Acrylamide and glycidamide: genotoxic effects in V79-cells and human blood

Baum, Matthias; Fauth, Evelyne; Fritzen, Silke; Herrmann, Armin; Mertes, Peter; Merz, Karl‐Heinz; Rudolphi, Melanie; Zankl, Heinrich; Eisenbrand, Gerhard

doi:10.1016/j.mrgentox.2004.11.007

Cited by 72 publications

(63 citation statements)

References 45 publications

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“…Compared to AA, GA (2-4 mM) was much more mutagenic, about 5-10-fold more potent. This is consistent with several previously reported genotoxicity studies conducted using mammalian cells (Baum et al, 2005;Besaratinia and Pfeifer, 2003;Koyama et al, 2006;Martins et al, 2006). Since the genotoxic responses at higher concentration are reproducible, LOH analysis of the mutants induced by 4 mM GA and 16 mM AA treatments was conducted to determine the types of the mutations.…”

Section: Discussionsupporting

confidence: 89%

“…The genotoxicity of AA has been studied extensively, but there are fewer experimental data available with GA as the test substance (Baum et al, 2005;Besaratinia and Pfeifer, 2004;Koyama et al, 2006;Martins et al, 2006;Paulsson et al, 2003). AA is not mutagenic in bacterial assays, and it is mutagenic in mammalian somatic and germinal cells in vitro and in vivo (Dearfield et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

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Genotoxic effects of acrylamide and glycidamide in mouse lymphoma cells

Mei

Churchwell

et al. 2008

Food and Chemical Toxicology

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In addition to occupational exposures to acrylamide (AA), concerns about AA health risks for the general population have been recently raised due to the finding of AA in food. In this study, we evaluated the genotoxicity of AA and its metabolite glycidamide (GA) in L5178Y/ Tk +/− mouse lymphoma cells. The cells were treated with 2-18 mM of AA or 0.125-4 mM of GA for 4 h without metabolic activation. The DNA adducts, mutant frequencies and the types of mutations for the treated cells were examined. Within the dose range tested, GA induced DNA adducts of adenine and guanine [N3-(2-carbamoyl-2-hydroxyethyl)-adenine and N7-(2-carbamoyl-2-hydroxyethyl)-guanine] in a linear dose-dependent manner. The levels of guanine adducts were consistently about 60-fold higher across the dose range than those of adenine. In contrast, no GAderived DNA adducts were found in the cells treated with any concentrations of AA, consistent with a lack of metabolic conversion of AA to GA. However, the mutant frequency was significantly increased by AA at concentrations of 12 mM and higher. GA was mutagenic starting with the 2 mM dose, suggesting that GA is much more mutagenic than AA. The mutant frequencies were increased with increasing concentrations of AA and GA, mainly due to an increase of proportion of small colony mutants. To elucidate the underlying mutagenic mechanism, we examined the loss of heterozygosity (LOH) at four microsatellite loci spanning the entire chromosome 11 for mutants induced by AA or GA. Compared to GA induced mutations, AA induced more mutants whose LOH extended to D11Mit22 and D11Mit74, an alteration of DNA larger than half of the chromosome. Statistical analysis of the mutational spectra revealed a significant difference between the types of mutations induced by AA and GA treatments (P = 0.018). These results suggest that although both AA and GA generate mutations through a clastogenic mode of action in mouse lymphoma cells, GA induces mutations via a DNA adduct mechanism whereas AA induces mutations by a mechanism not involving the formation of GA adducts.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Genotoxic effects of acrylamide and glycidamide in mouse lymphoma cells

Mei

Churchwell

et al. 2008

Food and Chemical Toxicology

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“…In contrast to the negative result of AA obtained at the concentration up to 10 mM in V79 cells without the metabolic activation (34), GA showed a concentration dependent induction of Hprt mutations from 800 mM upwards (MF: 14±8×10 -6 ; solvent control MF: 4±2×10 -6 ). The TK gene mutation assay also demonstrated that GA is more potent than AA in mutation induction.…”

Section: Mammalian Gene Mutation Assays At the Hprt And Tk Locicontrasting

confidence: 79%

“…In the assessment of mutagenic eŠects induced by AA and its metabolite GA, the cell subclones employed in TK and HPRT gene mutation assays include L5178Y TK ＋/-mouse lymphoma cell (18,(28)(29)(30), human lymphoblastoid cell TK6 (31), Chinese hamster ovary (CHO) cell (32), Chinese hamster V79 cell (33)(34)(35) and human promyelocytic leukaemia cells HL-60 and NB4 (36). More recently, the development of the mammalian cell gene assays employing rodent lymphocytes has also contributed signiˆcantly to the understanding of in vivo somatic cell mutagenesis induced by AA, including the assays performed in Big Blue mice, B6C3F1/TK mice and Big Blue rats (37)(38)(39).…”

Section: Mammalian Gene Mutation Assays At the Hprt And Tk Locimentioning

confidence: 99%

“…Mutagenicity of AA and GA at the HPRT Locus in DiŠerent Test Systems GA is consistently mutagenic at HPRT mutation assays in various test systems involving mammalian cell lines (32,34,35) and rodents (37)(38)(39). On the contrary, some studies suggested that AA may not induce gene mutation in HPRT test.…”

Section: Mammalian Gene Mutation Assays At the Hprt And Tk Locimentioning

confidence: 99%

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Genotoxicity of Acrylamide and Glycidamide: A Review of the Studies by HPRT Gene and TK Gene Mutation Assays

Cao

2012

Genes and Environment

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Acrylamide (AA), a proven rodent carcinogen, is found in a variety of commonly consumed human foods, which has raised public health concerns. AA is largely oxidized to the chemically reactive epoxide, glycidamide (GA), by cytochrome P450 2E1. The genotoxic eŠects of AA and GA have been extensively evaluated. However, the results in mammalian gene mutation tests were inconsistent, especially the genotoxic eŠects at the HPRT gene and TK gene. In this article, the relevant mutations induced by AA and GA on both gene loci in various test systems involving in vivo and in vitro tests are reviewed. It is conˆrmed that AA acts directly as a clastogen and produces weakly mutagenic eŠects at the HPRT gene probably by metabolic conversion of AA to GA. On the other hand, GA is a strong mutagen with high reactivity to DNA, inducing predominantly point mutations. The molecular mutation spectra of AA and GA at the HPRT and TK genes are also compared and summarized here, for better clarifying the mechanisms of mutation induced by these two compounds. These data would help to understand the mutagenicity of AA and its contribution to human cancers.

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