvironment of the hair follicle to switch pigment synthesis in the melanocyte between eumelanin (black or brown pigment) and phaeomelanin (yellow pigment). Many phenotypic variants of this locus have been described. The mechanism(s) of gene action causing such variation in coat-color phenotype is not known. The close linkage of an endogenous ecotropic murine leukemia provirus, Emv-15, to the lethal yellow mutation of the agouti locus provides a means to molecularly access genes at or near the agouti locus. We have identified and used a unique mouse sequence flanking the Emv-15 provirus to define three alleles of the Emv-15 locus. We found a correlation between the presence of specific Emv-15 alleles and the origins of specific agouti locus mutations, confirming close linkage. However, we found some exceptions which suggest that the Emv-15 locus is closely linked to, but genetically separable from, the agouti locus.

Alleles↗
PubMed1987

Genetic organization of the agouti region of the mouse.

The agouti locus on mouse chromosome 2 acts via the hair follicle to control the melanic type and distribution of hair pigments. The diverse phenotypes associated with various agouti mutations have led to speculation about the organization of the agouti locus. Earlier studies indicated that two presumed agouti alleles, lethal yellow (Ay) and lethal light-bellied nonagouti (ax), are pseudoallelic. We present genetic data showing probable recombination between Ay and three agouti mutations (at, a, and ax), which suggest that Ay is a pseudoallele of the agouti locus. The close linkage of an endogenous ecotropic murine leukemia provirus, Emv-15, to Ay provides a molecular access to genes at or near the agouti locus. However, previous studies suggested that the Emv-15 locus can recombine with some agouti alleles and therefore we analyzed mice from recombinant inbred strains and backcrosses to measure the genetic distance between various agouti alleles and the Emv-15 locus. Our data indicate that the Emv-15 locus is less than 0.3 cM from the agouti locus. These experiments provide a conceptual framework for initiating chromosome walking experiments designed to retrieve sequences from the agouti locus and give new insight into the genetic organization of the agouti region.

Animals↗
PubMed1986

Mouse specific-locus test for the induction of heritable gene mutations by dibromochloropropane (DBCP).

The nematocide DBCP (1,2-dibromo-3-chloropropane) produced negative results in a specific-locus test for gene-mutation induction in the germline of male (101 X C3H)F1 mice, most of which were treated with 5 daily intraperitoneal injections of 80 mg/kg (total exposure, 400 mg/kg); a few received lower exposures. For treated spermatogonial stem cells, the finding of 2 mutations among 39519 offspring--a rate almost identical to the control rate--rules out (at the 5% significance level) an induced mutation frequency greater than 2.0 times the historical control rate. From treated poststem-cell stages, no mutants were found among 6240 offspring, ruling out (at the 5% significance level) a multiple of 8.0 times the control for these cell types. A multiple rearrangement (7 chromosomes involved in 3 translocations) found in one of the mutants probably arose as a postmeiotic event not associated with the DBCP treatment. The fertility of DBCP-treated males was not disturbed, in keeping with the absence of germ-cell toxicity and dominant lethals found by other investigators in these mice, and in contrast to results in certain other species. While the treated (101 X C3H)F1 mice are Ah-responsive, other findings make it questionable whether biotransformation of DBCP to reactive intermediates is accomplished via the Ah-receptor system.

Animals↗
PubMed1986

Molecular genetic analysis of the dilute-short ear (d-se) region of the mouse.

Genes of the dilute-short ear (d-se) region of mouse chromosome 9 comprise an array of loci important to the normal development of the animal. Over 200 spontaneous, chemically induced and radiation-induced mutations at these loci have been identified, making it one of the most genetically well-characterized regions of the mouse. Molecular analysis of this region has recently become feasible by the identification of a dilute mutation that was induced by integration of an ecotropic murine leukemia virus genome. Several unique sequence cellular DNA probes flanking this provirus have now been identified and used to investigate the organization of wild-type chromosomes and chromosomes with radiation-induced d-se region mutations. As expected, several of these mutations are associated with deletions, and, in general, the molecular and genetic complementation maps of these mutants are concordant. Furthermore, a deletion breakpoint fusion fragment has been identified and has been used to orient the physical map of the d-se region with respect to the genetic complementation map. These experiments provide important initial steps for analyzing this developmentally important region at the molecular level, as well as for studying in detail how a diverse group of mutagens acts on the mammalian germline.

