Chromosome breaking

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. 

In a case-control study of pesticide factory workers in Brazil exposed to methyl parathion and formulating solvents, the incidence of chromosomal aberrations in lymphocytes was investigated (De Cassia Stocco et al. 1982). Though dichlorodiphenyltrichloroethane (DDT) was coformulated with methyl parathion, blood DDT levels in the methyl parathion-examined workers and "nonexposed" workers were not significantly different. These workers were presumably exposed to methyl parathion via both inhalation and dermal routes however, a dose level was not reported. The exposed workers showed blood cholinesterase depressions between 50 and 75%. However, the baseline blood cholinesterase levels in nonexposed workers were not reported. No increases in the percentage of lymphocytes with chromosome breaks were found in 15 of these workers who were exposed to methyl parathion from 1 week to up to 7 years as compared with controls. The controls consisted of 13 men who had not been occupationally exposed to any chemical and were of comparable age and socioeconomic level. This study is limited because of concomitant exposure to formulating solvents, the recent history of exposure for the workers was not reported, the selection of the control group was not described adequately, and the sample size was limited. 

On replication, insertion or deletion of bases may occur. Chain scission and chromosome breaks are also possible. Quinacrine is useful in human cytogenetics, since it intercalates significantly into the heterochromatin of the Y chromosome, making it fluoresce and rendering it identifiable cytologically. Detection of the Y chromosome is important in prenatal sex determination. Other dyes present in our environment are potentially mutagenic. For example, some hair dyes were shown to be mutagenic for E. coli. 

Growing tissues are most sensitive to ionizing radiation. DNA synthesis is inhibited, yet the action of x-rays is indirect. They produce free radicals, which in turn react with DNA and thus produce point mutations or chromosomal breaks. 

Structural chromosome aberrations, particularly chromatid gaps and increased frequency of fragment exchange, were observed in rat bone marrow cells after 14 days of exposure to 240 mg Zn/L drinking water (Kowalska-Wochna et al. 1988). Chromosomal aberrations were observed in bone marrow cells of mice fed diets equivalent to 650 mg Zn/kg BW daily, in mice exposed to zinc oxide by inhalation, and in mice maintained on a low-calcium diet (USPHS 1989). Aberrations in bone marrow of mice given 5000 mg Zn/kg diet may be associated with calcium deficiency (Leonard and Gerber 1989). Calcium is displaced by zinc in calcium-depleted conditions, leading to chromosomal breaks and interference in the repair process (USPHS 1989). 

Erythroblasts in bone marrow undergo a final chromosome replication after which they divide and differentiate into PCEs. Chromosomal breaks or interference in the mitotic process that result in the lagging chromosomes during this division lead to the formation of micronuclei that are similar in appearance but much smaller than the nucleus in immature, nucleated erythrocytes. During differentiation, only the nucleus is expelled from the nucleated erythrocyte, leaving behind any micronuclei formed. 

Chronic myeloid leukemia (CML) occurs when there is a translocation of chromosomes 9 and 22 (also called Philadelphia translocation—a chromosomal abnormality). These two different chromosomes break off and reattach on the opposite chromosome. A consequence is that the activity of the Bcr-Abl gene, which encodes the enzyme tyrosine kinase, is turned on all the time. With this heightened activity, high levels of white blood cells are produced in the bone marrow. 

Chinese hamsters exposed to ozone at 0.2 ppm for 5 h had an increased number of chromosomal breaks in their circulating lymphocytes. Blood samples for study were obtained immediately after exposure and 6 and 15.5 days later. The highest break frequency was observed after the longest delay. The authors compared the effects of X irradiation and ozone singly and combined, in their system. The combined effects were less than additive this suggested some protective mechanism, perhaps analogous to that observed by Hattori et al When the authors extrapolated their data to acceptable industrial-hygiene exposures to ozone and radiation, ozone was found to be much more likely than X irradiation to produce chromosomal breaks in such exposures. 

Lymphocyte chromosomal breaks Increased red-cell spherocytosis after in vitro radiation... 

Newman A (1995) Atrazine found to cause chromosomal breaks. Environ. Sci. Technol. 29 450A... 

