An association between mutagenicity of the Ara test of <i>Salmonella typhimurium</i> and carcinogenicity in rodents for 16 halogenated aliphatic hydrocarbons

Roldán-Arjona, Teresa; García-Pedrajas, Maria D.; Luque-Romero, Francisco L.; Hera, Concepción; Pueyo, Carmen

doi:10.1093/mutage/6.3.199

Cited by 25 publications

(9 citation statements)

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“…On the other hand, our data are in accordance with observation that rodent bioassays are useful for investigating the pharmacokinetics, mechanisms of action, and differential toxicity of various chemicals (Roldan-Arjona et al , 1991). …”

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confidence: 91%

Cytotoxic and genotoxic effects of Br-containing oxaphosphole on Allium cepa L. root tip cells and mouse bone marrow cells

et al. 2009

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The continuous production and release of chemicals into the environment has led to the need to assess their genotoxicity. Numerous organophosphorus compounds with different structures have been synthesized in recent years, and several oxaphosphole derivatives are known to possess biological activity. Such chemical compounds may influence proliferating cells and cause disturbances of the genetic material. In this study, we examined the cytotoxicity and genotoxicity of 4-bromo-N,N-diethyl-5,5-dimethyl-2,5-dihydro-1,2-oxaphosphol-2-amine 2-oxide (Br-oxph). In A. cepa cells, Br-oxph (10 -9 M, 10 -6 M and 10 -3 M) reduced the mitotic index 48 h after treatment with the two highest concentrations, with no significant effect at earlier intervals. Mitotic cells showed abnormalities 24 h and 48 h after treatment with the two lowest concentrations but there were no consistent changes in interphase cells. Bone marrow cells from mice treated with Br-oxph (2.82 x 10 -3 mg/kg) also showed a reduced mitotic index after 48 h and a greater percentage of cells with aberrations (principally chromatid and isochromatid breaks). These findings indicate the cytotoxicity and genotoxicity of Br-oxph in the two systems studied. The chemistry of organophosphorus compounds is a subject of increasing interest, and a large number of compounds with different structures, properties and biological activites have been synthesized (Smee and Reist, 1996;Leblond et al., 2002). Heterocyclic organophosphorous compounds are an interesting group of molecules, especially oxaphosphole derivatives that contain oxygen and phosphorus. Enchev et al. (1986) demonstrated that some oxaphospholes possess biological activity. Chemical compounds that possess biological activity may influence proliferating cells and cause disturbances of the genetic material. Since many organophosphorus compounds are known to be mutagenic (Lieberman et al., 1998;Blasiak et al., 1999), there is need to screen new organophosphorus compounds for possible genotoxicity.To assess the potential genotoxicity of any compound, its ability to cause chromosomal damage needs to be evaluated in multiple tests (Repetto et al., 2001). Higher plants provide reliable bioassays for monitoring and testing genotoxins (Grant, 1999), with the Allium test being particularly sensitive and reproducible (Fiskesjö, 1985). Small mammals are also useful models for testing genotoxicity (Topashka-Ancheva et al., 2003). The aim of this work was to investigate the cytotoxicity and genotoxicity of 4-bromo-N,N-diethyl-5,5-dimethyl-2,5-dihydro-1,2-oxaphosphol-2-amine 2-oxide (Br-oxph) using Allium cepa L. root tip cells and ICR mouse bone marrow cells.Br-oxph was synthesized in the Laboratory of Organic Chemistry of the University of Shumen (Bulgaria) (Angelov and Enchev, 1987). Since Enchev et al. (1986) showed that some oxaphospholes affected plant growth at concentrations of 10 -9 M, 10 -6 M and 10 -3 M, these concentrations were also used in the Allium test. The solutions were prepared immediately before u...

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confidence: 91%

Cytotoxic and genotoxic effects of Br-containing oxaphosphole on Allium cepa L. root tip cells and mouse bone marrow cells

et al. 2009

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“…DBE and DBM are strong, direct-acting mutagens in bacteria. Large numbers of forward mutations to L-arabinose resistance are induced in Salmonella typhirnurium in the concentration range 0.5-3.0 pmol/plate; this mutagenicity is, however, not enhanced by the addition of a mammalian metabolic activation system (S9 mixture) [6,7]. The His reverse mutation test classifies DBE and DBM as base-pair substitution mutagens [3,4]: DBE shows a clear preference for inducing transition mutations at both GC and AT base pairs, and DBE mutations also appear more frequent at GC than at AT base pairs [8].…”

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confidence: 99%

ogt alkyltransferase enhances dibromoalkane mutagenicity in excision repair–deficient escherichia coli K‐12

