Lethal mutation

Ethylene oxide has been shown to produce mutagenic and cytogenic effects in a variety of test systems (226). An increased frequency of chromosomal aberrations in peripheral lymphocytes of monkey exposed to ethylene oxide for 104 weeks has been reported (240). In mice, it is an effective inducer of chromosome breaks leading to dominant-lethal mutations. In addition, ethylene oxide has been shown to induce heritable effects in the heritable translocation test conducted in mice exposed to ethylene oxide by inhalation (241,242). In this study, male mice were exposed to ethylene oxide ranging from 165 to 300 ppm for 6 h per day 5 or 7 days/week for 8.5 weeks. Ethylene oxide has also been shown to bind to proteins (243) as well as to DNA (244). Several studies on ethylene oxide-exposed workers have demonstrated an increased incidence of chromosomal aberrations and sister chromatid exchanges the relevance of such effects to human health evaluation is currendy uncertain. 

Insect systems Drosophila melanogaster (sex-linked recessive lethal test) Recessive lethal mutation + Velazquez et al. 1984... 

Reproductive values indicated no dominant lethal mutations during 35 days post-treatment (Table IV). The period examined corresponded to postmeiotic stages of spermatogenesis. The incidence of pregnancies at all mating trials in the treated groups remained lower than the control. 

In male rats 2,3,7,8-tetrachlorodibenzo-p-dioxin induced hyperplastic changes and sperm granulomas in the epididymis, but no apparent lethal mutations were noted during post-meiotic phases of spermatogenesis. 

Chromosomal aberrations Gene mutation Dominant lethal mutation Micronucleus formation Micronucleus formation Micronucleus formation Chromosomal aberrations Sister chromatid exchange Micronucleus formation Chromosomal aberrations Sister chromatid exchange DNA-protein cross-links Nondisjunction of Y chromosome in sperm DNA damage (single-strand breaks)... 

Slacik-Erben R, Roll R, Franke G, et al. 1980. Trichloroethylene vapors do not produce dominant lethal mutations in male mice. Arch Toxicol 45 37. 

In rats, nickel carbonyl is reported to cause dominant lethal mutations (WHO 1991), but this needs verification. Nickel sulfate, when given subcutaneously at 2.4 mg Ni/kg B W daily for 120 days causes infertility testicular tissues are adversely affected after the first injection (USEPA 1980). Nickel salts given intraperitoneally to rats at 6 mg Ni/kg BW daily for 14 days did not produce significant chromosomal changes in bone marrow or spermatogonial cells (Mathur et al. 1978). 

Populations of soil mites were reduced in the Chernobyl area, but no population showed a catastrophic drop in numbers. By 1987, soil microfauna — even in the most heavily contaminated plots — were comparable to controls. Flies (Drosophila spp.) from various distances from the accident site and bred in the laboratory had higher incidences of dominant lethal mutations (14.7%, estimated dose of 0.8 mGy/h) at sites nearest the accident than controls (4.3%). Fish populations seemed unaffected in July/August 1987, and no grossly deformed individuals were found. However, 34+ i 37( s levels were elevated in young fishes. The most heavily contaminated teleost in May 1987 was the carp (Carassius carassius). But carp showed no evidence of mutagenesis, as judged by incidence of chromosomal aberrations in cells from the corneal epithelium of carp as far as 60 km from Chernobyl (Sokolov et al. 1990). 

Radiation causes dominant lethal mutations in the medaka (Oryzias latipes) (Shima and Shimada 1991). Mosquitofish (Gambusia spp.) from radionuclide-contaminated ponds in South Carolina differed from conspecifics in reference ponds, as judged by the frequency of DNA markers, and this is consistent with the hypothesis that these DNA markers may originate from genetic elements that provide a selective advantage in contaminated habitats (Theodorakis et al. 1998). Ionizing radiation at low-level chronic exposure reportedly has no deleterious genetic effects on aquatic populations because exposure is compensated by density-dependent responses in fecundity (IAEA 1976). However, this needs verification. 

Research on radiation-induced recessive lethal mutations — the predominant type of radiation-induced mutation — and dominant mutation systems (Sankaranarayanan 1991c)... 

Accelerating research on radiation-induced lethal mutations... 

Mouse Dominant lethal mutation - Litton Bionetics 1980... 

It is known that more fetal wastage than generally believed and many spontaneous abortions arise as a result of the presence of dominant lethal mutations in the developing embryo, many of which appear to be due to major chromosomal damage. In addition, impairment of male fertility may also be a consequence of exposure to mutagens. 

Simon GS, Kipps BR, Tarcliff RG, et al. 1978. Failure of Kepone and hexachlorobenzene to induce dominant lethal mutations in the rat. Toxicol Appl Pharmacol 45 330-331. 

Teramoto S, Saito R, Aoyama H, et al. 1980. Dominant lethal mutation induced in male rats by 1 2 Dibromo-3-chloro propane (DBCP). Mutat Res 77 71-78. 

Sex-linked recessive lethal mutations were not produced in Drosophila fed ethanol solution containing 50 ppm 1,2-diphenylhydrazine for 3 days (Yoon et al. 1985). No oral genotoxicity studies of 1,2-diphenylhydrazine in mammals were located. 

Sex-linked recessive Drosophila melanogaster/ lethal mutation feeding... 

Chalhoub, N., Benachenhou, N., Rajapurohitam, V., Pata, M., Perron, M., Frattini, A., Villa, A., and Vacher, J. (2003) Grey-lethal Mutation Induces Severe Malignant Autosomal Recessive Osteopetrosis in Mouse and Human. Nature Medicine, 399-406. 

The test is used to detect dominant lethal mutations. A dominant lethal mutation is one occurring in a germ cell, which does not cause dysfunction of the gamete but which is lethal to the fertihzed egg or developing embryo. 

A positive response in the rodent dominant lethal test indicates that the test substance may be genotoxic in the germ cells of the treated sex of the test species as evaluated by an increase in the number of dominant lethals evaluated as the sum of pre- and postimplantation loss. A dominant lethal mutation is one occurring in a germ cell, which does not cause dysfunction of the gamete but which is lethal to the fertilized egg or developing embryo. 

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