A formula, based on the Poisson distribution of radiation-induced chromosomal deletions, was derived to predict the frequency of transmission of acentric fragments between subsequent mitoses. The frequency of deletions observed in the i(th) + 1 division subsequent to fragment distribution at the i(th) division anaphase is independent of the cell death resulting from fragment loss. Further, the transmission frequency of chromosome acentric fragments is mathematically equal to the fragment frequency observed in the i(th) + 1 generation divided by the mean fragment frequency in the i(th) generation. The formula was also extended to chromatid deletions.

Animals↗

PubMedDate not supplied

Review of literature on chemical-induced aneuploidy in mammalian male germ cells.

80 papers published between 1970 and 1984 were evaluated for results pertaining to chemical-induced aneuploidy in mammalian male germ cells. Diverse assays and end points were represented. The assays considered to involve direct measures of aneuploidy were based upon chromosome counts in premeiotic, meiotic, and embryonic cells, and the male pronucleus, or upon phenotypic expression of X-linked genetic markers. Assays in which indirect measures were interpreted as evidence for aneuploidy included those primarily assessing chiasma frequencies, univalent frequencies, and spermatid/sperm sex chromosome body counts. An initial screening to reject studies with insufficient data and those which did not involve a single chemical test agent led to the elimination of 39 papers from further review. The remaining 41 papers reported effects from 46 different chemicals. These papers were rigorously assessed for adequacy of experimental protocols, relevance of end points as direct measures of aneuploidy, and completeness of data presentation and statistical analysis. Criteria specific to each assay were also considered. 4 chemical tests were considered to provide reliable positive or negative aneuploidy data. Cyclophosphamide and chloral hydrate each caused metaphase II hyperploidy when injected into mice. Very limited analyses of trenimon and isoniazid provided negative results. Test findings for 44 chemicals were viewed as inconclusive. It was concluded that standardization of tests to evaluate chemical-induced aneuploidy in male germ cells and the application of these tests towards increasing the data base are badly needed.

Aneuploidy↗

PubMedDate not supplied

Comparative genotoxic effects of the cooked-food-related mutagens Trp-P-2 and IQ in bacteria and cultured mammalian cells.

As part of a major study to evaluate the mutagenicity of chemicals produced during the cooking of foods, we examined the responses of bacteria and cultured Chinese hamster cells to the compounds Trp-P-2 (3-amino-1-methyl-5H-pyrido[4,3-b]indole) and IQ (2-amino-3-methylimidazo[4,5-f]quinoline), constituents identified in cooked beef and fish. In the Ames/Salmonella tester strain TA1538, both compounds were confirmed to be extremely potent mutagens that were active at levels below 1 ng/plate in the presence of hamster-liver S9 microsomal fraction. 50-fold higher doses of both compounds were required for mutagenicity in the uvr+ tester strain TA1978. Trp-P-2 also behaved as a strong mutagen in CHO cells using the standard exogenous activation with hamster-liver S9 fraction. At concentrations below 1 microgram/ml it produced dose-dependent increases in cell killing, mutations at the hprt and aprt loci, sister-chromatid exchanges, and chromosomal aberrations. An excision-repair-deficient strain was about 2-fold more sensitive than the normal CHO cells with respect to these genotoxic effects of Trp-P-2. IQ had unexpectedly weak activity for all genetic endpoints in the CHO cells, and it produced clear-cut responses only in the repair-deficient cells and only above a concentration of 10 micrograms/ml. The toxicity that was observed with IQ was not affected by the repair capacity of the cells and was not associated with chromosomal aberrations, indicating that damage to cellular structures other than nuclear DNA was likely the predominant pathway for cell killing. Because the culture conditions normally used for CHO cell exposure were shown to be competent in producing bacterial mutagenicity with IQ, it was concluded that the active metabolite of IQ was present in the medium but was somehow ineffective in reaching the DNA of CHO cells and/or reacting with it. These results suggest that the relative mutagenic potency of compounds in Salmonella may bear no direct relationship to relative mutagenicity in CHO cells, emphasizing precaution in attempting to extrapolate microbial data to mammalian somatic cells. This study illustrates the use and merits of a multi-endpoint assay for genetic damage in CHO cells, the utility of using CHO cells that are defective in excision repair of DNA, and the importance of comparative testing between bacterial and mammalian systems.

