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Marco Peluso - One of the best experts on this subject based on the ideXlab platform.
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Bulky DNA Adducts and breast cancer risk in the prospective EPIC-Italy study
Breast Cancer Research and Treatment, 2011Co-Authors: Calogero Saieva, Armelle Munnia, Marco Peluso, Giovanna Masala, Marco Ceroti, Sara Piro, Francesco Sera, Benedetta Bendinelli, Valeria Pala, Sabina SieriAbstract:The role of environmental carcinogen exposure in breast cancer development has long been suspected, but no specific association has been identified so far. A few molecular epidemiology studies reported that DNA Adducts detected by different methods are associated with a modest increase of breast cancer risk. We aimed to evaluate the association between bulky DNA Adducts, detected by the P-postlabelling method in peripheral leukocytes, and the risk of developing breast cancer in the female Italian cohorts of the EPIC (European Prospective Investigation into Cancer and nutrition) study. By using a case-control design, breast cancer cases identified in the follow-up of over 30,000 women of EPIC-Italy study have been matched to controls by specific criteria. We measured the levels of bulky DNA Adducts by the P-postlabelling method in peripheral leukocytes donated at enrolment. Conditional regression analyses adjusted for selected potential confounders were used. Results on DNA adduct levels were available for 292 cases and 292 matched controls. The mean DNA adduct levels were similar in both groups ( = 0.62). Multivariate regression analyses failed to show any significant association between bulky DNA Adducts and breast cancer. Our results do not support any association of breast cancer risk with exposure to environmental carcinogens as measured through the levels of bulky DNA Adducts in pre-diagnostic white blood cells. Larger studies by using different methods and/or biomarkers are needed to better evaluate the role of specific environmental carcinogens in breast carcinogenesis.
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DNA Adducts and lung cancer risk a prospective study
Cancer Research, 2005Co-Authors: Marco Peluso, Armelle Munnia, Seymour Garte, Gerard Hoek, Michal Krzyzanowski, Fabrizio Veglia, Luisa Airoldi, Herman Autrup, Alison M Dunning, Pierre HainautAbstract:Objectives were to investigate prospectively the ability of DNA Adducts to predict cancer and to study the determinants of Adducts, especially air pollutants. DNA Adducts were measured in a case-control study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC) investigation. Cases included newly diagnosed lung cancer (n = 115), upper respiratory cancers (pharynx and larynx; n = 82), bladder cancer (n = 124), leukemia (n = 166), and chronic obstructive pulmonary disease or emphysema deaths (n = 77) accrued after a median follow-up of 7 years among the EPIC former smokers and never-smokers. Three controls per case were matched for questionnaire analyses and two controls per case for laboratory analyses. Matching criteria were gender, age, smoking status, country of recruitment, and follow-up time. Individual exposure to air pollution was assessed using concentration data from monitoring stations in routine air quality monitoring networks. Leukocyte DNA Adducts were analyzed blindly using 32P postlabeling technique. Adducts were associated with the subsequent risk of lung cancer, with an odds ratio (OR) of 1.86 [95% confidence interval (95% CI), 0.88-3.93] when comparing detectable versus nondetectable Adducts. The association with lung cancer was stronger in never-smokers (OR, 4.04; 95% CI, 1.06-15.42) and among the younger age groups. After exclusion of the cancers occurring in the first 36 months of follow-up, the OR was 4.16 (95% CI, 1.24-13.88). A positive association was found between DNA Adducts and ozone (O3) concentration. Our prospective study suggests that leukocyte DNA Adducts may predict lung cancer risk of never-smokers. Besides, the association of DNA adduct levels with O3 indicates a possible role for photochemical smog in determining DNA damage.
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Exocyclic malondialdehyde and aromatic DNA Adducts in larynx tissues.
