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David H Phillips - One of the best experts on this subject based on the ideXlab platform.
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variation in pah related DNA Adduct levels among non smokers the role of multiple genetic polymorphisms and nucleotide excision repair phenotype
International Journal of Cancer, 2013Co-Authors: Roger W L Godschalk, David H Phillips, Arash Etemadi, Farhad Islami, Asieh Golozar, Farin KamangarAbstract:Polycyclic aromatic hydrocarbons (PAHs) likely play a role in many cancers even in never-smokers. We tried to find a model to explain the relationship between variation in PAH-related DNA Adduct levels among people with similar exposures, multiple genetic polymorphisms in genes related to metabolic and repair pathways, and nucleotide excision repair (NER) capacity. In 111 randomly selected female never-smokers from the Golestan Cohort Study in Iran, we evaluated 21 SNPs in 14 genes related to xenobiotic metabolism and 12 SNPs in eight DNA repair genes. NER capacity was evaluated by a modified comet assay, and aromatic DNA Adduct levels were measured in blood by32P-postlabeling. Multivariable regression models were compared by Akaike's information criterion (AIC). Aromatic DNA Adduct levels ranged between 1.7 and 18.6 per 10(8) nucleotides (mean: 5.8 ± 3.1). DNA Adduct level was significantly lower in homozygotes for NAT2 slow alleles and ERCC5 non-risk-allele genotype, and was higher in the MPO homozygote risk-allele genotype. The sum of risk alleles in these genes significantly correlated with the log-Adduct level (r = 0.4, p < 0.001). Compared with the environmental model, adding Phase I SNPs and NER capacity provided the best fit, and could explain 17% more of the variation in Adduct levels. NER capacity was affected by polymorphisms in the MTHFR and ERCC1 genes. Female non-smokers in this population had PAH-related DNA Adduct levels three to four times higher than smokers and occupationally-exposed groups in previous studies, with large inter-individual variation which could best be explained by a combination of Phase I genes and NER capacity.
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polycyclic aromatic hydrocarbon pah exposure and DNA Adduct semi quantitation in archived human tissues
International Journal of Environmental Research and Public Health, 2011Co-Authors: Margaret M Pratt, David H Phillips, Kaarthik John, Allan B Maclean, Senait Afework, Miriam C. PoirierAbstract:Polycyclic aromatic hydrocarbons (PAHs) are combustion products of organic materials, mixtures of which contain multiple known and probable human carcinogens. PAHs occur in indoor and outdoor air, as well as in char-broiled meats and fish. Human exposure to PAHs occurs by inhalation, ingestion and topical absorption, and subsequently formed metabolites are either rendered hydrophilic and excreted, or bioactivated and bound to cellular macromolecules. The formation of PAH-DNA Adducts (DNA binding products), considered a necessary step in PAH-initiated carcinogenesis, has been widely studied in experimental models and has been documented in human tissues. This review describes immunohistochemistry (IHC) studies, which reveal localization of PAH-DNA Adducts in human tissues, and semi-quantify PAH-DNA Adduct levels using the Automated Cellular Imaging System (ACIS). These studies have shown that PAH-DNA Adducts concentrate in: basal and supra-basal epithelium of the esophagus, cervix and vulva; glandular epithelium of the prostate; and cytotrophoblast cells and syncitiotrophoblast knots of the placenta. The IHC photomicrographs reveal the ubiquitous nature of PAH-DNA Adduct formation in human tissues as well as PAH-DNA Adduct accumulation in specific, vulnerable, cell types. This semi-quantative method for PAH-DNA Adduct measurement could potentially see widespread use in molecular epidemiology studies.
