The Genotoxicity of Acrylamide and Glycidamide in Big Blue Rats

Mei, Nan; McDaniel, L. Patrice; Dobrovolsky, Vasily N.; Guo, Xiaoqing; Shaddock, Joseph G.; Mittelstaedt, Roberta A.; Azuma, Mizuo; Shelton, Sharon D.; McGarrity, Lynda J.; Doerge, Daniel R.; Heflich, Robert H.

doi:10.1093/toxsci/kfq069

Cited by 68 publications

(53 citation statements)

References 49 publications

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“…We previously have reported that AA and GA were mutagenic in a large variety of somatic and reproductive tissues of rodents, some of which were also the tumor target tissues (Manjanatha et al, 2006(Manjanatha et al, , 2015Mei et al, 2010;Wang et al, 2010). In addition to carcinogenic 25.0 ± 5.0 § Animals given 7.0 mM AA in drinking water manifested toxicity and therefore were removed from the chemical exposure after 3 weeks, while AA low dose and GA low and high dose treatments continued for 4 weeks.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of <i>cII</i> gene mutation in the brains of Big Blue mice exposed to acrylamide and glycidamide in drinking water

Shelton

Townsend

et al. 2016

J. Toxicol. Sci.

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-Potential health risks for humans from dietary exposure to acrylamide (AA) and its reactive epoxide metabolite, glycidamide (GA), exist because substantial amounts of AA are found in a variety of fried and baked starchy foods. AA is tumorigenic in rodents, and a large number of studies indicate that AA is genotoxic in multiple organs of mice and rats. Although AA is neurotoxic, there are no reports on AA-induced gene mutations in the mouse brain. Therefore, to investigate if gene mutation can be induced by AA or its metabolite GA, we screened brains for cII mutant frequency (MF) and scored for mutation types in previously treated male and female Big Blue mice with 0, 1.4 mM, and 7.0 mM AA or GA in drinking water for up to 4 weeks. High doses of AA and GA induced similar cII MFs in males and females but only the induced cII MF in males was significantly higher than the corresponding male control MF (p < 0.05). Molecular analysis of the cII mutants from males showed that AA and GA each induced at least a 2.5-fold increase in the incidence of G:C → T:A, A:T → T:A, and A:T → C:G transversions compared to the vehicle controls, with similar mutational spectra observed when comparing AA with GA treatment. These results suggest that the MFs and types of mutations induced by AA and GA in the brain are consistent with AA exerting its genotoxicity via metabolism to GA.

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Section: Discussionmentioning

confidence: 99%

Evaluation of <i>cII</i> gene mutation in the brains of Big Blue mice exposed to acrylamide and glycidamide in drinking water

Shelton

Townsend

et al. 2016

J. Toxicol. Sci.

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“…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%

“…Although a linear increase in the mutant frequency (MF) with the increasing concentration of AA was found, the signiˆcant diŠerence occurred only at the highest concentration of AA (700 mg/L) in HL-60 cells (pº0.01) and NB4 cells ( pº0.01), respectively, where the MF was aboutˆve times higher than that of the control cultures in both cell lines. More recently, there was increasing evidence which suggested that AA as well as GA, produced increased lymphocyte Hprt mutant frequencies (MFs) in rodent animals, including in Big Blue mice, B6C3F1/TK mice and Big Blue rats (37)(38)(39). Manjanatha et al investigated the mutagenicity of AA and GA in Big Blue mice (37).…”

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

confidence: 99%

“…Although the result indicated that AA was a mutagen in mice via oral administration, the doses of AA used in the study were higher than those used in cancer bioassays. In the subsequent study, the same research group continued the examination of mutagenicity of AA and GA in Big Blue rats exposed to the doses similar to that used in cancer bioassays (39), 0.7 and 1.4 mM (equivalent to ¿5 and 10 mg/kg body weight/day ) of AA or GA via oral administration for 2 months. Data showed both compounds produced small but signiˆcant increases in spleen lymphocyte Hprt MF ( pº0.05), with the increases having dose-related linear trend ( pº0.05 to pº0.001).…”

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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Human genetic risk of treatment with antiviral nucleoside analog drugs that induce lethal mutagenesis: the special case of molnupiravir

Waters

Warren

Hughes

et al. 2022

Environ and Mol Mutagen

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This review considers antiviral nucleoside analog (NA) drugs, including ribavirin, favipiravir, and molnupiravir, which induce genome error catastrophe in SARS‐CoV or SARS‐CoV‐2 via lethal mutagenesis as a mode of action. In vitro data indicate that molnupiravir may be 100 times more potent as an antiviral agent than ribavirin or favipiravir. Molnupiravir has recently demonstrated efficacy in a phase 3 clinical trial. Because of its anticipated global use, its relative potency, and the reported in vitro “host” cell mutagenicity of its active principle, β‐d‐N4‐hydroxycytidine, we have reviewed the development of molnupiravir and its genotoxicity safety evaluation, as well as the genotoxicity profiles of three congeners, that is, ribavirin, favipiravir, and 5‐(2‐chloroethyl)‐2′‐deoxyuridine. We consider the potential genetic risks of molnupiravir on the basis of all available information and focus on the need for additional human genotoxicity data and follow‐up in patients treated with molnupiravir and similar drugs. Such human data are especially relevant for antiviral NAs that have the potential of permanently modifying the genomes of treated patients and/or causing human teratogenicity or embryotoxicity. We conclude that the results of preclinical genotoxicity studies and phase 1 human clinical safety, tolerability, and pharmacokinetics are critical components of drug safety assessments and sentinels of unanticipated adverse health effects. We provide our rationale for performing more thorough genotoxicity testing prior to and within phase 1 clinical trials, including human PIG‐A and error corrected next generation sequencing (duplex sequencing) studies in DNA and mitochondrial DNA of patients treated with antiviral NAs that induce genome error catastrophe via lethal mutagenesis.

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The Genotoxicity of Acrylamide and Glycidamide in Big Blue Rats

Cited by 68 publications

References 49 publications

Evaluation of <i>cII</i> gene mutation in the brains of Big Blue mice exposed to acrylamide and glycidamide in drinking water

Evaluation of <i>cII</i> gene mutation in the brains of Big Blue mice exposed to acrylamide and glycidamide in drinking water

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

Human genetic risk of treatment with antiviral nucleoside analog drugs that induce lethal mutagenesis: the special case of molnupiravir

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