Free radical biology & medicine, 2004Co-Authors: Armelle Munnia, Maria Enrica Amasio, Marco PelusoAbstract:Cigarette smoking and alcohol consumption, known to cause free radical generation and lipid peroxidation, are established risk factors for larynx cancer. Malondialdehyde (MDA) is a naturally occurring product of lipid peroxidation, capable of interacting with DNA to form exocyclic MDA-DNA Adducts. In the present study, we investigated if the production of MDA-DNA Adducts was increased in larynx cancer patients with respect to controls using (32)P-DNA postlabeling techniques. Moreover, we examined the potential effects of cigarette smoking and alcohol consumption on endogenous DNA Adducts. We then analyzed the same set of larynx tissues for the presence of (32)P-postlabeled aromatic DNA Adducts to determine more about the levels and types of Adducts formed in the larynx. We observed that cancer patients tended to have increased levels of MDA and aromatic DNA Adducts with respect to controls. In addition, smoking and alcohol were found to influence the formation of endogenous Adducts in the larynx tissues. Finally, the amounts of endogenous Adducts were found to be comparable to those observed for aromatic DNA Adducts in the same set of larynx tissues. These findings imply that endogenous lesions, if not repaired, may contribute to larynx cancer development.
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white blood cell DNA Adducts and fruit and vegetable consumption in bladder cancer
Carcinogenesis, 2000Co-Authors: Marco Peluso, Armelle Munnia, Luisa Airoldi, Cinzia Magagnotti, Laura Fiorini, A Hautefeuille, C Malaveille, Paolo VineisAbstract:The ‘Mediterranean diet’, a diet rich in cereals, fruit and The consumption of phenolics or flavonoids has been shown vegetables, has been associated with lowering the risk of a to decrease the level of DNA Adducts in experimental studies variety of cancers of the digestive tract and the bladder. in humans and animals: moderate wine consumption (a source In a previous study, we showed that the high phenolic of phenolics) inhibited peroxide-induced micronucleated cells content these dietary components produce in the urine (8) and the consumption of flavonoids inhibited DNA damage could be associated with higher antimutagenic properties of related to lipid peroxidation (9). A high concentration of the urine and lower arylamine–DNA Adducts in exfoliated flavonoids and other phenolics can be found in onions, lettuce, bladder cells. We have conducted a case–control study on red wine and other components of the Mediterranean diet. 162 bladder cancer patients and 104 hospital controls. We have shown previously that urine extracts contain Total aromatic DNA Adducts were measured in white blood substances that strongly inhibit urinary mutagenicity related cells (WBC) of all subjects by 32 P-post-labelling. Genetically to smoking (10). Building on these findings, we conducted
Armelle Munnia - One of the best experts on this subject based on the ideXlab platform.
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Bulky DNA Adducts and breast cancer risk in the prospective EPIC-Italy study
Breast Cancer Research and Treatment, 2011Co-Authors: Calogero Saieva, Armelle Munnia, Marco Peluso, Giovanna Masala, Marco Ceroti, Sara Piro, Francesco Sera, Benedetta Bendinelli, Valeria Pala, Sabina SieriAbstract:The role of environmental carcinogen exposure in breast cancer development has long been suspected, but no specific association has been identified so far. A few molecular epidemiology studies reported that DNA Adducts detected by different methods are associated with a modest increase of breast cancer risk. We aimed to evaluate the association between bulky DNA Adducts, detected by the P-postlabelling method in peripheral leukocytes, and the risk of developing breast cancer in the female Italian cohorts of the EPIC (European Prospective Investigation into Cancer and nutrition) study. By using a case-control design, breast cancer cases identified in the follow-up of over 30,000 women of EPIC-Italy study have been matched to controls by specific criteria. We measured the levels of bulky DNA Adducts by the P-postlabelling method in peripheral leukocytes donated at enrolment. Conditional regression analyses adjusted for selected potential confounders were used. Results on DNA adduct levels were available for 292 cases and 292 matched controls. The mean DNA adduct levels were similar in both groups ( = 0.62). Multivariate regression analyses failed to show any significant association between bulky DNA Adducts and breast cancer. Our results do not support any association of breast cancer risk with exposure to environmental carcinogens as measured through the levels of bulky DNA Adducts in pre-diagnostic white blood cells. Larger studies by using different methods and/or biomarkers are needed to better evaluate the role of specific environmental carcinogens in breast carcinogenesis.
