Chromatid

Teratogenic effects have been noted with 2- and 4-aminophenol in the hamster, but 3-aminophenol was without effect in the hamster and rat (129,130). 4-Aminophenol is known to inhibit DNA synthesis and alter DNA stmcture in human lymphoblasts (131,132) and is mutagenic in mouse micronuclei tests (133). The aminophenols have been shown to be genotoxic, as evidenced by the induction of sister chromatid exchanges (134,135), but they also exert a protective effect against DNA interaction with other noxious chemicals (136). After assessment of available data a recent report stated that the aminophenols were safe as cosmetic ingredients in their present uses and concentrations (137). 

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. 

FIGURE 12.31 A model for chromosome structure, human chromosome 4. The 2-um DNA helix is wound twice around histone octamers to form 10-um uucleosomes, each of which contains 160 bp (80 per turn). These uucleosomes are then wound in solenoid fashion with six uucleosomes per turn to form a 30-nm filament. In this model, the 30-nm filament forms long DNA loops, each containing about 60,000 bp, which are attached at their base to the nuclear matrix. Eighteen of these loops are then wound radially around the circumference of a single turn to form a miniband unit of a chromosome. Approximately 10 of these minibands occur in each chromatid of human chromosome 4 at mitosis. 

Mitomycin C was found to have broad activity against a range of tumors and has been used clinically since the early 1960s [14, 15]. It causes many specific cellular effects, including inhibition of DNA synthesis, recombination, chromosome breakage, sister chromatid exchange, induction of DNA repair, and induction of... 

The eukaryotic somatic cell cycle is defined by a sequential order of tasks a dividing cell has to complete it must replicate its DNA, segregate its chromosomes, grow, and divide. The cell cycle can be divided into four discrete phases. DNA replication is restricted to S phase (DNA synthesis phase), which is preceded by a gap phase called G1 and followed by a gap phase called G2. During mitosis (M phase) the sister chromatids are segregated into two new daughter nuclei and mitosis is completed by the division of the cytoplasm termed cytokinesis (Fig. 1). 

The phase of the cell cycle where the sister chromatids are separated and distributed onto two daughter nuclei. First, upon entry into mitosis the chromosomes are condensed followed by the breakdown of the nuclear-envelope (prophase). The two centrosomes are separated and induce the formation of the mitotic spindle. Then, the chromosomes are captures by the spindle and aligned on the metaphase plate (metaphase). The sister-chromatids are separated and pulled to the poles of the spindle (anaphase). In telophase, two new nuclei are formed around the separated chromatids. 

APC is active from mid-M phase (anaphase) to the end of G1 phase and required for disconnecting sister chromatids and exit from M-Phase to Gl. The complex mediates the ubiquitination of Securin and Cyclin B. Degradation of these proteins, which block mitotic progression, promotes anaphase onset and exit from mitosis. 

Radial arrays are best exemplified by mitotic half-spindles, which have a central MTOC, the centrosome. The centrosome consists of two centrioles (which are homologous with the basal body) surrounded by dense pericentriolar material (Kalt and Schliwa, 1993). In plant cells, the MTOC of the mitotic spindle consists of dense material only without centrioles. The plus ends of microtubules of the mitotic spindle are directed toward the equator of the cell. Some are free, and others attach to kinetochores on chromatids (see Figure 4). 

In a similar study, the lymphoeytes from live patients who ingested methyl parathion (Wofatox) in suicide attempts were examined for aneuploidy, chromatid aberrations, and ehromosome aberrations (Czeizel 1994). No significant differences from the 15 control patients were seen in these end points. 

Sister chromatid exchange Sister chromatid exchange Sister chromatid exchange Sister chromatid exchange... 