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DNA Adduct formation and mutation induction by aristolochic acid in rat kidney and liver
Mutation Research, 2006Co-Authors: Nan Mei, David H Phillips, Volker M Arlt, Robert H Heflich, Tao ChenAbstract:Abstract Aristolochic acid (AA) is a potent nephrotoxin and carcinogen and is the causative factor for Chinese herb nephropathy. AA has been associated with the development of urothelial cancer in humans, and kidney and forestomach tumors in rodents. To investigate the molecular mechanisms responsible for the tumorigenicity of AA, we determined the DNA Adduct formation and mutagenicity of AA in the liver (nontarget tissue) and kidney (target tissue) of Big Blue rats. Groups of six male rats were gavaged with 0, 0.1, 1.0 and 10.0 mg AA/kg body weight five times/week for 3 months. The rats were sacrificed 1 day after the final treatment, and the livers and kidneys were isolated. DNA Adduct formation was analyzed by 32 P-postlabeling and mutant frequency (MF) was determined using the λ Select- cII Mutation Detection System. Three major Adducts (7-[deoxyadenosin- N 6 -yl]-aristolactam I, 7-[deoxyadenosin- N 6 -yl]-aristolactam II and 7-[deoxyguanosin- N 2 -yl]-aristolactam I) were identified. There were strong linear dose-responses for AA-induced DNA Adducts in treated rats, ranging from 25 to 1967 Adducts/10 8 nucleotides in liver and 95–4598 Adducts/10 8 nucleotides in kidney. A similar trend of dose-responses for mutation induction also was found, the MFs ranging from 37 to 666 × 10 −6 in liver compared with the MFs of 78–1319 × 10 −6 that we previously reported for the kidneys of AA-treated rats. Overall, kidneys had at least two-fold higher levels of DNA Adducts and MF than livers. Sequence analysis of the cII mutants revealed that there was a statistically significant difference between the mutation spectra in both kidney and liver of AA-treated and control rats, but there was no significant difference between the mutation spectra in AA-treated livers and kidneys. A:T → T:A transversion was the predominant mutation in AA-treated rats; whereas G:C → A:T transition was the main type of mutation in control rats. These results indicate that the AA treatment that eventually results in kidney tumors in rats also results in significant increases in DNA Adduct formation and cII MF in kidney. Although the same treatment does not produce tumors in rat liver, it does induce DNA Adducts and mutations in this tissue, albeit at lower levels than in kidney.
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DNA Adduct formation by the environmental contaminant 3 nitrobenzanthrone after intratracheal instillation in rats
International Journal of Cancer, 2005Co-Authors: Christian A Bieler, David H Phillips, Volker M Arlt, Michael G Cornelius, Reinhold Klein, Manfred Wiessler, Heinz H SchmeiserAbstract:3-Nitrobenzanthrone (3-NBA) is an environmental pollutant and suspected human carcinogen found in emissions from diesel and gasoline engines and on the surface of ambient air particulate matter; human exposure to 3-NBA is likely to occur primarily via the respiratory tract. In our study female Sprague Dawley rats were treated by intratracheal instillation with a single dose of 0.2 or 2 mg/kg body weight of 3-NBA. Using the butanol enrichment version of the (32)P-postlabeling method, DNA Adduct formation by 3-NBA 48 hr after intratracheal administration in different organs (lung, pancreas, kidney, urinary bladder, heart, small intestine and liver) and in blood was investigated. The same Adduct pattern consisting of up to 5 DNA Adduct spots was detected by thin layer chromatography in all tissues and blood and at both doses. Highest total Adduct levels were found in lung and pancreas (350 +/- 139 and 620 +/- 370 Adducts per 10(8) nucleotides for the high dose and 39 +/- 18 and 55 +/- 34 Adducts per 10(8) nucleotides for the low dose, respectively) followed by kidney, urinary bladder, heart, small intestine and liver. Adduct levels were dose-dependent in all organs (approximately 10-fold difference between doses). It was demonstrated by high performance liquid chromatography (HPLC) that all 5 3-NBA-derived DNA Adducts formed in rats after intratracheal instillation are identical to those formed by other routes of application and are, as previously shown, formed from reductive metabolites bound to purine bases. Although total Adduct levels in the blood were much lower (41 +/- 27 and 9.5 +/- 1.9 Adducts per 10(8) nucleotides for the high and low dose, respectively) than those found in the lung, they were related to dose and to the levels found in lung. These results show that uptake of 3-NBA by the lung induces high levels of specific DNA Adducts in several organs of the rat and an identical Adduct pattern in DNA from blood. Therefore, 3-NBA-DNA Adducts present in the blood are useful biomarkers for exposure to 3-NBA and may help to assess the effective biological dose in humans exposed to it.