Animals↗
PubMed1986

A new type of nonhomologous synapsis in T(X;4)1R1 translocation male mice.

The synaptonemal complexes of T(X;4)1R1 (abbreviated R1) translocation heterozygotes have been examined by electron microscopy and compared with those of two X-7 translocations: R5 and R6. The X chromosome breakpoint of R1 is estimated to lie between 78 and 82% from the proximal end of the X, in the same general region as the R5 and R6 breakpoints. The position of the autosomal breakpoint of R1, like that of R6, is about 30% from the proximal end of the respective autosome. R1 is also similar to R6 in that there is extensive nonhomologous synapsis both in quadrivalents and heteromorphic bivalents. We have recently found that the location of breakpoints with respect to the position of the G-bands appears to be related to the synaptic behavior seen in translocation heterozygotes. If both breaks of a reciprocal translocation lie in G-light bands, as was the case with R5, synapsis is confined to homology. However, if one break lies in or immediately adjacent to a G-dark band, there is nonhomologous synapsis, as occurs with R1 and R6. Comparison of the synaptic behavior of R1 with R5 and R6 leads to the conclusion that this G-band-related nonhomologous synapsis is of a different type than the "synaptic adjustment" phenomenon that has been described by Moses (1977a). This G-band-related nonhomologous synapsis is not substage-specific, but competes with homologous synapsis during zygotene-early pachytene.

Animals↗
PubMed1986

Information from specific-locus mutants on the nature of induced and spontaneous mutations in the mouse.

Genetic and molecular analyses of mutations are increasing the qualitative capabilities of the specific-locus test (SLT). Some mutations are found to be deletions of large numbers of genes, including some that control survival at various developmental stages, neurological functions, enzyme syntheses, etc. Smaller (including possibly single-gene) deletions are also detected. A third group of SLT mutations represents intragenic lesions. -- For at least three of the loci, mutations may now be qualitatively grouped on the basis of simple phenotypic findings. Type of mutagen and germ-cell stage exposed strongly influence the nature of the lesions. The qualitative information from SLT results makes possible conclusions about relative potential harmfulness of different types of exposures that may yield equal mutation rates, about differences between induced and spontaneous mutations, etc. It also identifies genetic material suitable for basic studies.

Animals↗
PubMed1985

Issues in the design of future preventive medicine studies.

This paper discusses some of the design issues that are most important as cost-effectiveness analysis of preventive care advances from a novel application of economic reasoning to become an accepted aid in decision-making. In this new role, cost-effectiveness studies must be more consistent in approach and more standardized in assumptions than they have been in the past, so that valid comparisons can be made on the basis of studies done by different authors, or by the same authors at different times. The paper discusses the issues of the perspective of the study; the choice of discount rate; medical care costs in added years of life; measurement of the costs of institutionalization; measures of health effects that reflect changes in the quality as well as the quantity of life; and the proper place of estimates of earnings. Proposals are made in each of these areas to help standardize future studies.

Cost-Benefit Analysis↗
PubMed1985

Experimental approaches for the detection of chromosomal malsegregation occurring in the germline of mammals.

Existing and newly proposed methods to detect the induction of heritable aneuploidy are summarized, and their favorable and unfavorable features discussed. Among the tests involving direct chromosomal examination, those involving study of pronuclear chromosomes at first cleavage are judged to be the most universally informative and reliable, provided tertiary trisomy can be ruled out. Measurement of postmidterm (fetal) death is proposed as a trisomy prescreen that can be readily combined with a dominant-lethal test. Among the genetic procedures for identifying the results of malsegregation events, direct detection of aneuploids has a number of advantages over complementation methods, in which only a fraction of the products of aneuploid gametes is detectable. Direct detection of aneuploids must, however, be restricted to sex chromosomes if postnatal animals are examined. A genetic marker system to detect autosomal trisomies in fetuses is proposed. An examination of experimental parameters that might maximize induction of malsegregation leads to the recommendation to include preleptotene among exposed germ-cell stages.

