Nitrilotriacetic acid (NTA) induces aneuploidy in drosophila and mouse germ‐line cells

Costa, Rodolfo; Russo, Antonella; Zordan, Mauro Agostino; Pacchierotti, Francesca; Tavella, Adriana; Levis, Angelo Gino

doi:10.1002/em.2860120408

Cited by 22 publications

(8 citation statements)

References 36 publications

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“…The results obtained in Drosophila and the mouse with two chelating agents, NTA and EDTA [Costa et al, 1988;Russo et al, 1989;Zordan et al, 1990;present study] were encouraging for a reciprocal validation of the aneuploidy assays available for these organisms. Not only we observed that each compound acts with the same modality [chromosomal gain for NTA, Costa et al, 1988; chromosomal loss for EDTA, Zordan et al, 1990, and present results] on different eukaryotic test systems, but we also noticed, at least as far as EDTA is concerned, a different response of somatic with respect to germ cells both in Drosophila and the mouse [Zordan et al, 1990, and present results, Fig. 11. This recurrence is suggestive, even taking into consideration some limits, such as the lack of a complete dose-effect relationship for MN induction by EDTA in mouse cells, or the not perfect endpoint overlapping of the somatic and germ tests in Drosophila.…”

Section: Discussionmentioning

confidence: 95%

“…This recurrence is suggestive, even taking into consideration some limits, such as the lack of a complete dose-effect relationship for MN induction by EDTA in mouse cells, or the not perfect endpoint overlapping of the somatic and germ tests in Drosophila. Also in previous experiments with NTA, the ability of this chelating agent to induce aneuploidy in the mouse was specifically referred to the germ cells [Costa et al, 1988;Russo et al, 19891. These results confirm that the enrichment of a specific data base for germinal effects of chemicals present in the environment is an urgent goal.…”

Section: Discussionmentioning

confidence: 99%

“…Chromosome counting approaches may fail to identify the induction of chromosome lagging, which may give rise to hypoploidy since hypoploid cells are widely represented in metaphase preparations but are discarded because they may arise from artifactual chromosome loss. Their high ratory [Costa et al, 1988;Zordan et al, 19901. The effects of NTA in the two organisms were in good concordance, as this compound induced chromosome gain after treatment of DrosoPhilu ffxde germ cells, and hyperhaploidy after treatment of mouse cells approaching the first meiotic frequency in control preparations does not allow the detection of possible hypoploidy increases after exposure to chemicals.…”

Section: Introductionmentioning

confidence: 99%

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Further evidence for the aneuploidogenic properties of chelating agents: Induction of micronuclei in mouse male germ cells by EDTA

Russo

Levis

1992

Environ and Mol Mutagen

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A micronucleus assay based on cytogenetic analysis of early spermatids (Tates et al.; Mutation Research 121:131-138, 1983) was applied to determine if the chelating agent ethylenedinitrilotetraacetic acid (EDTA) may induce aneuploidy in mouse meiotic cells. Previous results indicated aneuploidogenic activity of EDTA in Drosophila female germ cells (induction of chromosome loss; Zordan et al.: Environ Mol Mutagen 15:205-213, 1990). In the same study, a standard aneuploidy test based on chromosome counting in mouse secondary spermatocytes failed however to show aneuploidogenic properties of EDTA in mouse somatic and germ cells. In the present study the effects of two clastogens, adriamycin (ADM) and mitomycin C (MMC), and of the aneuploidogenic agent chloral hydrate (CH) were also evaluated. All compounds were tested at a single dose level and at two time intervals corresponding to the treatment of diakinesis/metaphase I/metaphase II spermatocytes. The clastogenic potential of the compounds under study was also evaluated, by chromosomal aberration analysis in mouse spermatogonia, in an independent set of experiments. The results obtained indicate that ADM, CH and EDTA are able to induce micronuclei at meiosis. On the contrary, only ADM and MMC induced chromosomal aberrations in mouse spermatogonia. Therefore, the most probable origin of micronuclei produced by CH and EDTA is whole chromosome lagging. These results provide further evidence for the aneuploidogenic properties of these chelating agents.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Further evidence for the aneuploidogenic properties of chelating agents: Induction of micronuclei in mouse male germ cells by EDTA

Russo

Levis

1992

Environ and Mol Mutagen

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“…The hybridization data of Table 1 were used to calculate an overall sperm aneuploidy frequency for comparison with these literature values. By Beatty et al, 1975Miller and Adler, 1992Brook and Chandley, 1986Liang et al, 1986Liang and Pacchierotti, 1988 Liang Hunt, 1987Costa et al, 1988Zordan et al, 1990Pacchierotti et al, 1987Risley et al, 1990Risley et al, 1990 Maudlin we obtained a n average per-chromosome frequency of 2.9 hyperhaploid spermatids per 10,000. Multiplying this frequency by the number of mouse chromosomes and by a factor of 2 (to account for an equal number of hyperhaploid and hypohaploid cells), we obtained an overall frequency of sperm aneuploidy of 1.16.…”

