Accumulation of M1dG DNA adducts after chronic exposure to PCBs, but not from acute exposure to polychlorinated aromatic hydrocarbons

Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, NC 27599, USA.
Free Radical Biology and Medicine (Impact Factor: 5.74). 06/2008; 45(5):585-91. DOI: 10.1016/j.freeradbiomed.2008.04.043
Source: PubMed


Oxidative DNA damage is one of the key events thought to be involved in mutation and cancer. The present study examined the accumulation of M1dG, 3-(2'-deoxy-beta-D-erythro-pentofuranosyl)-pyrimido[1,2-a]-purin-10(3H)-one, DNA adducts after single dose or 1-year exposure to polyhalogenated aromatic hydrocarbons (PHAH) in order to evaluate the potential role of oxidative DNA damage in PHAH toxicity and carcinogenicity. The effect of PHAH exposure on the number of M1dG adducts was explored initially in female mice exposed to a single dose of either 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or a PHAH mixture. This study demonstrated that a single exposure to PHAH had no significant effect on the number of M1dG adducts compared to the corn oil control group. The role of M1dG adducts in polychlorinated biphenyl (PCB)-induced toxicity and carcinogenicity was further investigated in rats exposed for a year to PCB 153, PCB 126, or a mixture of the two. PCB 153, at doses up to 3000 microg/kg/day, had no significant effect on the number of M1dG adducts in liver and brain tissues from the exposed rats compared to controls. However, 1000 ng/kg/day of PCB 126 resulted in M1dG adduct accumulation in the liver. More importantly, coadministration of equal proportions of PCB 153 and PCB 126 resulted in dose-dependent increases in M1dG adduct accumulation in the liver from 300 to 1000 ng/kg/day of PCB 126 with 300-1000 microg/kg/day of PCB 153. Interestingly, the coadministration of different amounts of PCB 153 with fixed amounts of PCB 126 demonstrated more M1dG adduct accumulation with higher doses of PCB 153. These results are consistent with the results from cancer bioassays that demonstrated a synergistic effect between PCB 126 and PCB 153 on toxicity and tumor development. In summary, the results from the present study support the hypothesis that oxidative DNA damage plays a key role in toxicity and carcinogenicity following long-term PCB exposure.

