Genotoxicity of glycidamide in comparison to (±)‐anti‐benzo[<i>a</i>]pyrene‐7,8‐dihydrodiol‐9,10‐epoxide and α‐acetoxy‐<i>N</i>‐nitroso‐diethanolamine in human blood and in mammalian V79‐cells

Thielen, Silke; Baum, Matthias; Hoffmann, Michelle; Loeppky, Richard N.; Eisenbrand, Gerhard

doi:10.1002/mnfr.200500227

Cited by 30 publications

(29 citation statements)

References 39 publications

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“…GA can react directly with DNA forming two alkylated adducts N7‐GA‐Gua and to a lesser extent N3‐GA‐Ade (Gamboa da Costa et al ., ; Ghanayem et al ., ; Maniere et al ., ). The N7‐GA‐Gua‐lesion has slow repair kinetics (Gamboa da Costa et al ., ; Maniere et al ., ) and is proposed to be recognised by Fpg in a modified version of the comet assay (Thielen et al ., ; Hansen et al ., ; Nixon et al ., ). In a previous study, the human Ogg1 enzyme which shows narrower substrate specificity than Fpg for oxidative damage detection in the comet assay was used to detect GA‐induced DNA lesions.…”

Section: Discussionmentioning

confidence: 99%

“…Fpg has been reported to recognise not only oxidised DNA lesions but also GA‐induced DNA lesions, supposedly the N7‐(2‐carbamoyl‐2‐hydroxyethyl)guanine (N7‐GA‐Gua) adduct and to a lesser extent N3‐(2‐carbamoyl‐2‐hydroxyethyl)adenine (N3‐GA‐Ade) adduct (Thielen et al ., ; Hansen et al ., ). The response in the comet assay was high in the Fpg‐treated and GA‐exposed samples possibly reducing the sensitivity of the measurements.…”

Section: Methodsmentioning

confidence: 99%

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Enhanced susceptibility of obese mice to glycidamide‐induced sperm chromatin damage without increased oxidative stress

et al. 2016

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Diet-induced obesity is known to impair male reproduction and may aggravate the male reproductive toxicity of the food contaminant acrylamide. Exposure of male mice to acrylamide induces paternally mediated pre- and post-implantation losses because of spermatozoal toxicity and these effects are potentiated in mice fed a high-fat diet. Glycidamide - an acrylamide metabolite - is the primary mediator of reproductive effects in males. The mechanisms causing the interaction between diet and acrylamide are not clear. However, diet-induced obesity is associated with oxidative stress in male reproductive tissues which might contribute to increased germ cell susceptibility. In this study, we investigated whether a moderate diet-induced obesity regimen could interfere with glycidamide-induced spermatozoal toxicity and increase oxidative stress. For this purpose, sperm chromatin integrity, oxidised DNA and protein levels, transcript levels of oxidative stress responsive genes and glycidamide-induced DNA and haemoglobin adducts were analysed in samples from male mice exposed to a high-fat diet for 6 weeks in combination with a single glycidamide exposure 7 days prior to sacrifice. We found that glycidamide-induced sperm DNA fragmentation was markedly higher in obese than in lean mice. However, the levels of oxidised DNA and/or protein in blood, liver and testicular tissue was lower in obese than in lean mice. Accompanying the reduced level of oxidised macromolecules, the transcript levels of several oxidative stress-related genes were altered in the liver and testis from obese mice suggesting induction of an antioxidant response in these animals. The haemoglobin-glycidamide adduct levels were higher in obese than in lean animals, whereas obesity did not seem to increase the level of glycidamide-induced DNA adducts. These findings show that a moderate diet-induced obesity regimen may potentiate glycidamide-induced sperm cells toxicity and suggest that the increase in glycidamide-induced sperm toxicity observed in obese mice does not depend on overt oxidative stress.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Enhanced susceptibility of obese mice to glycidamide‐induced sperm chromatin damage without increased oxidative stress

et al. 2016

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“…Therefore, like acrylamide, glycidamide covalently bonds to cellular components containing sulfhydryl and amino groups. Nucleophilic nitrogens in DNA are also susceptible to form adducts especially with glycidamide, which is thought mainly to be responsible for the genotoxicity [19][20][21][22][23]. Glycidamide can be further hydrolyzed by an epoxide hydrolase to glyceramide (2,3-dihydroxypropionamide) [15,18].…”

