title: DNA Product Formation in Female Sprague-Dawley Rats Following Polyhalogenated Aromatic Hydrocarbon (PHAH) Exposure.
abstract: DNA oxidation damage has been regarded as one of the possible mechanisms for the hepatic carcinogenesis of dioxin-like compounds (DLCs). In this study, we evaluated the toxic equivalency factor (TEF) from the standpoint of induced DNA oxidation products and their relationship to toxicity and carcinogenicity. Nine DNA oxidation products were analyzed in the liver of female Sprague-Dawley rats exposed to 2,3,7,8-tetrachlorodibenzo-pdioxin (TCDD) alone or the tertiary mixture of TCDD, 3,3',4,4',5-pentachlorobiphenyl (PCB 126), and 2,3,4,7,8-pentachlorodibenzofuran (PeCDF) by gavage for 14, 31, and 53 weeks (5 days/week) by LC-MS/MS: 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dGuo); 1,N6-etheno-2'-deoxyadenosine (1,N6-εdAdo); N2,3-ethenoguanine (N2,3-εG); 7-(2-oxoethly)guanine (7-OEG); 1,N2-etheno-2'-deoxyguanosine (1,N2-εdGuo); malondialdehyde (M1dGuo); acrolein (AcrdGuo); crotonaldehyde (CrdGuo); and 4-hydroxynonenal (HNEdGuo) derived 2'-deoxyguanosine adducts. Exposure to TCDD (100 ng/kg/day) significantly induced 1,N6-εdAdo at 31 and 53 weeks, while no increase of 8-oxo-dGuo was observed. Significant increases were observed for 8-oxo-dGuo and 1,N6-εdAdo at all time points following exposure to the tertiary mixture (TEQ 100 ng/kg/day). Exposure to TCDD for 53 weeks only significantly increased 1,N6-εdAdo, while increases of N2,3-εG and 7-OEG were only found in the highest dose group (100 ng/kg/day). Exposure to the tertiary mixture for 53 weeks had no effect on N2,3-εG in any exposure group (TEQ 0, 22, 46, or 100 ng/kg/day), while significant increases were observed for 1,N6-εdAdo (all dose groups), 8-oxo-dGuo (46 and 100 ng/kg/day), and 7-OEG (100 ng/kg/day). While no significant increase was observed at 53 weeks for 1,N2-εdGuo, M1dGuo, AcrdGuo, or CrdGuo following exposure to TCDD (100 ng/kg/day), all of them were significantly induced in animals exposed to the tertiary mixture (TEQ 100 ng/kg/day). This oxidation DNA product data suggest that the simple TEF methodology cannot be applied to evaluate the diverse patterns of toxic effects induced by DLCs.
authors.forename: Lina
authors.initials: L
authors.lastname: Gao
authors.affiliation: National Toxicology Program, National Institute of Environmental Health Sciences, NIH, RTP , Durham, North Carolina 27709, United States.
authors.forename: Esra
authors.initials: E
authors.lastname: Mutlu
authors.forename: Leonard B
authors.initials: LB
authors.lastname: Collins
authors.affiliation: National Toxicology Program, National Institute of Environmental Health Sciences, NIH, RTP , Durham, North Carolina 27709, United States.
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Walker
authors.forename: Hadley J
authors.identifier: 0000-0003-4453-3266
authors.initials: HJ
authors.lastname: Hartwell
authors.affiliation: Department of Pharmacology and Toxicology, State University of New York at Buffalo , Buffalo, New York 14214, United States.
authors.forename: James R
authors.initials: JR
authors.lastname: Olson
authors.forename: Wei
authors.initials: W
authors.lastname: Sun
authors.forename: Avram
authors.initials: A
authors.lastname: Gold
authors.forename: Louise M
authors.initials: LM
authors.lastname: Ball
authors.forename: James A
authors.initials: JA
authors.lastname: Swenberg
mesh_terms: D000818:Animals; D004247:DNA / Q000187:drug effects*; D005260:Female; D011084:Polycyclic Aromatic Hydrocarbons / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D011084:Polycyclic Aromatic Hydrocarbons; D004247:DNA