Results of methyl parathion assays involving effects on chromosomes have also been contradictory. For sister chromatid exchange, Waters et al. (1982) reported a positive response in Chinese hamster ovary cells only in the presence of metabolic activation system, while methyl parathion tested positive without a metabolic activation system in Chinese hamster V79 cells (Chen et al. 1981), cultured normal human lymphoid cells (Chen et al. 1981 Gomez-Arroyo et al. 1987 Sobti et al. 1982), and Burkitt s l5miphoma cells (Chen et al. 1981). Chen et al. (1981) found a significant dose-related increase in sister chromatid exchange in both hamster and human cultured cells, but dose-related cell cycle delays were less pronounced in human cell lines than in V79 cells. Negative results were obtained for chromosomal aberrations in human lymphocytes without a metabolic activation system (Kumar et al. 1993). 

Genotoxicity. No reliable data in humans exist to indicate whether methyl parathion may act by a genotoxic mechanism. One study reported a temporary but significant increase in chromatid breaks and stable chromosomal aberrations in two subjects after ingestion of methyl parathion (Van Bao et al. 1974), but another study reported no significant differences in five subjects after ingestion of methyl parathion when compared with 15 controls (Czeizel 1994). A study that involved combined inhalation and dermal exposure of workers to methyl parathion showed no increase in chromosomal aberrations in their... 

Since in vivo tests in exposed human populations would involve concomitant exposure to other toxicants, it would be difficult to assess the genotoxic potential of methyl parathion alone. Therefore, additional well-designed in vitro studies using human cell lines are needed to determine the effects of methyl parathion on various genotoxic parameters (e.g., sister chromatid exchange, chromosomal aberrations, unscheduled DNA synthesis). 

Carrano AV, Thompson LH, Lindl PA, et al. 1978. Sister-chromatid exchange as an indicator of mutagenesis. Nature 271 551-553. 

Chen HH, Sirianni SR, Huang CC. 1982. Sister chromatid exchanges in Chinese hamster cells treated with seventeen organophosphorus compounds in the presence of a metabolic activation system. Environ Mutagen 4 621-624. 

Chen MM, Hsueh JE, Sirianni SR, et al. 1981. Induction of sister-chromatid exchanges and cell cycle delay in cultured mammalian cells treated with eight organophosphorus pesticides. Mutat Res 88 307-316. 

Das P, John G. 1999. Induction of sister chromatid exchanges and chromosome aberrations in vivo in Etroplus suratensis (Bloch) following exposure to organophosphorus pesticides. Toxicol Lett 104 111-116. 

De Ferrari M, Artuso M, Bonassi S, et al. 1991. Cytogenic biomonitoring of an Italian population exposed to pesticides Chromosome aberration and sister-chromatid exchange analysis in peripheral blood lymphocytes. Mutat Res 260 105-113. 

Dulout FN, Pastori MC, Olivero OA, et al. 1985. Sister-chromatid exchanges and chromosomal aberrations in a population exposed to pesticides. Mutat Res 143 237-244. 

Gomez-Arroyo S, Noriega-Aldana N, Juarez-Rodriguez D, et al. 1987. Sister chromatid exchanges induced by the organophosphorus insecticides methyl parathion, dimethoate, phoxim and methyl azinphos in cultured human lymphocytes. Contaminacion Ambiental 3 63-70. 

Sirianni SR, Huang CC. 1980. Comparison of induction of sister chromatid exchange, 8-azaguanine- and ouabain-resistant mutants by cyclophosphamide, ifosfamide and l-(pyridyl-3)-3,3-dimethyltriazene in Chinese hamster cells cultured in diffusion chambers in mice. Carcinogenesis 1 353-355. 

Cultured human lymphocytes Sister chromatid exchange + + Sobti et al. 1983... 

Gertain cells of insects, eg, Chironomus, contain giant chromosomes that have been repficated for ten cycles without separation of daughter chromatids. These copies of DNA fine up side by side in precise register and produce a banded chromosome containing regions of condensed chromatin and fighter bands of... 

At metaphase, mammalian chromosomes possess a twofold symmetry, with the identical duplicated sister chromatids connected at a centromere, the relative po-... 

The packaging of nucleoproteins within chromatids is not random, as evidenced by the characteristic patterns observed when chromosomes are stained with specific dyes such as quinacrine or Giemsa s stain (Figure 36-6). 

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