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DNA Adducts and lung cancer risk a prospective study
Cancer Research, 2005Co-Authors: Marco Peluso, Armelle Munnia, Seymour Garte, Gerard Hoek, Michal Krzyzanowski, Fabrizio Veglia, Luisa Airoldi, Herman Autrup, Alison M Dunning, Pierre HainautAbstract:Objectives were to investigate prospectively the ability of DNA Adducts to predict cancer and to study the determinants of Adducts, especially air pollutants. DNA Adducts were measured in a case-control study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC) investigation. Cases included newly diagnosed lung cancer (n = 115), upper respiratory cancers (pharynx and larynx; n = 82), bladder cancer (n = 124), leukemia (n = 166), and chronic obstructive pulmonary disease or emphysema deaths (n = 77) accrued after a median follow-up of 7 years among the EPIC former smokers and never-smokers. Three controls per case were matched for questionnaire analyses and two controls per case for laboratory analyses. Matching criteria were gender, age, smoking status, country of recruitment, and follow-up time. Individual exposure to air pollution was assessed using concentration data from monitoring stations in routine air quality monitoring networks. Leukocyte DNA Adducts were analyzed blindly using 32P postlabeling technique. Adducts were associated with the subsequent risk of lung cancer, with an odds ratio (OR) of 1.86 [95% confidence interval (95% CI), 0.88-3.93] when comparing detectable versus nondetectable Adducts. The association with lung cancer was stronger in never-smokers (OR, 4.04; 95% CI, 1.06-15.42) and among the younger age groups. After exclusion of the cancers occurring in the first 36 months of follow-up, the OR was 4.16 (95% CI, 1.24-13.88). A positive association was found between DNA Adducts and ozone (O3) concentration. Our prospective study suggests that leukocyte DNA Adducts may predict lung cancer risk of never-smokers. Besides, the association of DNA adduct levels with O3 indicates a possible role for photochemical smog in determining DNA damage.
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Exocyclic malondialdehyde and aromatic DNA Adducts in larynx tissues.
Free radical biology & medicine, 2004Co-Authors: Armelle Munnia, Maria Enrica Amasio, Marco PelusoAbstract:Cigarette smoking and alcohol consumption, known to cause free radical generation and lipid peroxidation, are established risk factors for larynx cancer. Malondialdehyde (MDA) is a naturally occurring product of lipid peroxidation, capable of interacting with DNA to form exocyclic MDA-DNA Adducts. In the present study, we investigated if the production of MDA-DNA Adducts was increased in larynx cancer patients with respect to controls using (32)P-DNA postlabeling techniques. Moreover, we examined the potential effects of cigarette smoking and alcohol consumption on endogenous DNA Adducts. We then analyzed the same set of larynx tissues for the presence of (32)P-postlabeled aromatic DNA Adducts to determine more about the levels and types of Adducts formed in the larynx. We observed that cancer patients tended to have increased levels of MDA and aromatic DNA Adducts with respect to controls. In addition, smoking and alcohol were found to influence the formation of endogenous Adducts in the larynx tissues. Finally, the amounts of endogenous Adducts were found to be comparable to those observed for aromatic DNA Adducts in the same set of larynx tissues. These findings imply that endogenous lesions, if not repaired, may contribute to larynx cancer development.
