A Balanced Translocation in Mice with a Neurological Defect

Rutledge, Joe C.; Cain, K.T.; Cacheiro, N.L.A.; Cornett, C.V.; Wright, CS; Generoso, W.M.

doi:10.1126/science.3941902

Cited by 29 publications

(16 citation statements)

References 14 publications

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“…Studies of the effects of TEM on mouse germ cells have shown this chemical to be highly mutagenic, causing specific-locus mutations in both poststem cell and stem-cell spermatogonial stages (28). TEM is a primary carcinogen that has experimentally produced a variety of cancers (33,36) and was implicated in the production of an inherited reciprocal translocation that produced a neurological disease with characteristics like that of a single gene dominant trait (30). Thus, for this drug, the correlation between specific-locus mutagenicity, clastogenicity, the production of a genetic disease in mammals, cancer induction, and increase in the CVs of DNA flow histograms is well established.…”

mentioning

confidence: 99%

Further flow cytometric studies of the effects of triethylenemelamine on somatic and testicular tissues of the rat

Bickham¹,

Sawin²,

McBee³

et al. 1994

Cytometry

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Exposure to the mutagen triethylenemelamine on rat bone marrow, blood, and testis was studied using flow cytometry of DAPI-stained nuclei. Increased coefficients of variation (CVs) of the GI peaks were observed in bone marrow and blood after both 1 d and 5 d exposures. After 5 d exposure and 7 d recovery both tissues had recovered, in some cases to significantly lower CVs. Increased CVs of the 1C peak of testis were observed only after 5 d exposure to the high dose with no subsequently observed recovery. Bone marrow cells also were stained with Hoechst 33258 and Propidium Iodide. No differences among dyes were observed indicating that increased CVs likely are due to DNA damage resulting from interactions with the mutagen rather than differences in how the dyes bind to DNA relative to mutagen binding. This study demonstrates that differences occur among tissues in how quickly they respond and recover from mutagen exposure. Increased CVs, cell cycle alterations, and decreased CVs after recovery are all potentially useful biomarkers of effect for laboratory and field studies in environmental toxicology. 0 1994 Wiley-Liss, Inc.

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mentioning

confidence: 99%

Further flow cytometric studies of the effects of triethylenemelamine on somatic and testicular tissues of the rat

Bickham¹,

Sawin²,

McBee³

et al. 1994

Cytometry

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“…Admittedly, the natures of most of these mutations remain unclear. However, at least two dominant mutations have been associated with deletions [ThP, Brachyury-hairpin (36); W19H, Dominant spotting-19H (37)] and others have been associated with translocation breakpoints [ five Si (Steel) mutations (38, and L. B. Russell, unpublished observations) and the "Diver" neurological mutation (39)], much the same as a dominant phenotype of oncogenesis is often associated with translocations in somatic cells (25).…”

Section: Discussionmentioning

confidence: 99%

Molecular analysis of heritable mouse mutations.

Rinchik

1987

Environ Health Perspect

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Germ-line mutations of the mouse have for years comprised one class of biological markers for mammalian reproductive and developmental toxicology. Understanding the molecular nature of mutations and the mechanisms by which mutations are translated into specific (and often complex) phenotypes, however, still looms as a major goal of mammalian biology. Molecular genetic analysis of heritable mouse mutations constitutes a significant, experimentally malleable strategy for relating genomic DNA structure to genic expression and function in mammals. The integrated use of recombinant DNA technology, which allows both the identification and analysis of expression of single genes, and classical genetic and cytogenetic analysis, which allow the important correlation between basic DNA defects and the organismic consequences of such defects, has been crucial to this strategy. Some of the approaches (e.g., specific-gene cloning, random-clone analysis of genomic regions, insertional mutagenesis) for studying the nature and effect of both mutations and their wild-type counterparts that have resulted from this integration of genetic analysis and molecular biology have been applied to many loci within the murine genome. Studies of the nature and effects of a complex set of radiation-induced mutations at the dilute-short ear (d-se) region of chromosome 9, a specific example of this type of integrated analysis, are discussed.

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“…In mice, heritable translocations induced by chemical mutagens are sometimes associated with neurological disorders, blindness, and skeletal abnormalities (26,27). In humans, cases are known where translocations are associated with skeletal abnormalities and various other conditions.…”

Section: Extrapolation From Increased Mutation Rates To Adverse Healtmentioning

confidence: 99%

“…In addition, half of the gametes of a translocation carrier contain unbalanced, aneuploid segregants. Rutledge et al (27) found a high incidence of developmental anomalies in mice, as exencephaly and cleft palate among descendants of translocation carriers. Although the majority of these unbalanced zygotes will lead to stillbirths in man, 6% of these are assumed to result in congenitally malformed children (28).…”

Section: Extrapolation From Increased Mutation Rates To Adverse Healtmentioning

confidence: 99%

Approaches to assessing genetic risks from exposure to chemicals.

Sobels

1993

Environ Health Perspect

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An effort to assess and quantify genetic risks from human exposure to mutagenic chemicals is urgently needed; otherwise genetic toxicology may well lose its credibility. Genetic biomonitoring provides us with an indication of mutagenic effectiveness in human somatic cells. The populations and chemicals selected for such studies form a useful database for genetic risk-assessment studies. Extrapolation to what can be expected in germ cells of exposed individuals should be possible by using good dosimetry (adducts) and a parallelogram approach. The principle is that genetic damage in the inaccessible human germ cells can be estimated by determining the effects on lymphocytes (or other somatic cells) from humans and mice and in germ cells of mice. Worldwide, opportunities for the costly mouse germ cell studies are limited. Knowledge of type of DNA adducts, their persistence and/or removal and dominant lethal studies, will be helpful in predicting stage sensitivity. Extrapolation from a lowest effective dose level is proposed. The available data for ethylene oxide and benzene are reviewed. The risk of heritable translocations in progeny of populations exposed to ethylene oxide is so high that more precise estimates seem desirable. In discussing the expression of the induced mutations, the importance of dominant mutations and of heterozygous effects of deletions and other recessives is pointed out. The molecular changes underlying dominant mutations in man are more limited than is the case for recessive mutations. This raises the question whether mutagenic agents can produce the specific changes leading to recoverable, dominant mutations. Extrapolation from increased mutation rates to predictable increases of human disease, whether by doubling dose or direct methods, have been criticized.

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A Balanced Translocation in Mice with a Neurological Defect

Cited by 29 publications

References 14 publications

Further flow cytometric studies of the effects of triethylenemelamine on somatic and testicular tissues of the rat

Further flow cytometric studies of the effects of triethylenemelamine on somatic and testicular tissues of the rat

Molecular analysis of heritable mouse mutations.

Approaches to assessing genetic risks from exposure to chemicals.

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