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Hepatic DNA Adduct dosimetry in rats fed tamoxifen: A comparison of methods
Mutagenesis, 2005Co-Authors: Laura J. Schild, Mark Gaskell, Elizabeth Wright, Martin R Osborne, Karen Brown, Alan Hewer, Mona I. Churchwell, David H Phillips, Frederick A Beland, Miriam C. PoirierAbstract:Hepatic DNA Adduct dosimetry in rats fed tamoxifen: a comparison of methods Liver homogenates from rats fed tamoxifen (TAM) in the diet were shared among four different laboratories. TAM-DNA Adducts were assayed by high pressure liquid chromatography- electrospray tandem mass spectrometry (HPLC-ES-MS/MS), TAM-DNA chemiluminescence immunoassay (TAM-DNA CIA), and P-32- postlabeling with either thin layer (P-32-P-TLC) or liquid chromatography (P-32-P-HPLC) separation. In the first study, rats were fed a diet containing 500 p.p.m. TAM for 2 months, and the values for measurements of the (E)-alpha- (deoxyguanosin-N-2-yl)-tamoxifen (dG-N-2-TAM) Adduct in replicate rat livers varied by 3.5-fold when quantified using 'in house' TAM-DNA standards, or other approaches where appropriate. In the second study, rats were fed 0, 50, 250 or 500 p.p.m. TAM for 2 months, and TAM-DNA values were quantified using both 'in house' approaches as well as a newly synthesized [N-methyl-H-3]TAM-DNA standard that was shared among all the participating groups. In the second study, the total TAM-DNA Adduct values varied by 2-fold, while values for the dG-N-2-TAM varied by 2.5-fold. Ratios of dG-N-2-TAM:(E)-alpha- (deoxyguanosin-N-2-yl)-N-desmethyltamoxifen (dG-N-2-N- desmethyl-TAM) in the second study were similar to 1:1 over the range of doses examined. The study demonstrated a remarkably good agreement for TAM-DNA Adduct measurements among the diverse methods employed.
Miriam C. Poirier - One of the best experts on this subject based on the ideXlab platform.
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Carcinogen–DNA Adduct Formation and DNA Repair
Encyclopedia of Toxicology, 2014Co-Authors: Ainsley Weston, Miriam C. PoirierAbstract:Carcinogen–DNA Adducts can form following endogenous or exogenous exposure to reactive chemical species, usually electrophiles, that modify the structure of DNA. The DNA repair system comprises the products of more than 150 genes that form discrete units or an apparatus of one to eight proteins, which can detect DNA damage, effect cell cycle arrest if necessary, eliminate the damage, patch the DNA molecule, and reconstitute the DNA helix (usually by ligation). The carcinogen–DNA Adduct formation is a DNA-damaging event that potentiates the development of mutations, which constitute the molecular basis of a disease, including cancer. The process of DNA repair can mitigate the molecular basis of disease, but it is complex and sometimes imperfect. This article is an attempt to outline some of the many ways that carcinogen–DNA Adducts are formed, and to describe the basic mechanisms of DNA repair.
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DNA Adduct Measurements and Tumor Incidence during Chronic Carcinogen Exposure in Rodents
2013Co-Authors: Miriam C. Poirier, Frederick A. BelAbstract:In an attempt to elucidate the relationship between DNA Adduct formation and tumorigenesis, DNA Adducts were measured in the livers and bladders of mice during chronic exposure to several different doses of 2-acetylaminofluorene (2-AAF) and 4-aminobiphenyl (4-ABP). Continuous oral administration of these compounds for 4 weeks produced an increase in DNA Adduct formation during the first 2 weeks, followed by a plateau, which presumably occurred because the rate of Adduct removal offset the rate of Adduct formation. The quantity of DNA Adducts present at equilibrium correlated directly with the carcinogen concentration; therefore, when exposure was continued for 4 weeks, DNA Adducts that reflected the plateau level at each dose could be expressed as a function of dose. Liver and bladder DNA Adduct profiles thus obtained during administration of multiple doses of 2-AAF (to female mice) and 4-ABP (to male and female mice) were compared to profiles for tumor incidences obtained during lifetime exposures to the same doses. These experiments demonstrated similar profiles for DNA Adduct formation and tumorigenesis in liver. In the bladder, DNA Adducts were linear, but tumors only appeared at the higher doses in conjunction with cell proliferation. In addition to these aromatic amines, similar data are available for aflatoxin B1, diethylnitrosamine, and (methyinitrosamino)-1-(3-pyridyl)-1-butanone (also known as nicotine-derived nitrosoketone). Of the nine different biological situations (carcinogen/species/sex/organ) for which data are available, correlations between steadystate DNA Adduct levels and tumorigenic response at the different doses were linear in five of the nine biological models. When the relationship between DNA Adduct formation and tumor incidence was not linear, the profiles observed were considered to be the result of tissue-specific phenomena such as metabolic activation, cell proliferation, or cytotoxicity.