Abril

Luque-Romero

Prieto‐Álamo

et al. 1995

Molecular Carcinogenesis

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We examined the role of the O6-alkylguanine-DNA alkyltransferase encoded by ogt gene in the sensitivity of Escherichia coli to the mutagenic effects of the dibromoalkanes, dibromoethane and dibromomethane, by comparing responses in ogt- bacteria to those in their isogenic ogt+ parental counterparts. The effects of the uvrABC excision-repair system, the adaptive response, mucAB and umuDC mutagenic processing, and glutathione bioactivation on the differential responses of ogt- and ogt+ bacteria were also studied. Mutation induction was monitored by measuring the frequency of forward mutations to L-arabinose resistance. Induced mutations occurred only in excision repair-defective strains and were totally (with dibromomethane) or substantially (with dibromoethane) dependent on the alkyltransferase (ATase) encoded by the ogt gene. An increased mutagenic response to both dibromoalkanes was also seen in ogt- bacteria that overexpressed the ogt protein from a multicopy plasmid, indicating that the differences in mutability between ogt+ and ogt- bacteria were not dependent on the ogt- null allele carried by the defective strain. The ATase encoded by the constitutive ogt gene was more effective in promoting dibromoalkane mutagenicity than the ada ATase induced by exposure to low doses of a methylating agent. The mutagenicity promoted by the ogt ATase was dependent on both glutathione bioactivation and SOS mutagenic processing. To our knowledge, this paper presents for the first time evidence that DNA ATases, in particular the ATase encoded by the ogt gene, can increase the mutagenic effects of a DNA-damaging agent. The mechanism of this effect has yet to be established.

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“…Rodent animal bioassays are valuable tools for investigating the pharmacokinetics, mechanisms of action, and differential toxicity of various chemicals [ 3 ]. The data obtained from this study clearly shows that 1,1-DCE significantly increased the number of chromosomal aberrations and the formation of micronuclei as compared to the control.…”

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confidence: 99%

“…DCE is among the widely used chlorinated hydrocarbon and is currently assigned the classification of C (Possible Human Carcinogen) by the U.S. Environmental Protection Agency [ 2 ]. The major concerns for this group of compounds are their widespread distribution, in addition to occupational exposure [ 3 ]. Several chlorinated alkanes and alkenes have been found to induce genotoxic effects [ 4 , 5 ], and also caused miscarriages in women [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Cytogenetic Effects of 1,1-Dichloroethane in Mice Bone Marrow Cells

Patlolla

Tchounwou

2005

IJERPH

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The major concern for the halogenated compounds is their widespread distribution, in addition to occupational exposures. Several chlorinated alkanes and alkenes were found to induce toxic effects. In this study, we investigated the genotoxic potential of 1,1-dichloroethane in the bone marrow cells obtained from Swiss-Webster mice, using chromosomal aberrations (CA), mitotic index (MI), and micronuclei (MN) formation as toxicological endpoints. Five groups of three male mice each, weighing an average of 24 ± 2 g, were injected intraperitoneally, once with doses of 100, 200, 300, 400, 500 mg/kg body weight (BW) of 1,1-dichloroethane dissolved in ethanol. A control group was also made of three animals injected with ethanol (1%) without the chemical. All animals were sacrificed 24 hours after the treatment. Chromosome and micronuclei preparations were obtained from bone marrow cells following standard protocols. Chromatid and chromosome aberrations were investigated in 100 metaphase cells per animal and percent micronuclei frequencies were investigated in 1,000 metaphase cells per animal. 1,1-dichloroethane exposures significantly increased the number of chromosomal aberrations and the frequency of micronucleated cells in the bone marrow cells of Swiss-Webster mice. Percent chromosomal aberrations of 2.67 ± 0.577, 7.66 ± 2.89, 8.33 ± 2.08, 14.67 ± 2.51, 20.3 ± 3.21, 28 ± 3.61; mitotic index of 9.4%, 7.9%, 6.2%, 4.3%, 3.0%, 2.6% and micronuclei frequencies of 3.33 ± 0.7, 7.33 ± 0.9, 8.00 ± 1.0, 11.67 ± 1.2, 15.33 ± 0.7, 18.00 ± 1.7 were recorded for the control, 100, 200, 300, 400, and 500 mg/kg BW respectively; indicating a gradual increase in number of chromosomal aberrations and micronuclei formation, with increasing dose of 1,1,-dichloroethane. Our results indicate that 1,1-dichloroethane has a genotoxic potential as measured by the bone marrow CA and MN tests in Swiss-Webster mice.

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An association between mutagenicity of the Ara test of Salmonella typhimurium and carcinogenicity in rodents for 16 halogenated aliphatic hydrocarbons

Cited by 25 publications

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Cytotoxic and genotoxic effects of Br-containing oxaphosphole on Allium cepa L. root tip cells and mouse bone marrow cells

Cytotoxic and genotoxic effects of Br-containing oxaphosphole on Allium cepa L. root tip cells and mouse bone marrow cells

ogt alkyltransferase enhances dibromoalkane mutagenicity in excision repair–deficient escherichia coli K‐12

Cytogenetic Effects of 1,1-Dichloroethane in Mice Bone Marrow Cells

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