Section: Resultsmentioning

confidence: 92%

Aneuploidy in late‐step spermatids of mice detected by two‐chromosome fluorescence in situ hybridization

Wyrobek

Lowe

Pinkel

et al. 1995

Molecular Reproduction Devel

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A multicolor procedure employing fluorescence in situ hybridization is described for detecting chromosomal domains and germinal aneuploidy in late-step spermatids in mice using DNA probes specific for repetitive sequences near the centromeres of chromosomes 8 and X. These probes were nick-translated with biotin- or digoxigenin-labeled nucleotides, and were detected with FITC or rhodamine. Probe and hybridization specificities were confirmed using metaphase chromosomes from spleen and bone marrow cells as well as from primary and secondary spermatocytes. Late-step spermatids, identified in testicular preparations by their hooked shape, yielded compact fluorescence domains in approximately 50% and > 99% of cells when hybridized with probes for chromosomes X and 8, respectively. In a survey of > 80,000 late-step spermatids from 8 healthy young adult C57BL/6 or B6C3F1 mice, approximately 3/10,000 spermatids had fluorescence phenotypes indicative of X-X or 8-8 hyperhaploidy. These frequencies are consistent with published frequencies of aneuploidy in meiotic metaphase II and first cleavage metaphases of the mouse, providing preliminary validation of sperm hybridization for the detection of aneuploidy. No significant animal or strain differences were observed. In addition, the hyperhaploidy frequencies for murine spermatids were indistinguishable for those for sperm from healthy men obtained by a similar hybridization procedure. These procedures for detecting aneuploid male gametes are examples of "bridging biomarkers" between human and animal studies. They have promising applications for investigations of the genetic, reproductive, and toxicological factors leading to abnormal reproductive outcomes of paternal origin.

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“…This weak effect may be compared to the results obtained by Bora [1975] which related a significantly high frequency of tetraploïd cells and endoreplication in human lymphocytes after very long treatments and to the results presented by Modesti et al [1995] which showed that NTA interacted with tubulin in vitro in mammalian cells. Furthermore, NTA was shown to be able to induce in vivo aneuploidy in Drosophila and mouse germ-line cells [Costa et al, 1988] and mitotic recombination and possible aneuploidy in somatic cells of Drosophila [Zordan et al, 1991].…”

Section: Discussionmentioning

confidence: 98%

Characterization of the genotoxicity of nitrilotriacetic acid

Nesslany

Simar-Meintières

Watzinger

et al. 2008

Environ and Mol Mutagen

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The chelating agent nitrilotriacetic acid (NTA), classified as an epigenetic rodent carcinogen, was assessed in the in vivo rodent Comet assay on isolated kidney cells. Unexpected potent increases in DNA damage were obtained in both the short (3-6 hr) and long-term (22-26 hr) expression times after a single oral treatment at 1,000-2,000 mg/kg bw. NTA was assayed in the Ames test using TA1537, TA98, TA100, and TA102 tester strains, and in the in vitro micronucleus assay on L5178Y mouse lymphoma cells and on CTLL2 and CTLL2/Bcl2 cells coupled to the apoptosis measurement, both with and without metabolic activation by aroclor 1254-induced liver or kidney rat S9-mix. Whatever the S9 origin, neither genotoxicity nor apoptosis was detected, while a strong increase in the micronuclei formation was observed without S9 without any apoptosis induction. The direct genotoxicity of NTA was confirmed in the mouse lymphoma tk+/- gene mutation assay and in the chromosomal aberrations test on human lymphocytes. When tested in combination with an excess of Ca2+, NTA gave negative results on L5178Y mouse lymphoma cells in the in vitro Comet and micronucleus assays but still induced DNA damage on rat primary kidney cells. The higher sensitivity of renal cells to Ca2+ variations could explained the positive response observed in vivo. The carcinogenicity of NTA could be a consequence of the survival of kidney cells to intracellular variations of Ca2+, leading to a local and indirect genotoxicity. This suggests that threshold dose exists beyond which tumor-generating events will be displayed.

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Nitrilotriacetic acid (NTA) induces aneuploidy in drosophila and mouse germ‐line cells

Cited by 22 publications

References 36 publications

Further evidence for the aneuploidogenic properties of chelating agents: Induction of micronuclei in mouse male germ cells by EDTA

Further evidence for the aneuploidogenic properties of chelating agents: Induction of micronuclei in mouse male germ cells by EDTA

Aneuploidy in late‐step spermatids of mice detected by two‐chromosome fluorescence in situ hybridization

Characterization of the genotoxicity of nitrilotriacetic acid

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