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white blood cell DNA Adducts and fruit and vegetable consumption in bladder cancer
Carcinogenesis, 2000Co-Authors: Marco Peluso, Armelle Munnia, Luisa Airoldi, Cinzia Magagnotti, Laura Fiorini, A Hautefeuille, C Malaveille, Paolo VineisAbstract:The ‘Mediterranean diet’, a diet rich in cereals, fruit and The consumption of phenolics or flavonoids has been shown vegetables, has been associated with lowering the risk of a to decrease the level of DNA Adducts in experimental studies variety of cancers of the digestive tract and the bladder. in humans and animals: moderate wine consumption (a source In a previous study, we showed that the high phenolic of phenolics) inhibited peroxide-induced micronucleated cells content these dietary components produce in the urine (8) and the consumption of flavonoids inhibited DNA damage could be associated with higher antimutagenic properties of related to lipid peroxidation (9). A high concentration of the urine and lower arylamine–DNA Adducts in exfoliated flavonoids and other phenolics can be found in onions, lettuce, bladder cells. We have conducted a case–control study on red wine and other components of the Mediterranean diet. 162 bladder cancer patients and 104 hospital controls. We have shown previously that urine extracts contain Total aromatic DNA Adducts were measured in white blood substances that strongly inhibit urinary mutagenicity related cells (WBC) of all subjects by 32 P-post-labelling. Genetically to smoking (10). Building on these findings, we conducted
Suzanne M. Cutts - One of the best experts on this subject based on the ideXlab platform.
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Detection of adriamycin-DNA Adducts by accelerator mass spectrometry.
Methods in molecular biology (Clifton N.J.), 2009Co-Authors: Kate E. Coldwell, Suzanne M. Cutts, Ted Ognibene, Paul T. Henderson, Don R. PhillipsAbstract:There have been many attempts in the past to determine whether significant levels of Adriamycin-DNA Adducts form in cells and contribute to the anticancer activity of this agent. Supraclincal drug levels have been required to study drug-DNA Adducts because of the lack of sensitivity associated with many of the techniques employed, including liquid scintillation counting of radiolabeled drug. The use of accelerator mass spectrometry (AMS) has provided the first direct evidence of Adriamycin-DNA adduct formation in cells at clinically relevant Adriamycin concentrations. The exceedingly sensitive nature of AMS has enabled over three orders of magnitude increased sensitivity of Adriamycin-DNA adduct detection (compared to liquid scintillation counting) and has revealed adduct formation within an hour of drug treatment. The rigorous protocol required for this approach, together with many notes on the precautions and procedures required in order to ensure that absolute levels of Adriamycin-DNA Adducts can be determined with good reproducibility, is outlined in this chapter.
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detection of adriamycin DNA Adducts by accelerator mass spectrometry at clinically relevant adriamycin concentrations
Nucleic Acids Research, 2008Co-Authors: Kate E. Coldwell, Suzanne M. Cutts, Ted Ognibene, Paul T. Henderson, Don R. PhillipsAbstract:Limited sensitivity of existing assays has prevented investigation of whether Adriamycin-DNA Adducts are involved in the anti-tumour potential of Adriamycin. Previous detection has achieved a sensitivity of a few Adriamycin-DNA Adducts/10(4) bp DNA, but has required the use of supra-clinical drug concentrations. This work sought to measure Adriamycin-DNA Adducts at sub-micromolar doses using accelerator mass spectrometry (AMS), a technique with origins in geochemistry for radiocarbon dating. We have used conditions previously validated (by less sensitive decay counting) to extract [(14)C]Adriamycin-DNA Adducts from cells and adapted the methodology to AMS detection. Here we show the first direct evidence of Adriamycin-DNA Adducts at clinically-relevant Adriamycin concentrations. [(14)C]Adriamycin treatment (25 nM) resulted in 4.4 +/- 1.0 Adducts/10(7) bp ( approximately 1300 Adducts/cell) in MCF-7 breast cancer cells, representing the best sensitivity and precision reported to date for the covalent binding of Adriamycin to DNA. The exceedingly sensitive nature of AMS has enabled over three orders of magnitude increased sensitivity of Adriamycin-DNA adduct detection and revealed adduct formation within an hour of drug treatment. This method has been shown to be highly reproducible for the measurement of Adriamycin-DNA Adducts in tumour cells in culture and can now be applied to the detection of these Adducts in human tissues.
