title: Environmental carcinogens and mutational pathways in atherosclerosis.
abstract: Atherosclerosis is associated with DNA damage in both circulating and vessel-wall cells and DNA adducts derived from exposure to environmental mutagens are abundant in atherosclerotic vessels. Environmental chemical carcinogens identified as risk factor for atherosclerosis include polycyclic aromatic hydrocarbons (benzo(a)pyrene, dimethylbenz(a)anthracene, beta-naphthoflavone, pyrene, 3-methylcolanthrene), arsenic, cadmium, 1,3-butadiene, cigarette smoke. Accordingly, polymorphisms of genes encoding for phase I/II metabolic reaction and DNA repair are risk factor for cardiovascular diseases, although their role is negligible as compared to other risk factors. The pathogenic relevance of mutation-related molecular damage in atherosclerosis has been demonstrated in experimental animal models involving the exposure to chemical mutagens. The relevance of mutation-related events in worsening atherosclerosis prognosis has been demonstrated in human clinical studies mainly as referred to mitochondrial DNA damage. Atherosclerosis is characterized by the occurrence of high level of oxidative damage in blood vessel resulting from both endogenous and exogenous sources. Mitochondrial damage is a main endogenous source of oxidative stress whose accumulation causes activation of intrinsic apoptosis through BIRC2 inhibition and cell loss contributing to plaque development and instability. Environmental physical mutagens, including ionizing radiation, are a risk factor for atherosclerosis even at the low exposure dose occurring in case of occupational exposure or the high exposure doses occurring during radiotherapy. Conversely, the role of exciting UV radiation in atherosclerosis is still uncertain. This review summarizes the experimental and clinical evidence supporting the pathogenic role of mutation-related pathway in atherosclerosis examining the underlying molecular mechanisms.
authors.affiliation: Department of Health Sciences, University of Genoa, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Pulliero
authors.affiliation: Department of Toxicology, School for Nutrition, Toxicology and Metabolism (NUTRIM), Maastricht UMC+, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Godschalk
authors.affiliation: CNR Institute of Clinical Physiology, Via Moruzzi 1, 56124 Pisa, Italy.
authors.forename: M G
authors.initials: MG
authors.lastname: Andreassi
authors.affiliation: Department of Toxicology, School for Nutrition, Toxicology and Metabolism (NUTRIM), Maastricht UMC+, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands.
authors.forename: D
authors.initials: D
authors.lastname: Curfs
authors.affiliation: Department of Toxicology, School for Nutrition, Toxicology and Metabolism (NUTRIM), Maastricht UMC+, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands.
authors.forename: F J
authors.initials: FJ
authors.lastname: Van Schooten
authors.affiliation: Department of Health Sciences, University of Genoa, Italy; IRCCS AOU San Martino-IST Genoa, Italy. Electronic address: izzotti@unige.it.
authors.forename: A
authors.initials: A
authors.lastname: Izzotti
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000209:etiology*; D002274:Carcinogens, Environmental / Q000009:adverse effects*; D004247:DNA / Q000187:drug effects; D018736:DNA Adducts / Q000378:metabolism*; D004249:DNA Damage; D004781:Environmental Exposure / Q000009:adverse effects*; D004785:Environmental Pollutants / Q000009:adverse effects; D006801:Humans; D009153:Mutagens / Q000009:adverse effects*; D009154:Mutation
chemical_list: D002274:Carcinogens, Environmental; D018736:DNA Adducts; D004785:Environmental Pollutants; D009153:Mutagens; D004247:DNA
keywords: Atherosclerosis; Carcinogens; Cardiovascular diseases; DNA damage; Polycyclic aromatic hydrocarbons; Radiation