title: The genetic consequences of paternal acrylamide exposure and potential for amelioration.
abstract: Acrylamide is a toxin that humans are readily exposed to due to its formation in many carbohydrate rich foods cooked at high temperatures. Acrylamide is carcinogenic, neurotoxic and causes reproductive toxicity when high levels of exposure are reached in mice and rats. Acrylamide induced effects on fertility occur predominantly in males. Acrylamide exerts its reproductive toxicity via its metabolite glycidamide, a product which is only formed via the cytochrome P450 detoxifying enzyme CYP2E1. Glycidamide is highly reactive and forms adducts with DNA. Chronic low dose acrylamide exposure in mice relevant to human exposure levels results in significantly increased levels of DNA damage in terms of glycidamide adducts in spermatocytes, the specific germ cell stage where Cyp2e1 is expressed. Since cells in the later stages of spermatogenesis are unable to undergo DNA repair, and this level of acrylamide exposure causes no reduction in fertility, there is potential for this damage to persist until sperm maturation and fertilisation. Cyp2e1 is also present within epididymal cells, allowing for transiting spermatozoa to be exposed to glycidamide. This could have consequences for future generations in terms of predisposition to diseases such as cancer, with growing indications that paternal DNA damage can be propagated across multiple generations. Since glycidamide is the major contributor to DNA damage, a mechanism for preventing these effects is inhibiting the function of Cyp2e1. Resveratrol is an example of an inhibitor of Cyp2e1 which has shown success in reducing damage caused by acrylamide treatment in mice.
authors.affiliation: Reproductive Science Group, School of Environmental and Life Sciences, University of Newcastle, Callaghan, New South Wales 2308, Australia.
authors.forename: Aimee L
authors.initials: AL
authors.lastname: Katen
authors.affiliation: Reproductive Science Group, School of Environmental and Life Sciences, University of Newcastle, Callaghan, New South Wales 2308, Australia; The Australian Research Council Centre of Excellence in Biotechnology and Development, Callaghan, New South Wales 2308, Australia; The Priority Research Centres for Reproductive Sciences and Chemical Biology, University of Newcastle, Callaghan, New South Wales 2308, Australia. Electronic address: shaun.roman@newcastle.edu.au.
authors.forename: Shaun D
authors.initials: SD
authors.lastname: Roman
mesh_terms: D020106:Acrylamide / Q000633:toxicity*; D000818:Animals; D063646:Carcinogenesis / Q000187:drug effects; D002273:Carcinogens / Q000633:toxicity*; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects*; D004260:DNA Repair / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004852:Epoxy Compounds / Q000633:toxicity; D006801:Humans; D008297:Male; D051379:Mice; D018812:Paternal Exposure / Q000009:adverse effects*; D051381:Rats; D012098:Reproduction / Q000187:drug effects; D013090:Spermatocytes / Q000187:drug effects; D013091:Spermatogenesis / Q000187:drug effects
chemical_list: D002273:Carcinogens; D004852:Epoxy Compounds; D020106:Acrylamide; C071834:glycidamide; D019392:Cytochrome P-450 CYP2E1
keywords: Cyp2e1; Genotoxin; Glycidamide; Resveratrol; Spermatocyte; Testis