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doxorubicin DNA Adducts induce a non topoisomerase ii mediated form of cell death
Cancer Research, 2006Co-Authors: Lonnie P Swift, Don R. Phillips, Ada Rephaeli, Abraham Nudelman, Suzanne M. CuttsAbstract:Doxorubicin (Adriamycin) is one of the most commonly used chemotherapeutic drugs and exhibits a wide spectrum of activity against solid tumors, lymphomas, and leukemias. Doxorubicin is classified as a topoisomerase II poison, although other mechanisms of action have been characterized. Here, we show that doxorubicin-DNA Adducts (formed by the coadministration of doxorubicin with non-toxic doses of formaldehyde-releasing prodrugs) induce a more cytotoxic response in HL-60 cells than doxorubicin as a single agent. Doxorubicin-DNA Adducts seem to be independent of classic topoisomerase II-mediated cellular responses (as observed by employing topoisomerase II catalytic inhibitors and HL-60/MX2 cells). Apoptosis induced by doxorubicin-DNA Adducts initiates a caspase cascade that can be blocked by overexpressed Bcl-2, suggesting that Adducts induce a classic mode of apoptosis. A reduction in the level of topoisomerase II-mediated double-strand-breaks was also observed with increasing levels of doxorubicin-DNA Adducts and increased levels of apoptosis, further confirming that Adducts exhibit a separate mechanism of action compared with the classic topoisomerase II poison mode of cell death by doxorubicin alone. Collectively, these results indicate that the presence of formaldehyde transfers doxorubicin from topoisomerase II-mediated cellular damage to the formation of doxorubicin-DNA Adducts, and that these Adducts are more cytotoxic than topoisomerase II-mediated lesions. These results also show that doxorubicin can induce apoptosis by a non-topoisomerase II-dependent mechanism, and this provides exciting new prospects for enhancing the clinical use of this agent and for the development of new derivatives and new tumor-targeted therapies.
Deliang Tang - One of the best experts on this subject based on the ideXlab platform.
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PhIP-DNA Adducts as a biomarker for prostate carcinogenesis
Cancer Research, 2006Co-Authors: Deliang Tang, Jason Liu, Adnan T. Savera, Andrew Rundle, Christine Neslund-dudas, James J. Yang, Benjamin A. RybickiAbstract:2057 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is the most abundant heterocyclic amine in the human diet, and is formed during the cooking of meat. PhiP-DNA Adducts provide a measure of chemical-specific genetic damage that has been associated with increased risk of cancer. This study examined the relationship between PhiP-DNA Adducts measured by immunohistochemistry in nontumorous and tumorous prostatic epithelial cells. Study subjects were 125 men who underwent prostatectomy and were part of the Henry Ford Health System, in Detroit, Michigan. . The mean level of PhiP-DNA Adducts in prostatic epithelial nontumor cells was significantly higher than the mean level of PhiP-DNA Adducts in tumor cells (0.055 units) (p
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Polycyclic aromatic hydrocarbon-DNA Adducts in prostate cancer.