Section: Biotransformationmentioning

confidence: 99%

Metabolism of Acrylamide in Humans and Biomarkers of Exposure to Acrylamide

Kocadağlı

Gökmen

2016

Acrylamide in Food

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“…The major DNA adducts that glycidamide forms are N7-(2-carbamoyl-2-hydroxyethyl)guanine (N7-GA-Gua) and N3-(2-carbamoyl-2-hydroxyethyl)adenine (N3-GA-Ade) [20]. The cleavage enzyme, FPG, has been used in previous studies in the comet assay to recognise these glycidamide adducts and introduce strand breaks at these adduct sites [46], [47]. In the absence of FPG, a significant increase in DNA damage was induced in spermatocytes treated with glycidamide ( p <0.05, Fig.…”

Section: Discussionmentioning

confidence: 99%

Mouse Spermatocytes Express CYP2E1 and Respond to Acrylamide Exposure

et al. 2014

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Metabolism of xenobiotics by cytochrome P450s (encoded by the CYP genes) often leads to bio-activation, producing reactive metabolites that interfere with cellular processes and cause DNA damage. In the testes, DNA damage induced by xenobiotics has been associated with impaired spermatogenesis and adverse effects on reproductive health. We previously reported that chronic exposure to the reproductive toxicant, acrylamide, produced high levels of DNA damage in spermatocytes of Swiss mice. CYP2E1 metabolises acrylamide to glycidamide, which, unlike acrylamide, readily forms adducts with DNA. Thus, to investigate the mechanisms of acrylamide toxicity in mouse male germ cells, we examined the expression of the CYP, CYP2E1, which metabolises acrylamide. Using Q-PCR and immunohistochemistry, we establish that CYP2E1 is expressed in germ cells, in particular in spermatocytes. Additionally, CYP2E1 gene expression was upregulated in these cells following in vitro acrylamide exposure (1 µM, 18 h). Spermatocytes were isolated and treated with 1 µM acrylamide or 0.5 µM glycidamide for 18 hours and the presence of DNA-adducts was investigated using the comet assay, modified to detect DNA-adducts. Both compounds produced significant levels of DNA damage in spermatocytes, with a greater response observed following glycidamide exposure. A modified comet assay indicated that direct adduction of DNA by glycidamide was a major source of DNA damage. Oxidative stress played a small role in eliciting this damage, as a relatively modest effect was found in a comet assay modified to detect oxidative adducts following glycidamide exposure, and glutathione levels remained unchanged following treatment with either compound. Our results indicate that the male germ line has the capacity to respond to xenobiotic exposure by inducing detoxifying enzymes, and the DNA damage elicited by acrylamide in male germ cells is likely due to the formation of glycidamide adducts.

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Genotoxicity of glycidamide in comparison to (±)‐anti‐benzo[a]pyrene‐7,8‐dihydrodiol‐9,10‐epoxide and α‐acetoxy‐N‐nitroso‐diethanolamine in human blood and in mammalian V79‐cells

Cited by 30 publications

References 39 publications

Enhanced susceptibility of obese mice to glycidamide‐induced sperm chromatin damage without increased oxidative stress

Enhanced susceptibility of obese mice to glycidamide‐induced sperm chromatin damage without increased oxidative stress

Metabolism of Acrylamide in Humans and Biomarkers of Exposure to Acrylamide

Mouse Spermatocytes Express CYP2E1 and Respond to Acrylamide Exposure

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