Comparison of flow cytometry- and microscopy-based methods for measuring micronucleated reticulocyte frequencies in rodents treated with nongenotoxic and genotoxic chemicals

Witt, Kristine L.; Livanos, Elizabeth; Kissling, Grace E.; Torous, Dorothea K.; Caspary, William J.; Tice, Raymond R.; Recio, Leslie

doi:10.1016/j.mrgentox.2007.08.004

Cited by 106 publications

(105 citation statements)

References 41 publications

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“…AA w fpg: significant increase in tail DNA % (about 2 per control w fpg) GA w fpg: significant increase in tail DNA % (about 1.5 times control w fpg) Resveratrol w fpg: no effect AA + resveratrol w fpg: no effect GA + resveratrol w fpg: significant increase in tail DNA % (about 2 times control w fpg) Nixon et al (2014) AA w hOGG1: significant increase in tail DNA % (about 1.2 times control) GA w hOGG1: no effect Resveratrol: no effect AA + resveratrol w hOGG1: no effect GA + resveratrol w hOGG1: no effect Induction by AA of structural chromosome aberrations, micronuclei or polyploidy was observed in various studies in mice treated in vivo (doses 25-100 mg/kg b.w.) (Witt et al, 2008;ATSDR, 2012). The effects were observed in various tissues: bone marrow, spleen lymphocytes, splenocytes, peripheral blood reticulocytes, erythrocytes, spermatocytes, etc.…”

Section: Genotoxicitymentioning

confidence: 99%

Scientific Opinion on acrylamide in food

Publication¹

2015

EFS2

285

148

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EFSA was asked to deliver a scientific opinion on acrylamide (AA) in food. AA has widespread uses as an industrial chemical. It is also formed when certain foods are prepared at temperatures above 120 °C and low moisture, especially in foods containing asparagine and reducing sugars. The CONTAM Panel evaluated 43 419 analytical results from food commodities. AA was found at the highest levels in solid coffee substitutes and coffee, and in potato fried products. Mean and 95th percentile dietary AA exposures across surveys and age groups were estimated at 0.4 to 1.9 µg/kg body weight (b.w.) per day and 0.6 to 3.4 µg/kg b.w. per day, respectively. The main contributor to total dietary exposure was generally the category 'Potato fried products (except potato crisps and snacks)'. Preferences in home-cooking can have a substantial impact on human dietary AA exposure. Upon oral intake, AA is absorbed from the gastrointestinal tract and distributed to all organs. AA is extensively metabolised, mostly by conjugation with glutathione but also by epoxidation to glycidamide (GA). Formation of GA is considered to represent the route underlying the genotoxicity and carcinogenicity of AA. Neurotoxicity, adverse effects on male reproduction, developmental toxicity and carcinogenicity were identified as possible critical endpoints for AA toxicity from experimental animal studies. The data from human studies were inadequate for dose-response assessment. The CONTAM Panel selected BMDL 10 values of 0.43 mg/kg b.w. per day for peripheral neuropathy in rats and of 0.17 mg/kg b.w. per day for neoplastic effects in mice. The Panel concluded that the current levels of dietary exposure to AA are not of concern with respect to non-neoplastic effects. However, although the epidemiological associations have not demonstrated AA to be a human carcinogen, the margins of exposure (MOEs) indicate a concern for neoplastic effects based on animal evidence. © European Food SUMMARYFollowing a request from the European Commission, the Panel on Contaminants in the Food Chain (CONTAM Panel) was asked to deliver a scientific opinion on acrylamide (AA) in food. The Panel developed the draft scientific opinion which underwent a public consultation from 1 July 2014 to 15 September 2014. The comments received and how they were taken into account when finalising the scientific opinion were published in an EFSA Technical Report (EFSA, 2015).AA is a low molecular weight, highly water soluble, organic compound. It is used inter alia as an industrial chemical and in the production of polyacrylamides. Heightened concerns about exposure to AA arose in 2002 when it was discovered that it forms when certain foods are prepared at temperatures usually above 120 °C and low moisture. It forms, at least in part, due to a Maillard reaction between certain amino acids, such as asparagine, and reducing sugars. However, several other pathways and precursors have also been proposed to contribute to AA formation. AA forms in numerous baked or fried carbohydrate-rich f...

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Section: Genotoxicitymentioning

confidence: 99%

Scientific Opinion on acrylamide in food

Publication¹

2015

EFS2

285

148

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“…However, the situation is less clear for rats and humans, that produce less glycidamide than mice at equivalent exposure levels (33). In general, acrylamide genotoxic potential in mice as measured by DNA and chromosomal damage has been detected only at concentrations exceeding those found to be carcinogenic in the rodent cancer bioassays (20,21,(34)(35)(36). The recent development of the Pig-a (phosphatidylinositol glycan, Class A) gene mutation assay (37-41) now readily permits highly sensitive evaluation of the mutagenic potential of acrylamide at carcinogenic exposure levels using the same rodent strains tested in the cancer bioassays.…”

Section: Introductionmentioning

confidence: 99%

Differential genotoxicity of acrylamide in the micronucleus andPig-a gene mutation assays in F344 rats and B6C3F1 mice

Hobbs¹,

Davis²,

Shepard³

et al. 2016

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Acrylamide is used in many industrial processes and is present in a variety of fried and baked foods. In rodent carcinogenicity assays, acrylamide exposure leads to tumour formation at doses lower than those demonstrated to induce genotoxic damage. We evaluated the potential of acrylamide to induce structural DNA damage and gene mutations in rodents using highly sensitive flow cytometric analysis of micronucleus and Pig-a mutant frequencies, respectively. Male F344 rats and B6C3F1 mice were administered acrylamide in drinking water for 30 days at doses spanning and exceeding the range of acrylamide exposure tested in cancer bioassays-top dose of 12.0 and 24.0 mg/kg/day in mice and in rats, respectively. A positive control, N-ethyl-N-nitrosourea, was administered at the beginning and end of the study to meet the expression time for the two DNA damage phenotypes. The results of the micronucleus and Pig-a assays were negative and equivocal, respectively, for male rats exposed to acrylamide at the concentrations tested. In contrast, acrylamide induced a dose-dependent increase in micronucleus formation but tested negative in the Pig-a assay in mice. Higher plasma concentrations of glycidamide in mice than rats are hypothesized to explain, at least in part, the differences in the response. Benchmark dose modelling indicates that structural DNA damage as opposed to point mutations is most relevant to the genotoxic mode of action of acrylamide-induced carcinogenicity. Moreover, the lack of genotoxicity detected at <6.0 mg/kg/day is consistent with the notion that non-genotoxic mechanisms contribute to acrylamide-induced carcinogenicity in rodents.

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“…6 Some good examples of such cells are lymphocytes, exfoliated epithelial cells and fibroblasts. It's important to note that MN of exfoliated cells are not induced when the cells are at the epithelial surface, but when they are in the basal layer.…”

Section: A Typical Methodology For Micronucleus Testmentioning

confidence: 99%

“…In mammals, the in vivo MNT is used to trace the mitotic apparatus of the erythroblasts or the chromosomal damage that is triggered by the test substance, by analyzing either a sample of erythrocytes obtained from the bone marrow or peripheral blood cells of the mammals. 1,6 The absence of nucleus in these cells makes it easier to visualize the micronuclei. An increase in the frequency of micronucleated polychromatic erythrocytes in treated animals is an indication of induced chromosome damage.…”

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confidence: 99%