Cancer research, 2004Co-Authors: Benjamin A. Rybicki, Andrew Rundle, Adnan T. Savera, Steadman S. Sankey, Deliang TangAbstract:The formation of DNA Adducts can lead to DNA replication errors and the potential for carcinogenesis. DNA Adducts have been detected in prostate cells, but the distribution of Adducts with respect to prostate cancer risk factors and histology is unknown. In a study of 130 Caucasian (n = 61) and African-American (n = 69) men with prostate cancer who underwent radical prostatectomy, we quantified polycyclic aromatic hydrocarbon (PAH)-DNA Adducts in prostate tumor and adjacent nontumor cells by immunohistochemistry. A strong correlation between paired adduct levels in the two cell types was observed (r = 0.56; P < 0.0001); however, nontumor cells had a significantly higher level of Adducts compared with tumor (0.30 absorbance units +/- 0.05 versus 0.17 absorbance units +/- 0.04; P < 0.0001). Variables significantly associated with PAH-DNA adduct levels in tumor cells included primary Gleason grade, tumor volume, and log-transformed prostate-specific antigen (PSA) at time of diagnosis. Tumors with a primary Gleason grade of 5 had significantly lower PAH-DNA adduct levels than tumor cells with a primary Gleason grade of 3 or 4 (P < 0.0001 for both). Tumors that involved 10% or less of the prostate gland had significantly higher PAH-DNA adduct levels than tumors that involved 15 to 20% of the prostate gland (P = 0.004). PSA levels were inversely associated with PAH-DNA adduct levels in tumor cells (P = 0.009). A similar, albeit less significant, inverse association was observed between PSA and PAH-DNA adduct levels in nontumor cells (P = 0.07). Interestingly, increasing primary Gleason grade was associated with increasing PAH-DNA adduct levels in adjacent nontumor cells (P = 0.008). Our results show that PAH-DNA Adducts are present in the prostate but vary with regard to cellular histology. In prostate tumor cells, decreased cellular differentiation and increased tumor proliferation may reduce PAH-DNA adduct levels.
James A Swenberg - One of the best experts on this subject based on the ideXlab platform.
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endogenous versus exogenous DNA Adducts their role in carcinogenesis epidemiology and risk assessment
Toxicological Sciences, 2011Co-Authors: James A Swenberg, Patricia B. Upton, Benjamin C Moeller, Lina Gao, Jun Nakamura, Thomas B StarrAbstract:There is a strong need for science-based risk assessment that utilizes known data from diverse sources to arrive at accurate assessments of human health risk. Such assessments will protect the public health without mandating unreasonable regulation. This paper utilizes 30 years of research on three “known human carcinogens”: formaldehyde, vinyl chloride (VC), and ethylene oxide (EO), each of which forms DNA Adducts identical to endogenous DNA Adducts in all individuals. It outlines quantitative data on endogenous Adducts, mutagenicity, and relationships between endogenous and exogenous Adducts. Formaldehyde has the richest data set, with quantitative data on endogenous and exogenous DNA Adducts from the same samples. The review elaborates on how such data can be used to inform the current risk assessment on formaldehyde, including both the biological plausibility and accuracy of projected risks. Finally, it extends the thought process to VC, EO, and additional areas of potential research, pointing out needs, nuances, and potential paths forward to improved understanding that will lead to strong science-based risk assessment.
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molecular dosimetry of n2 hydroxymethyl dg DNA Adducts in rats exposed to formaldehyde
Chemical Research in Toxicology, 2011Co-Authors: Benjamin C Moeller, Melanie Doyleeisele, Jacob D Mcdonald, James A SwenbergAbstract:In this study, both endogenous and exogenous N(2)-hydroxymethyl-dG Adducts in nasal DNA of rats exposed to 0.7, 2, 5.8, 9.1, or 15.2 ppm [(13)CD(2)] formaldehyde for 6 h were quantified by a highly sensitive nano-UPLC-MS/MS method. Our data clearly demonstrated that exogenous formaldehyde DNA Adducts form in a highly nonlinear fashion, with a 21.7-fold increase in exposure causing a 286-fold increase in exogenous Adducts. The ratio of exogenous/endogenous DNA Adducts demonstrated that endogenous DNA Adducts dominated at low exposures, comprising more than 99%. In contrast, exogenous Adducts were not detectable in the bone marrow of rats exposed to 15.2 ppm [(13)CD(2)] formaldehyde.
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Applications of mass spectrometry for quantitation of DNA Adducts.
