title: Polycyclic aromatic hydrocarbons-induced ROS accumulation enhances mutagenic potential of T-antigen from human polyomavirus JC.
abstract: Polycyclic aromatic hydrocarbons (PAHs) are the products of incomplete combustion of organic materials, which are present in cigarette smoke, deep-fried food, and in natural crude oil. Since PAH-metabolites form DNA adducts and cause oxidative DNA damage, we asked if these environmental carcinogens could affect transforming potential of the human Polyomavirus JC oncoprotein, T-antigen (JCV T-antigen). We extracted DMSO soluble PAHs from Deepwater Horizon oil spill in the Gulf of Mexico (oil-PAHs), and detected several carcinogenic PAHs. The oil-PAHs were tested in exponentially growing cultures of normal mouse fibroblasts (R508), and in R508 stably expressing JCV T-antigen (R508/T). The oil-PAHs were cytotoxic only at relatively high doses (1:50-1:100 dilution), and at 1:500 dilution the growth and cell survival rates were practically unaffected. This non-toxic dose triggered however, a significant accumulation of reactive oxygen species (ROS), caused oxidative DNA damage and the formation of DNA double strand breaks (DSBs). Although oil-PAHs induced similar levels of DNA damage in R508 and R508/T cells, only T-antigen expressing cells demonstrated inhibition of high fidelity DNA repair by homologous recombination (HRR). In contrast, low-fidelity repair by non-homologous end joining (NHEJ) was unaffected. This potential mutagenic shift between DNA repair mechanisms was accompanied by a significant increase in clonal growth of R508/T cells chronically exposed to low doses of the oil-PAHs. Our results indicate for the first time carcinogenic synergy in which oil-PAHs trigger oxidative DNA damage and JCV T-antigen compromises DNA repair fidelity.
authors.affiliation: Neurological Cancer Research at Stanley S Scott Cancer Center, New Orleans, Louisiana, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Wilk
authors.forename: Piotr
authors.initials: P
authors.lastname: Waligórski
authors.forename: Adam
authors.initials: A
authors.lastname: Lassak
authors.forename: Himanshu
authors.initials: H
authors.lastname: Vashistha
authors.forename: David
authors.initials: D
authors.lastname: Lirette
authors.forename: David
authors.initials: D
authors.lastname: Tate
authors.forename: Arnold H
authors.initials: AH
authors.lastname: Zea
authors.forename: Shahriar
authors.initials: S
authors.lastname: Koochekpour
authors.forename: Paulo
authors.initials: P
authors.lastname: Rodriguez
authors.forename: Leonard G
authors.initials: LG
authors.lastname: Meggs
authors.forename: John J
authors.initials: JJ
authors.lastname: Estrada
authors.forename: Augusto
authors.initials: A
authors.lastname: Ochoa
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Reiss
mesh_terms: D000818:Animals; D000957:Antigens, Viral, Tumor / Q000235:genetics*; D016923:Cell Death / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D005591:Chemical Fractionation; D002851:Chromatography, High Pressure Liquid; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D059766:DNA End-Joining Repair / Q000187:drug effects; D004121:Dimethyl Sulfoxide / Q000737:chemistry; D006657:Histones / Q000378:metabolism; D006801:Humans; D007577:JC Virus / Q000235:genetics*; D051379:Mice; D016296:Mutagenesis / Q000187:drug effects*; D018384:Oxidative Stress / Q000187:drug effects; D010578:Petroleum; D011084:Polycyclic Aromatic Hydrocarbons / Q000633:toxicity*; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D000957:Antigens, Viral, Tumor; D006657:Histones; D010578:Petroleum; D011084:Polycyclic Aromatic Hydrocarbons; D017382:Reactive Oxygen Species; C475961:gamma-H2AX protein, mouse; D004121:Dimethyl Sulfoxide
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