Alleles↗
PubMed1985

Tests for heritable genetic damage and for evidence of gonadal exposure in mammals.

Tests for the induction of genetic damage in mammalian germ cells provide the data needed for human genetic risk assessment and are used as standards for judging the ability of shorter-term tests to predict genetic hazard. In this review, 15 mammalian germ-cell tests and their variants are described. These tests are of two general types: (a) those designed to detect certain classes of genetic damage (gene mutations, chromosome breakage and/or rearrangement, and chromosome mis-segregation), regardless of whether or not the endpoint scored has any significance to human health, and (b) those designed to detect phenotypes that have human health implications, while the nature of the genetic damage is not usually known. Exposure to a mutagenic agent presents no genetic hazard if the chemical or its metabolites fail to reach the reproductive cells. Tests for gonadal exposure are, therefore, important, as preliminaries or components of studies on germ-cell mutagenicity. Seven of these tests and their variants are briefly described in the second part of the paper.

Abnormalities, Drug-Induced↗
PubMed1984

Dual energy CT scanning for analysis of brain damage due to X-irradiation.

Therapeutic irradiation is commonly used in the treatment of malignant brain tumors and has the potential to cause severe injury to normal tissues adjacent to a lesion. Computed tomography (CT) can be used not only to visualize tissue damage but to monitor the development of a lesion using advanced quantitative CT techniques. We have used a postprocessing dual energy CT method to quantify changes in tissue composition following large single doses of X-rays to the normal canine brain. The results suggest that these techniques will provide more information about the character of a lesion than is obtainable from conventional imaging procedures.

Animals↗
PubMed1984

Specific-locus mutation rates in the mouse following inhalation of ethylene oxide, and application of the results to estimation of human genetic risk.

Male (101 X C3H)F1 mice were exposed in an inhalation chamber to ethylene oxide (EtO) in air at a concentration of (generally) 255 ppm. After accumulating total exposures of 101 000 or 150 000 ppm.h in 16-23 weeks, the males were mated to T-stock females for a standard specific-locus mutation-rate study in which 71387 offspring were observed. The spermatogonial stem-cell mutation rate at each exposure level, as well as the combined result, does not differ significantly from the historical control frequency. At the lower and higher exposure levels, the results rule out (at the 5% significance level) an induced frequency that is, respectively, 0.97 and 6.33 times the spontaneous rate; the combined results rule out a multiple of 1.64. The relationship between mouse spermatogonial stem-cell mutation rates and EtO-induced testis ethylations was compared with the relationship between Drosophila post-stem-cell mutation rates and sperm ethylations (Lee, 1980). The comparison does not rule out equal mutability per ethylation; but it cannot prove parallelism. An assessment of the mouse-Drosophila relationship will require a more efficient alkylator than EtO and the use of comparable germ-cell stages. More meaningful conclusions may be drawn by utilizing the data for direct estimation of human risk by expressing the induced mutation frequency that is ruled out (at the 5% significance level) as a multiple of control rate and extrapolating to human exposure levels. The probable absence of major stem-cell killing (and thus, possibly, cell selection) by EtO indicates that such extrapolation probably does not produce an underestimate. For a human exposure concentration of 0.1 ppm on working days during the reproductive lifespan, the mouse experimental results rule out (at the 5% significance level) an induced spermatogonial stem-cell gene mutation rate greater than 8% of the spontaneous rate; for 1.0 ppm, they rule out an induced rate roughly equal to the spontaneous rate. The induced rate for any one poststem-cell stage would have to be about 3 orders of magnitude higher than that for stem cells to constitute an equivalent risk.

Animals↗