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DNA Product Formation in Female Sprague-Dawley Rats Following Polyhalogenated Aromatic Hydrocarbon (PHAH) Exposure

Gao L, Mutlu E, Collins LB, Walker NJ, Hartwell HJ, Olson JR, Sun W, Gold A, Ball LM, Swenberg JA
Chemical Research in Toxicology (2017) DOI: https://doi.org/10.1021/acs.chemrestox.6b00368 PMID: 28207250


Publication


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.

Figures


Figure 1. Illustration of the major DNA adducts induced by ROS/RNS.

Figure 2. Chemical structures of PCB 126, TCDD, and PeCDF.

Figure 3. Cell proliferation.

(Top) Cell proliferation in the liver of female Sprague–Dawley rats exposed to TCDD (100 ng/kg/day) or the tertiary mixture of TCDD, PCB 126, and PeCDF (TEQ 100 ng/kg/day) at 14, 31, and 53 weeks.
(Bottom) Cell proliferation in the liver of female Sprague–Dawley rats exposed to TCDD (0, 22, 46, and 100 ng/kg/day) or the tertiary mixture of TCDD, PCB 126, and PeCDF (TEQ 0, 22, 46, and 100 ng/kg/day) at 53 weeks.(21, 24) ∗, Significantly different (p ≤ 0.05) from the vehicle control group by Shirley’s test.

Figure 4. Tumor incidence from 2-year cancer bioassay of female Sprague–Dawley rat livers.

Figure 4. Tumor incidence from 2-year cancer bioassay of female Sprague–Dawley rat livers exposed to TCDD (0, 22, 46, and 100 ng/kg/day) or the tertiary mixture of TCDD, PCB 126, and PeCDF (TEQ 0, 22, 46, and 100 ng/kg/day).

Tables


Table 1. Number of 8-Oxo-dGuo and 1,N6-εdAdo Measured.

Number of 8-Oxo-dGuo Adducts/106 dGuo and 1,N6-εdAdo Adducts/108 dAdo Measured in Female Sprague–Dawley Rat Hepatic DNA Following Exposure to TCDD (100 ng/kg/day) or the Tertiary Mixture of TCDD, PCB 126, and PeCDF (TEQ 100 ng/kg/day) for 14, 31, and 53 Weeks

Table 2. Number of N2,3-εG, 7-OEG, 8-Oxo-dGuo, and 1,N6-εdAdo Measured.

Number of N2,3-εG Adducts/108 G, 7-OEG Adducts/107 G, 8-Oxo-dGuo Adducts/106 dGuo, and 1,N6-εdAdo Adducts/108 dAdo Measured in Female Sprague–Dawley Rat Hepatic DNA Following Exposure to Multiple Concentrations of TCDD or the Tertiary Mixture of TCDD, PCB 126, and PeCDF for 53 Weeks

Table 3. Number of 1,N2-εdGuo, M1dGuo, CrdGuo, HNEdGuo, and AcrdGuo Measured.

Number of 1,N2-εdGuo Adducts/108 dGuo, M1dGuo adducts/108 dGuo, CrdGuo Adducts/108 dGuo, HNEdGuo Adducts/108 dGuo, and AcrdGuo Adducts/108 dGuo Measured in Female Sprague–Dawley Rat Hepatic DNA Following Exposure to TCDD (100 ng/kg/day) or the Tertiary Mixture of TCDD, PCB 126, and PeCDF (TEQ 100 ng/kg/day) for 53 Weeks