- Environ Health Perspect 102(Suppl 6):161-165 (1994
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polycyclic aromatic hydrocarbon pah exposure and DNA Adduct semi quantitation in archived human tissues
International Journal of Environmental Research and Public Health, 2011Co-Authors: Margaret M Pratt, David H Phillips, Kaarthik John, Allan B Maclean, Senait Afework, Miriam C. PoirierAbstract:Polycyclic aromatic hydrocarbons (PAHs) are combustion products of organic materials, mixtures of which contain multiple known and probable human carcinogens. PAHs occur in indoor and outdoor air, as well as in char-broiled meats and fish. Human exposure to PAHs occurs by inhalation, ingestion and topical absorption, and subsequently formed metabolites are either rendered hydrophilic and excreted, or bioactivated and bound to cellular macromolecules. The formation of PAH-DNA Adducts (DNA binding products), considered a necessary step in PAH-initiated carcinogenesis, has been widely studied in experimental models and has been documented in human tissues. This review describes immunohistochemistry (IHC) studies, which reveal localization of PAH-DNA Adducts in human tissues, and semi-quantify PAH-DNA Adduct levels using the Automated Cellular Imaging System (ACIS). These studies have shown that PAH-DNA Adducts concentrate in: basal and supra-basal epithelium of the esophagus, cervix and vulva; glandular epithelium of the prostate; and cytotrophoblast cells and syncitiotrophoblast knots of the placenta. The IHC photomicrographs reveal the ubiquitous nature of PAH-DNA Adduct formation in human tissues as well as PAH-DNA Adduct accumulation in specific, vulnerable, cell types. This semi-quantative method for PAH-DNA Adduct measurement could potentially see widespread use in molecular epidemiology studies.
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leukocyte polycyclic aromatic hydrocarbon DNA Adduct formation and colorectal adenoma
Carcinogenesis, 2007Co-Authors: Marc J Gunter, Rao L Divi, Martin Kulldorff, Roel Vermeulen, Kathryn J Haverkos, Maryanne M Kuo, Paul T Strickland, Miriam C. PoirierAbstract:Consumption of charbroiled red meat and meat-derived polycyclic aromatic hydrocarbons (PAHs) has been associated with risk of colorectal adenoma, a precursor of colorectal cancer. Furthermore, leukocyte PAH-DNA Adduct levels have been demonstrated to increase in response to charbroiled red meat intake but to date there have been no studies that have investigated the relationship between leukocyte PAH-DNA Adduct levels and risk of colorectal adenoma. We investigated the relation of leukocyte PAH-DNA Adduct formation and colorectal adenoma in a clinic-based case-control study of colorectal adenomas. The study comprised 82 cases of colorectal adenoma and 111 polyp-free controls, none of whom were current smokers. Leukocyte PAH-DNA Adducts were measured by a sensitive chemiluminescence immunoassay using an antiserum elicited against DNA modified with (+/-)-7beta,8alpha-dihydroxy-9alpha,10alpha-epoxy-7,8,9,10-tetrahydro-benzo[a]pyrene that recognizes several PAHs bound to human DNA. Leukocyte PAH-DNA Adduct levels were higher among colorectal adenoma cases (median, 1.4 Adducts per 10(8) nucleotides) than polyp-free controls (median, 1.2 Adducts per 10(8) nucleotides) (P = 0.02). There was a positive association between PAH-DNA Adduct level and adenoma prevalence: each unit increase in PAH-DNA Adduct level (per 10(8) nucleotides) was associated with an odds ratio (OR) of 1.5 [95% confidence interval (CI), 1.1-2.2]. In addition, a comparison of the lowest quartile for PAH-DNA Adduct level with the highest quartile yielded an OR of 2.8 (95% CI, 1.2-6.5; P(trend) = 0.048) for risk of colorectal adenoma. These data support a link between PAH exposure and colorectal adenoma.