The simplest and most sensitive assays for detecting clastogenic (i.e. chromosomal breaking) effects involve the use of mammalian cells. Cultures of established cell lines (e.g. Chinese hamster ovary) as well as primary cell cultures (e.g. human l)nnphocyte) may be used. After exposure to a range of chemical concentrations in the presence and absence of an appropriate metabolic activation system, the cell cultures are treated with a spindle inhibitor (e.g. vinblastine) to accumulate cells in a metaphaselike stage of mitosis. Cells are harvested at appropriate times and chromosome preparations are made, stained with DNA-specific dye and the metaphase cells are analysed under the microscope for chromosome abnormalities. 

Exposed workers had a marked increase in percentage of lymphocytes with chromatid breaks, chromosome breaks, severely damaged cells, and abnormal cells. ... 

HA was found to be mutagenic in bacteria, and it was reported that plant chromosomes break in the presence of HA, but it was found to be noncarcinogenic to mice. However, Gross did cite some A-hydroxy compounds (i.e. HA derivatives) as carcinogens . The mechanism of mutagenesis of HA was found to involve primarily interaction with the pyrimidine bases of the cytidine-guanosine pairs. 

Moynahan ME, Pierce AJ, Jasin M (2001) BRCA2 is required for homology-directed repair of chromosomal breaks. Mol Cell 7 263-272... 

Examples of sublesions are single chromosome breaks that combine to produce a dicentric aberration or single-strand DNA breaks, which, when in close proximity, result in double-stranded DNA breaks. The expression, Eq. (35), provides the link between the micro-dosimetric quantity z, and the dose-effect coefficients a and p. 

CS has been tested for its ability to cause chromosomal damage in a micronucleus test in mice. Micronucleus tests detect small nuclei that arise from chromosomal fragments or chromosomes that fail to be incorporated into normal daughter nuclei when cells divide. An increased frequency of micronuclei is evidence of chromosomal break-... 

Sloter E, Lowe X, Moore DH, Nath J, Wyrobek AJ (2000) Multicolor FISH analysis of chromosomal breaks, duplications, deletions, and numerical abnormalities in the sperm of healthy men. Am J Hum Genet, 67 862-872. 

Folic acid (or folate) deficiency, one of the most common vitamin deficiencies in the population consuming few dietary fruits and vegetables, causes chromosome breaks in humans,34 analogous to those caused by radiation. Folate supplementation above... 

Approximately 10 percent of the U.S. population40 had a lower folate level than that at which chromosome breaks occur.41 The recent decision in the United States to supplement flour, rice, pasta, and cornmeal with folate42 may reduce the percentage of the population with the deficiency. 

Other vitamins—vitamin R6 and niacin—complement folic acid. Vitamin R6 deficiency apparently causes chromosome breaks by the same mechanism as folate deficiency.43 Niacin is... 

Vitamins and minerals, whose main dietary sources are other than fruits and vegetables, are also likely to play a significant role in the prevention and repair of DNA damage, and thus are important to the maintenance of long-term health. Vitamin B12 is found in animal products, and deficiencies of B12 cause a functional folate deficiency, accumulation of the amino acid homocysteine (a risk factor for heart disease),46 and chromosome breaks. B12 supplementation above the RDA was necessary to minimize chromosome breakage.47 Strict vegetarians are at increased risk for developing vitamin B12 deficiency. 

Striking clinical results have been reported in inflammatory and auto-immune diseases, although in a somewhat limited number of cases . A low molecular mass chromosome-breaking agent was identified in the serum of patients with systemic lupus erythematosus. The chromosome aberrations in cultures of normal lymphocytes in the presence of this factor were reduced to normal values by the addition of BESOD to the culture medium... 

Other mutagens will also cause chromosome breaks such as bromouracil (see above) and the antibiotic streptonigrin, which is a very potent chromosome breaker. 

Phenol was reported to induce DNA oxidative damage in human promyelocytic HL60 cells and to inhibit repair of radiation-induced chromosomal breaks in human leukocytes (Morimoto et al., 1976). However, it only slightly inhibited DNA repair synthesis and DNA replication synthesis in WI-38 human diploid fibroblasts (Poirier et al., 1975). 

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