Animals↗

PubMedDate not supplied

In vivo cytogenetic effects of the cooked-food-related mutagens Trp-P-2 and IQ in mouse bone marrow.

Sister-chromatid exchange and chromosomal aberrations were measured in vivo in mouse bone marrow following intraperitoneal injection of the cooked food mutagens, Trp-P-2 and IQ. Trp-P-2 produced a significant positive dose response for both endpoints while IQ produced only a weak but significant sister-chromatid exchange response. The relative potency of these two chemicals is similar to that seen in mammalian cells in vitro but opposite to their potency in Salmonella.

Animals↗

PubMedDate not supplied

DNA-strand breaks associated with halogenated pyrimidine incorporation.

The alkaline elution of bromodeoxyuridine-containing (BrdUrd) DNA and chlorodeoxyuridine-containing ( CldUrd ) DNA was studied in two CHO lines, the parental AA8 and a mutant line, EM9 , which has a defect in repairing strand breaks and a 12-fold elevated baseline frequency of SCE. BrdUrd-DNA was found to have alkali-labile sites as well as direct breaks, neither of which were increased significantly by prior treatment of AA8 cells with an inhibitor (benzamide) or poly(adenosine diphosphoribose) polymerase. CldUrd -DNA, which gives higher frequencies of SCEs than BrdUrd-DNA, had more strand breaks than BrdUrd-DNA in AA8 cells after treatment with benzamide, while without benzamide there was no difference. The accumulation of breaks in CldUrd -DNA by benzamide was shown to occur rapidly, to reach a maximum by 90 min, and to be readily reversible after benzamide removal. Under all conditions, EM9 cells had more strand breaks than AA8 . These observed differences in strand breaks were not due to differences in incorporation efficiencies. For the different halogenated pyrimidines and cell types, there was a good correlation between the number of strand breaks and reduction in plating efficiencies.

Animals↗

PubMedDate not supplied

Human chromosome isolation from short-term lymphocyte culture for flow cytometry.

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Bisbenzimidazole↗

PubMedDate not supplied

Mutagenic and toxic activity of environmental effluents from underground coal gasification experiments.

Using bacterial bioassays, we have screened for the presence of mutagens and toxins in extracts from groundwater, and in tar from product gas, at the sites of two Lawrence Livermore National Laboratory (LLNL) in situ experiments: Hoe Creek II and Hoe Creek III. The sites exhibited different potential biological hazards, suggesting that different gasification processes may represent different human health concerns. We found that mutagens are present in groundwater, persist for at least 2 yr after gasification has been terminated, and show a change in activity with time-possibly in parallel with changes in chemical composition. Preliminary evidence suggests that the mutagens in groundwater are quinoline and aniline derivatives, while the toxins in groundwater may be phenolic compounds. In tar from the product gas, the organic bases and neutrals were found to be genotoxic in both bacterial and mammalian cells; the neutral compounds appear to be the major mutagenic health hazards. Neutral compounds constitute most of the tar (85-97 wt%) and were mutagenic in both the bacterial and mammalian cell assays. Tar in the gas stream may be a problem for the aboveground environment if gas escapes through fractures in the overburden. Because it is mutagenic and induces chromosomal damage to mammalian cells, the tar may represent a disposal problem as well. However, it is difficult to assess tar quantitatively as a health hazard because its mutagenic activity is low, possibly due to contaminants in the neutral fraction that act to suppress mutagenicity.

Animals↗