title: Mechanistic insights into the cytotoxicity and genotoxicity induced by glycidamide in human mammary cells.
abstract: Acrylamide (AA) is a well-known industrial chemical classified as a probable human carcinogen. Benign and malignant tumours at different sites, including the mammary gland, have been reported in rodents exposed to AA. This xenobiotic is also formed in many carbohydrate-rich foods prepared at high temperatures. For this reason, AA is an issue of concern in terms of human cancer risk. The epoxide glycidamide (GA) is thought to be the ultimate genotoxic AA metabolite. Despite extensive experimental and epidemiological data focused on AA-induced breast cancer, there is still lack of information on the deleterious effects induced by GA in mammary cells. The work reported here addresses the characterisation and modulation of cytotoxicity, generation of reactive oxygen species, formation of micronuclei (MN) and quantification of specific GA-DNA adducts in human MCF10A epithelial cells exposed to GA. The results show that GA significantly induces MN, impairs cell proliferation kinetics and decreases cell viability at high concentrations by mechanisms not involving oxidative stress. KU55933, an inhibitor of ataxia telangiectasia mutated kinase, enhanced the cytotoxicity of GA (P < 0.05), supporting a role of this enzyme in regulating the repair of GA-induced DNA lesions. Moreover, even at low GA levels, N7-GA-Gua adducts were generated in a linear dose-response manner in MCF10A cells. These results confirm that human mammary cells are susceptible to GA toxicity and reinforce the need for additional studies to clarify the potential correlation between dietary AA exposure and breast cancer risk in human populations.
authors.affiliation: Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, University of Lisbon, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal.
authors.forename: Susana
authors.initials: S
authors.lastname: Bandarra
authors.forename: Ana S
authors.initials: AS
authors.lastname: Fernandes
authors.forename: Inês
authors.initials: I
authors.lastname: Magro
authors.forename: Patrícia S
authors.initials: PS
authors.lastname: Guerreiro
authors.forename: Marta
authors.initials: M
authors.lastname: Pingarilho
authors.forename: Mona I
authors.initials: MI
authors.lastname: Churchwell
authors.forename: Octávia Monteiro
authors.initials: OM
authors.lastname: Gil
authors.forename: Ines
authors.initials: I
authors.lastname: Batinic-Haberle
authors.forename: Sandrina
authors.initials: S
authors.lastname: Gonçalves
authors.forename: José
authors.initials: J
authors.lastname: Rueff
authors.forename: Joana P
authors.initials: JP
authors.lastname: Miranda
authors.forename: M Matilde
authors.initials: MM
authors.lastname: Marques
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Beland
authors.forename: Matilde
authors.initials: M
authors.lastname: Castro
authors.forename: Jorge F
authors.initials: JF
authors.lastname: Gaspar
authors.forename: Nuno G
authors.initials: NG
authors.lastname: Oliveira
mesh_terms: D000975:Antioxidants / Q000494:pharmacology; D064007:Ataxia Telangiectasia Mutated Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D048749:Cytokinesis; D018736:DNA Adducts / Q000378:metabolism; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D004852:Epoxy Compounds / Q000494:pharmacology / Q000633:toxicity*; D005260:Female; D005978:Glutathione / Q000494:pharmacology; D006801:Humans; D042361:Mammary Glands, Human / Q000166:cytology*; D015162:Micronucleus Tests; D009025:Morpholines / Q000494:pharmacology; D009153:Mutagens / Q000494:pharmacology / Q000633:toxicity*; D010084:Oxidation-Reduction; D011753:Pyrones / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: C495818:2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one; D000975:Antioxidants; D018736:DNA Adducts; D004852:Epoxy Compounds; D009025:Morpholines; D009153:Mutagens; D011753:Pyrones; D017382:Reactive Oxygen Species; C071834:glycidamide; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D005978:Glutathione