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Available from: James Swenberg, Mar 27, 2015
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    • "This is consistent with our observation that co-exposure with PCB126 increased PCB153 accumulation in the livers, possibly through a sequestration mechanism like the one described for PCB126 and CYP1A2. This finding is also in agreement with the combined effect observed with PCB126 and PCB153 for cancer induction and M1dG adduct formation [13] [31] and our finding may provide the explanation for this combined effect, underscoring the need for more mixture experiments to achieve realistic risk assessments. PCB126 is the most potent AhR agonist among all PCB congeners tested [48]. "
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    ABSTRACT: A new delivery method via polymeric implants was used for continuous exposure to PCBs. Female Sprague-Dawley rats received subcutaneous polymeric implants containing PCB126 (0.15% load), PCB153 (5% load), or both, for up to 45 days and release kinetics and tissue distribution were measured. PCB153 tissue levels on day 15 were readily detected in lung, liver, mammary and serum, with highest levels in the mammary tissue. PCB126 was detected only in liver and mammary tissues. However, a completely different pharmacokinetics was observed on co-exposure of PCB153 and PCB126, with a 1.8-fold higher levels of PCB153 in the liver whereas a 1.7-fold lower levels in the mammary tissue. PCB126 and PCB153 caused an increase in expression of key PCB-inducible enzymes, CYP 1A1/2 and 2B1/2, respectively. Serum and liver activities of the antioxidant enzymes, PON1 and PON3, and AhR transcription were also significantly increased by PCB126. (32) P-Postlabeling for polar and lipophilic DNA-adducts showed significant quantitative differences: PCB126 increased 8-oxodG, an oxidative DNA lesion, in liver and lung tissues. Adduct levels in the liver remained upregulated up to 45 days, while some lung DNA adducts declined. This is the first demonstration that continuous low-dose exposure to PCBs via implants can produce sustained tissue levels leading to the accumulation of DNA-adducts in target tissue and induction of indicator enzymes. Collectively, these data demonstrate that this exposure model is a promising tool for long-term exposure studies.
    Toxicology Reports 12/2014; 1:820-833. DOI:10.1016/j.toxrep.2014.09.010
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    • "Theaboveresultsclearlydemonstratethatlowerchlorinated biphenylsmaybereadilybioactivatedtoreactiveintermediates, areneoxidesandparticularlyquinones,withthegenerationof ROS.ThesereactivespeciescaninteractwithDNAandwithprotein formingcovalentlyboundadductswhicharemostlikelythecause fortheobservedgene,chromosome,andgenomemutations.There areindicationsforadductformationandmutagenesisinhuman andenvironmentalbiospecimens,highlightingtherelevanceof laboratoryresearchtoprovideadvancedwarningandanunderstandingofpossiblemechanismsofbioactivation .Suchresearch mayalsoinformandaidinthedesignofefficienttoolsforbiomonitoring ,treatment,andchemoprevention.Dr.RameshGupta hadasignificantinfluenceinadvancingthesegoalsbydevelop- inghighlysensitivemethodsforDNAadductdetectionwhichhe andhiscoworkersthensuccessfullyappliedinPCBresearch [3] [41] [54] [66] [67] [70] [74] [75] [98].Thisresearchhassignificantlyad- vancedourunderstandingofthemechanismsofcancerinitiation byPCBs..W.Robertson,R.C.Gupta,Interactionof benzoquinone-andhydroquinone-derivativesoflowerchlorinated biphenylswithDNAandnucleotidesinvitro,Chem.Biol.Interact.142 (2003)307–316. "
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    ABSTRACT: PCBs are carcinogens, but for many decades it was assumed that PCBs may not possess initiating activity. Initiation is a process that involves changes in the DNA sequence, often, but not exclusively produced through DNA adduction by a reactive compound or reactive oxygen species (ROS). DNA adducts can be detected by (32)P-postlabeling, a method that Dr. Ramesh Gupta co-developed and refined. Today these types of assays together with other mechanistic studies provide convincing evidence that specific PCB congeners can be biotransformed to genotoxic and therefore potentially initiating metabolites. This review will provide an overview of our current knowledge of PCBs genotoxic potential and mechanism of action, emphasizing the contributions of Dr. Ramesh Gupta during his tenures at the Universities of Kentucky and Louisville.
    Cancer letters 12/2012; 334(1). DOI:10.1016/j.canlet.2012.11.041 · 5.62 Impact Factor
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    • "It is possible that the 8-oxo-dG measurement method is not as sensitive for measuring general oxidative DNA damage in wild populations. More studies that involve measuring different types of oxidative adducts, such as 3-(2 0 -deoxy-b- D-erythro-pentofuranosyl)-pyrimido[1,2-a]-purin-10(3H)- one, may shed more light on this issue (Jeong et al. 2008). Another possibility regarding the lack of oxidative DNA adducts, is that the AWI killifish are extremely efficient in countering oxidative stress. "
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    ABSTRACT: The Atlantic Wood Industries Superfund site (AWI) on the Elizabeth River in Portsmouth, VA is heavily contaminated with polycyclic aromatic hydrocarbons (PAHs) from a wood treatment facility. Atlantic killifish, or mummichog (Fundulus heteroclitus), at this Superfund site are exposed to very high concentrations of several carcinogens. In this study, we measured PAH concentrations in both fish tissues and sediments. Concurrently, we assessed different aspects of genotoxicity in the killifish exposed in situ. Both sediment and tissue PAH levels were significantly higher in AWI samples, relative to a reference site, but the chemistry profile was different between sediments and tissues. Killifish at AWI exhibited higher levels of DNA damage compared to reference fish, as measured via the flow cytometric method (FCM), and the damage was consistent with sediment PAH concentrations. Covalent binding of benzo[a]pyrene (BaP) metabolites to DNA, as measured via LC-MS/MS adduct detection methods, were also elevated and could be partially responsible for the DNA damage. Using similar LC-MS/MS methods, we found no evidence that oxidative DNA adducts had a role in observed genotoxicity.
    Ecotoxicology 06/2011; 20(8):1890-9. DOI:10.1007/s10646-011-0727-9 · 2.71 Impact Factor
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