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Hepatic DNA Adduct dosimetry in rats fed tamoxifen: A comparison of methods
Mutagenesis, 2005Co-Authors: Laura J. Schild, Mark Gaskell, Elizabeth Wright, Martin R Osborne, Karen Brown, Alan Hewer, Mona I. Churchwell, David H Phillips, Frederick A Beland, Miriam C. PoirierAbstract:Hepatic DNA Adduct dosimetry in rats fed tamoxifen: a comparison of methods Liver homogenates from rats fed tamoxifen (TAM) in the diet were shared among four different laboratories. TAM-DNA Adducts were assayed by high pressure liquid chromatography- electrospray tandem mass spectrometry (HPLC-ES-MS/MS), TAM-DNA chemiluminescence immunoassay (TAM-DNA CIA), and P-32- postlabeling with either thin layer (P-32-P-TLC) or liquid chromatography (P-32-P-HPLC) separation. In the first study, rats were fed a diet containing 500 p.p.m. TAM for 2 months, and the values for measurements of the (E)-alpha- (deoxyguanosin-N-2-yl)-tamoxifen (dG-N-2-TAM) Adduct in replicate rat livers varied by 3.5-fold when quantified using 'in house' TAM-DNA standards, or other approaches where appropriate. In the second study, rats were fed 0, 50, 250 or 500 p.p.m. TAM for 2 months, and TAM-DNA values were quantified using both 'in house' approaches as well as a newly synthesized [N-methyl-H-3]TAM-DNA standard that was shared among all the participating groups. In the second study, the total TAM-DNA Adduct values varied by 2-fold, while values for the dG-N-2-TAM varied by 2.5-fold. Ratios of dG-N-2-TAM:(E)-alpha- (deoxyguanosin-N-2-yl)-N-desmethyltamoxifen (dG-N-2-N- desmethyl-TAM) in the second study were similar to 1:1 over the range of doses examined. The study demonstrated a remarkably good agreement for TAM-DNA Adduct measurements among the diverse methods employed.
Ivonne M.c.m. Rietjens - One of the best experts on this subject based on the ideXlab platform.
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Molecular Dynamics and In Vitro Quantification of Safrole DNA Adducts Reveal DNA Adduct Persistence Due to Limited DNA Distortion Resulting in Inefficient Repair.
Chemical research in toxicology, 2020Co-Authors: Shuo Yang, Jakob D. H. Liu, Matthias Diem, Sebastiaan Wesseling, Jacques Vervoort, Chris Oostenbrink, Ivonne M.c.m. RietjensAbstract:The formation and repair of N2-(trans-isosafrol-3'-yl)-2'-deoxyguanosine (S-3'-N2-dG) DNA Adduct derived from the spice and herbal alkenylbenzene constituent safrole were investigated. DNA Adduct formation and repair were studied in vitro and using molecular dynamics (MD) simulations. DNA Adduct formation was quantified using liquid chromatography-mass spectrometry (LCMS) in wild type and NER (nucleotide excision repair) deficient CHO cells and also in HepaRG cells and primary rat hepatocytes after different periods of repair following exposure to safrole or 1'-hydroxysafrole (1'-OH safrole). The slower repair of the DNA Adducts found in NER deficient cells compared to that in CHO wild type cells indicates a role for NER in repair of S-3'-N2-dG DNA Adducts. However, DNA repair in liver cell models appeared to be limited, with over 90% of the Adducts remaining even after 24 or 48 h recovery. In our further studies, MD simulations indicated that S-3'-N2-dG Adduct formation causes only subtle changes in the DNA structure, potentially explaining inefficient activation of NER. Inefficiency of NER mediated repair of S-3'-N2-dG Adducts points at persistence and potential bioaccumulation of safrole DNA Adducts upon daily dietary exposure.
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Evaluation of Interindividual Human Variation in Bioactivation and DNA Adduct Formation of Estragole in Liver Predicted by Physiologically Based Kinetic/Dynamic and Monte Carlo Modeling
Chemical research in toxicology, 2016Co-Authors: Ans Punt, Benoît Schilter, Peter J. Van Bladeren, Alicia Paini, A. Spenkelink, Gabriele Scholz, Ivonne M.c.m. RietjensAbstract:Estragole is a known hepatocarcinogen in rodents at high doses following metabolic conversion to the DNA-reactive metabolite 1'-sulfooxyestragole. The aim of the present study was to model possible levels of DNA Adduct formation in (individual) humans upon exposure to estragole. This was done by extending a previously defined PBK model for estragole in humans to include (i) new data on interindividual variation in the kinetics for the major PBK model parameters influencing the formation of 1'-sulfooxyestragole, (ii) an equation describing the relationship between 1'-sulfooxyestragole and DNA Adduct formation, (iii) Monte Carlo modeling to simulate interindividual human variation in DNA Adduct formation in the population, and (iv) a comparison of the predictions made to human data on DNA Adduct formation for the related alkenylbenzene methyleugenol. Adequate model predictions could be made, with the predicted DNA Adduct levels at the estimated daily intake of estragole of 0.01 mg/kg bw ranging between 1.6 and 8.8 Adducts in 10(8) nucleotides (nts) (50th and 99th percentiles, respectively). This is somewhat lower than values reported in the literature for the related alkenylbenzene methyleugenol in surgical human liver samples. The predicted levels seem to be below DNA Adduct levels that are linked with tumor formation by alkenylbenzenes in rodents, which were estimated to amount to 188-500 Adducts per 10(8) nts at the BMD10 values of estragole and methyleugenol. Although this does not seem to point to a significant health concern for human dietary exposure, drawing firm conclusions may have to await further validation of the model's predictions.