Journal of chromatography. B Analytical technologies in the biomedical and life sciences, 2002Co-Authors: Hasan Koc, James A SwenbergAbstract:DNA Adducts are formed when electrophilic molecules or free radicals attack DNA. 32P-postlabeling has been the most commonly used assay for quantitation of DNA Adducts due mainly to its excellent sensitivity that allows quantitation at concentrations as low as approximately 1 adduct per 10(9) normal bases. Such methods, however, do not have the specificity desired for accurate and reliable quantitation, and are prone to produce false positives and artifacts. In the last decade, mass spectrometry in combination with liquid and gas chromatography has presented itself as a good alternative to these techniques since it can satisfy the need for specificity and reliability through the use of stable isotope-labeled internal standards and highly specific detection modes such as selected reaction monitoring and high-resolution mass spectrometry. In this article, the contribution of mass spectrometry to the quantitation of DNA Adducts is reviewed with special emphasis on unique applications of mass spectrometry in the area of DNA adduct quantitation and recent applications with improvements in sensitivity.
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Applications of mass spectrometry for quantitation of DNA Adducts
Journal of Chromatography B: Biomedical Sciences and Applications, 2002Co-Authors: Hasan Koc, James A SwenbergAbstract:DNA Adducts are formed when electrophilic molecules or free radicals attack DNA. 32 P-postlabeling has been the most commonly used assay for quantitation of DNA Adducts due mainly to its excellent sensitivity that allows quantitation at concentrations as low as ∼1 adduct per 10 9 normal bases. Such methods, however, do not have the specificity desired for accurate and reliable quantitation, and are prone to produce false positives and artifacts. In the last decade, mass spectrometry in combination with liquid and gas chromatography has presented itself as a good alternative to these techniques since it can satisfy the need for specificity and reliability through the use of stable isotope-labeled internal standards and highly specific detection modes such as selected reaction monitoring and high-resolution mass spectrometry. In this article, the contribution of mass spectrometry to the quantitation of DNA Adducts is reviewed with special emphasis on unique applications of mass spectrometry in the area of DNA adduct quantitation and recent applications with improvements in sensitivity.
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Analysis of DNA Adducts in rats exposed to pentachlorophenol
Carcinogenesis, 2002Co-Authors: Po-hsiung Lin, Patricia B. Upton, James A SwenbergAbstract:Pentachlorophenol (PCP) is a widely used biocide that has been reported to be hepatocarcinogenic in mice. Its effects in rats are equivocal, but the liver clearly is not a target organ for carcinogenesis. The carcinogenic effects of PCP in mice may relate to reactive oxygen species generated during metabolism. PCP is known to increase the hydroxyl radical-derived DNA lesion, 8-oxodeoxyguanosine (ohdG), in the liver of exposed mice. To investigate whether the generation of oxidative DNA damage and direct DNA Adducts may explain the species difference in carcinogenicity, we have analyzed ohdG in hepatic DNA from PCP-exposed rats. Rats were exposed acutely to PCP for 1 or 5 days. Tissues also were obtained from a 27 week interim sacrifice of the 2 year National Toxicology Program carcinogenesis bioassay. We used HPLC with electrochemical array detection for ohdG analysis. Single or 5 day exposure to PCP (up to 120 or 60 mg/kg/day, respectively) did not increase ohdG. Dietary exposure to 1000 p.p.m. PCP (equivalent to 60 mg/kg/day) for 27 weeks induced a 2-fold increase in ohdG (1.8 versus 0.9110 ‐6 in controls). In parallel, formation of direct DNA Adducts was analyzed by 32 P-post-labeling following nuclease P1 adduct enrichment. We detected two major DNA Adducts with relative adduct labeling of 0.7810 7 Adducts per total nucleotides. One of these Adducts was found to co-migrate with the adduct induced by the metabolite, tetrachloro1,4-benzoquinone. We observed differences in DNA adduct formation between acute and chronic studies, with acute studies not inducing any detectable amount of DNA Adducts. These results indicated that chronic, but not acute exposure to PCP increased ohdG and direct Adducts in hepatic DNA. As the same exposure conditions that enhanced ohdG did not produce liver cancer in rats, the generation of reactive oxygen species, oxidative DNA damage and direct DNA Adducts is not sufficient for the induction of hepatocarcinogenesis by PCP in the rat.