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In vivo validation of DNA Adduct formation by estragole in rats predicted by physiologically based biodynamic modelling
Mutagenesis, 2012Co-Authors: Alicia Paini, Ans Punt, Bert Spenkelink, Benoît Schilter, Peter J. Van Bladeren, Gabriele Scholz, Eric Gremaud, Gerrit M. Alink, Ivonne M.c.m. RietjensAbstract:Estragole is a naturally occurring food-borne genotoxic compound found in a variety of food sources, including spices and herbs. This results in human exposure to estragole via the regular diet. The objective of this study was to quantify the dose-dependent estragoleDNA Adduct formation in rat liver and the urinary excretion of 1'-hydroxyestragole glucuronide in order to validate our recently developed physiologically based biodynamic (PBBD) model. Groups of male outbred Sprague Dawley rats (n = 10, per group) were administered estragole once by oral gavage at dose levels of 0 (vehicle control), 5, 30, 75, 150, and 300mg estragole/kg bw and sacrificed after 48h. Liver, kidney and lungs were analysed for DNA Adducts by LC-MS/MS. Results obtained revealed a dose-dependent increase in DNA Adduct formation in the liver. In lungs and kidneys DNA Adducts were detected at lower levels than in the liver confirming the occurrence of DNA Adducts preferably in the target organ, the liver. The results obtained showed that the PBBD model predictions for both urinary excretion of 1'-hydroxyestragole glucuronide and the guanosine Adduct formation in the liver were comparable within less than an order of magnitude to the values actually observed in vivo. The PBBD model was refined using liver zonation to investigate whether its predictive potential could be further improved. The results obtained provide the first data set available on estragoleDNA Adduct formation in rats and confirm their occurrence in metabolically active tissues, i.e. liver, lung and kidney, while the significantly higher levels found in liver are in accordance with the liver as the target organ for carcinogenicity. This opens the way towards future modelling of dose-dependent estragole liver DNA Adduct formation in human.
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A physiologically based biodynamic (PBBD) model for estragole DNA binding in rat liver based on in vitro kinetic data and estragole DNA Adduct formation in primary hepatocytes
Toxicology and applied pharmacology, 2010Co-Authors: Alicia Paini, Ans Punt, Benoît Schilter, Peter J. Van Bladeren, Thierry Delatour, Gabriele Scholz, Florian Viton, Maricel Marin-kuan, Ivonne M.c.m. RietjensAbstract:Estragole has been shown to be hepatocarcinogenic in rodent species at high-dose levels. Translation of these results into the likelihood of formation of DNA Adducts, mutation, and ultimately cancer upon more realistic low-dose exposures remains a challenge. Recently we have developed physiologically based biokinetic (PBBK) models for rat and human predicting bioactivation of estragole. These PBBK models, however, predict only kinetic characteristics. The present study describes the extension of the PBBK model to a so-called physiologically based biodynamic (PBBD) model predicting in vivo DNA Adduct formation of estragole in rat liver. This PBBD model was developed using in vitro data on DNA Adduct formation in rat primary hepatocytes exposed to 1'-hydroxyestragole. The model was extended by linking the area under the curve for 1'-hydroxyestragole formation predicted by the PBBK model to the area under the curve for 1'-hydroxyestragole in the in vitro experiments. The outcome of the PBBD model revealed a linear increase in DNA Adduct formation with increasing estragole doses up to 100 mg/kg bw. Although DNA Adduct formation of genotoxic carcinogens is generally seen as a biomarker of exposure rather than a biomarker of response, the PBBD model now developed is one step closer to the ultimate toxic effect of estragole than the PBBK model described previously. Comparison of the PBBD model outcome to available data showed that the model adequately predicts the dose-dependent level of DNA Adduct formation. The PBBD model predicts DNA Adduct formation at low levels of exposure up to a dose level showing to cause cancer in rodent bioassays, providing a proof of principle for modeling a toxicodynamic in vivo endpoint on the basis of solely in vitro experimental data.
R K Bhattacharya - One of the best experts on this subject based on the ideXlab platform.
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action of some retinol derivatives and their provitamins on microsome catalyzed formation of benzo a pyrene DNA Adduct
Journal of Biochemical Toxicology, 1992Co-Authors: G M Shah, U C Goswami, R K BhattacharyaAbstract:Several vitamin A compounds have been tested for their ability to suppress formation of DNA Adduct by the carcinogen benzo[a]pyrene (B[a]P) in an in vitro reaction catalyzed by rat liver microsomes. Retinol, retinal, 3-dehydroretinol and 3-hydroxyretinol were found to be effective inhibitors of Adduct formation. Certain carotenoids that are precursors of these retinoids also displayed considerable inhibitory capacity. Carotenoids and the 3-substituted retinoids appeared to modulate the DNA Adduct formation exclusively through their action on microsomal enzymes, since an effective inhibition in each case was observed on the formation of B[a]P-7,8-diol, a proximate carcinogenic metabolite of B[a]P. Unsubstituted retinoids, on the other hand, had marginal effect on enzymes but were found effective in accelerating inactivation of B[a]P-7,8-diol-9,10-epoxide, the ultimate carcinogenic metabolite that binds to DNA.
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Action of some retinol derivatives and their provitamins on microsome‐catalyzed formation of benzo[a]pyrene‐DNA Adduct
Journal of biochemical toxicology, 1992Co-Authors: G M Shah, U C Goswami, R K BhattacharyaAbstract:Several vitamin A compounds have been tested for their ability to suppress formation of DNA Adduct by the carcinogen benzo[a]pyrene (B[a]P) in an in vitro reaction catalyzed by rat liver microsomes. Retinol, retinal, 3-dehydroretinol and 3-hydroxyretinol were found to be effective inhibitors of Adduct formation. Certain carotenoids that are precursors of these retinoids also displayed considerable inhibitory capacity. Carotenoids and the 3-substituted retinoids appeared to modulate the DNA Adduct formation exclusively through their action on microsomal enzymes, since an effective inhibition in each case was observed on the formation of B[a]P-7,8-diol, a proximate carcinogenic metabolite of B[a]P. Unsubstituted retinoids, on the other hand, had marginal effect on enzymes but were found effective in accelerating inactivation of B[a]P-7,8-diol-9,10-epoxide, the ultimate carcinogenic metabolite that binds to DNA.
Lynn Vanhaecke - One of the best experts on this subject based on the ideXlab platform.
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DNA Adduct profiling of in vitro colonic meat digests to map red vs. white meat genotoxicity.
Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association, 2018Co-Authors: Lieselot Hemeryck, Caroline Rombouts, Ellen De Paepe, Lynn VanhaeckeAbstract:The consumption of red meat has been linked to an increased colorectal cancer (CRC) risk. One of the major hypotheses states that heme iron (present in red meat) stimulates the formation of genotoxic N-nitroso compounds (NOCs) and lipid peroxidation products (LPOs). By means of DNA Adductomics, chemically induced DNA Adduct formation can be mapped in relation to e.g. dietary exposures. In this study, this state-of-the-art methodology was used to investigate alkylation and (lipid per)oxidation induced DNA Adduct formation in in vitro red vs. white meat digests. In doing so, 90 alkylation and (lipid per)oxidation induced DNA Adduct types could be (tentatively) identified. Overall, 12 NOC- and/or LPO-related DNA Adduct types, i.e. dimethyl-T (or ethyl-T), hydroxymethyl-T, tetramethyl-T, methylguanine (MeG), guanidinohydantoin, hydroxybutyl-C, hydroxymethylhydantoin, malondialdehyde-x3-C, O6-carboxymethylguanine, hydroxyethyl-T, carboxyethyl-T and 3,N4-etheno-C were singled out as potential heme-rich meat digestion markers. The retrieval of these DNA Adduct markers is in support of the heme, NOC and LPO hypotheses, suggesting that DNA Adduct formation may indeed contribute to red meat related CRC risk.
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DNA Adduct markers associated with the gastrointestinal digestion of red meat
2017Co-Authors: Lynn Vanhaecke, Caroline Rombouts, Thomas Van Hecke, Stefaan De Smet, Els Vossen, Lieselot HemeryckAbstract:Epidemiological research has demonstrated that the consumption of red meat contributes to colorectal cancer (CRC) risk. At the time, the main hypothesis on the red meat-CRC relationship is based on the fact that red, but not white meat consumption, has been linked to CRC, and that red meat contains more heme iron than white meat. More specifically, the heme hypothesis states that the ingestion of heme iron stimulates the formation of N-nitroso compounds (NOCs) and lipid peroxidation products (LPOs). Both NOCs and LPOs can exert geno- as well as cytotoxic effects, and as such contribute to carcinogenesis. In this study, beef (model for red meat) and chicken (model for white meat) were digested in vitro (static model) as well as in vivo (Sprague-Dawley rats) to investigate the gastrointestinal formation of DNA Adducts upon red vs. white meat digestion. DNA Adduct formation was assessed by means of a state-of-the-art UHPLC-HRMS DNA Adductomics platform (Q-Exactive TM ) and in-house DNA Adduct database, after which univariate (e.g. t-test) as well as multivariate (e.g. OPLS-DA) statistics were employed for red meat associated DNA Adduct marker discovery. Combining the results from 3 independent in vitro and 1 in vivo digestion experiment(s), 7 DNA Adduct types, including O6-carboxymethylguanine, dimethyl- or ethylthymine, methylguanine, heptanalguanine, a malondialdehyde-guanine Adduct, and a malondialdehyde-cytosine Adduct could be singled out as potential red meat digestion markers. This is highly relevant to the red meat-CRC hypothesis because the formation of the retrieved DNA Adduct types may be linked to DNA alkylation and/or oxidation by e.g. NOCs and/or LPOs. Therefore, follow-up research should focus on the role of DNA Adduct formation in the red meat-CRC pathway, as well as the mutagenic potential and human in vivo relevance of the proposed DNA Adduct markers.
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Diet-related DNA Adduct formation in relation to carcinogenesis.
Nutrition reviews, 2016Co-Authors: Lieselot Hemeryck, Lynn VanhaeckeAbstract:The human diet contributes significantly to the initiation and promotion of carcinogenesis. It has become clear that the human diet contains several groups of natural foodborne chemicals that are at least in part responsible for the genotoxic, mutagenic, and carcinogenic potential of certain foodstuffs. Electrophilic chemicals are prone to attack nucleophilic sites in DNA, resulting in the formation of altered nucleobases, also known as DNA Adducts. Since DNA Adduct formation is believed to signal the onset of chemically induced carcinogenesis, the DNA Adduct-inducing potential of certain foodstuffs has been investigated to gain more insight into diet-related pathways of carcinogenesis. Many studies have investigated diet-related DNA Adduct formation. This review summarizes work on known or suspected dietary carcinogens and the role of DNA Adduct formation in hypothesized carcinogenesis pathways.
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o6 carboxymethylguanine DNA Adduct formation and lipid peroxidation upon in vitro gastrointestinal digestion of haem rich meat
Molecular Nutrition & Food Research, 2014Co-Authors: Julie Vanden Bussche, Thomas Van Hecke, Stefaan De Smet, Lieselot Hemeryck, Gunter G C Kuhnle, Frank Pasmans, Sharon A Moore, Tom Van De Wiele, Lynn VanhaeckeAbstract:Scope Epidemiological and clinical studies have demonstrated that the consumption of red haem-rich meat may contribute to the risk of colorectal cancer. Two hypotheses have been put forward to explain this causal relationship, i.e. N-nitroso compound (NOC) formation and lipid peroxidation (LPO). Methods and Results In this study, the NOC-derived DNA Adduct O6-carboxymethylguanine (O6-CMG) and the LPO product malondialdehyde (MDA) were measured in individual in vitro gastrointestinal digestions of meat types varying in haem content (beef, pork, chicken). While MDA formation peaked during the in vitro small intestinal digestion, alkylation and concomitant DNA Adduct formation was observed in seven (out of 15) individual colonic digestions using separate faecal inocula. From those, two haem-rich meat digestions demonstrated a significantly higher O6-CMG formation (p < 0.05). MDA concentrations proved to be positively correlated (p < 0.0004) with haem content of digested meat. The addition of myoglobin, a haem-containing protein, to the digestive simulation showed a dose–response association with O6-CMG (p = 0.004) and MDA (p = 0.008) formation. Conclusion The results suggest the haem-iron involvement for both the LPO and NOC pathway during meat digestion. Moreover, results unambiguously demonstrate that DNA Adduct formation is very prone to inter-individual variation, suggesting a person-dependent susceptibility to colorectal cancer development following haem-rich meat consumption.