DOCSLIB.ORG

Biomarkers of Exposure to Polycyclic Aromatic Hydrocarbons from Environmental Air Pollution

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Biomarkers of Exposure to Polycyclic Aromatic Hydrocarbons from Environmental Air Pollution 1of9 Occup Environ Med: first published as 10.1136/oem.2003.008375 on 18 March 2004. Downloaded from ELECTRONIC REVIEW Biomarkers of exposure to polycyclic aromatic hydrocarbons from environmental air pollution G Castan˜o-Vinyals, A D’Errico, N Malats, M Kogevinas ............................................................................................................................... Occup Environ Med 2004;61:e12 (http://www.occenvmed.com/cgi/content/full/61/4/e12). doi: 10.1136/oem.2003.008375 Metabolites of pyrene and DNA adducts have been used side-stream smoke. Levels from passive smoking are lower, ranging from 0.0028 to 0.76 mg/ m3 of as biomarkers of high level exposure to polycyclic aromatic B(a)P.6 Beside occupational exposure, dietary hydrocarbons (PAHs). A systematic review was performed intake seems the most important source of to evaluate whether these biomarkers are also valid PAHs in non-smokers; in the USA, dietary intake of total PAHs has been estimated to be almost markers of low level environmental exposure to PAHs. 2 mg/kg food,6 with high levels of B(a)P found Thirty five studies were identified with more than 10 especially in charcoaled meat (8 mg/kg), while in subjects that evaluated environmental air pollution to PAHs a variety of other food products B(a)P levels from 0.09 to 30 mg/kg67have been reported. Levels in in relation to metabolites of PAHs, mainly hydroxypyrene water may range from 0 to 13 mg/l B(a)P. There is (1-OHP), PAH-DNA adducts, or protein adducts. PAH a high variation in atmospheric PAHs levels metabolites and, to a less extent, PAH-DNA adducts across geographical areas with B(a)P concentra- 3 8 correlated well at the group level with exposure to B(a)P tions ranging from 0.01 to 100 ng/m B(a)P). Airborne PAHs are usually analysed by gas even at low levels of air pollution. The use of these chromatography/mass spectrometry910 or high biomarkers should be more widely implemented in performance liquid chromatography,11–14 mostly combination with more traditional techniques for the from particles collected in a filter after extraction with organic solvents. assessment of general population exposure to PAHs from Pollution of air by PAHs is mainly due to the ambient air pollution. incomplete combustion of wood or fuel used for ........................................................................... residential heating and industrial or motor vehicle exhaust.11 The level of exposure to PAHs through this source is low compared to other olycyclic aromatic hydrocarbons (PAHs) are sources such as diet, occupation, or tobacco a group of organic chemicals characterised smoke. The half-life of airborne PAHs is of the Pby chemical stability, low volatility, and low order of days but can be longer when they are solubility in water. PAHs are formed during the bound to small particles.2 In the cities where http://oem.bmj.com/ incomplete combustion of organic substances, residential heating is the main source of PAHs, are widespread in the environment, and typically air pollutant PAH levels during winter are occur in mixtures. Health damage associated frequently higher than in summer.15–17 Never- with PAH exposure has been evaluated repeat- theless, some studies that found very low levels edly by different health and environmental of B(a)P (range 0.03–3.3 ng/m3) did not show a protection agencies, such as the International seasonal variation.11 Agency for Research on Cancer (IARC), the Inhaled PAHs are absorbed mainly through Environmental Protection Agency (EPA), the the bronchial epithelium. Absorption can be on September 29, 2021 by guest. Protected copyright. National Toxicology Program (NTP), and the influenced by the size of the particles, with a Agency for Toxic Substances and Disease slower clearance of those adsorbed on particles Registry (ATSDR). Seven compounds, including compared to PAHs in pure crystals.18 19 After benzo(a)anthracene, benzo(b)fluoranthene, absorption, PAHs are distributed to tissues where benzo(j)fluoranthene, benzo(k)fluoranthene, they are biotransformed by phase I metabolic benzo(a)pyrene, dibenz(a,h)anthracene, and enzymes to chemically reactive intermediates, indeno(1,2,3-c,d)pyrene, are considered by See end of article for that may bind covalently to DNA (DNA adducts), several agencies as human carcinogens. authors’ affiliations give rise to mutation and, eventually, tumour ....................... The main sources of human exposure to PAHs initiation. Furthermore, PAH metabolites are are occupation, passive and active smoking, food Correspondence to: mostly conjugated with glucuronic acid by phase and water, and air pollution.1 The total intake of Dr M Kogevinas, II enzymes and excreted as hydroxylated meta- carcinogenic PAHs in the general population has Respiratory and bolites or in a small proportion as sulphate or Environmental Health been estimated to be 3 mg/day.2 Levels of even unconjugated. PAHs are excreted mainly Research Unit, Municipal occupational exposure of benzo(a)pyrene Institute of Medical through the faeces; only about 10% are excreted (B(a)P), which is one of the main PAH com- Reseach (IMIM), 80 Dr in the urine. Aiguader Rd, Barcelona pounds, vary widely in different industrial 08003, Spain; activities and job titles, ranging from 0.1 to kogevinas@imim 48 000 ng/m3.3–5 In smokers, B(a)P levels range ................................................... Accepted from 0.5 to 7.8 mg/100 cigarettes when exposure 5 September 2003 is from mainstream smoke and from 2.5 to Abbreviations: B(a)P, benzo(a)pyrene; PAH, polycyclic ....................... 19.9 mg/100 cigarettes when it comes from aromatic hydrocarbon www.occenvmed.com 2of9 Electronic review Occup Environ Med: first published as 10.1136/oem.2003.008375 on 18 March 2004. Downloaded from Main messages Policy implications N Existing biomarkers for environmental exposure to The use of biomarkers of exposure to environmental levels of PAHs correlate well at group level, with exposure to PAHs should be more widely implemented in combination B(a)P even at low levels of air pollution. with more traditional techniques for the assessment of N general population exposure to PAHs from ambient air This association is stronger for PAH metabolites, pollution. particularly hydroxypyrene, but is also observed for PAH-DNA adducts. N The use of these biomarkers when assessing environ- pyrene) AND (biological monitoring OR biomonitoring OR mental exposure at the individual level is limited. biological markers OR biomarker OR biomarkers)’’. In addition, we checked our personal archives and examined the references of the papers identified. The difficulty of finding an index substance arises from the In the first search, we found 723 articles that included both fact that the composition of PAH mixtures depends on the animal and human studies. We reviewed the abstracts and combustion source. The most common compound used as a primarily selected 122 papers, after excluding animal studies, reference substance for carcinogenic PAHs is benzo(a)pyrene reviews, and human studies with less than 10 subjects. We (B(a)P). B(a)P was the first PAH recognised to display further excluded studies on occupationally exposed subjects carcinogenic activity; more importantly, it has a high and two studies on environmental exposure to PAHs, because carcinogenic potency and is present in all environmental DNA adduct levels were presented in units non-comparable 17 30 media. to those of other studies. Furthermore, five studies on The most commonly used biomarkers of PAH exposure are 1-OHP were not included: two measured B(a)P metabolites 31 32 metabolites of PAHs, particularly 1-hydroxypyrene, and PAH- instead of 1-OHP, two reported 1-OHP levels in units not 33 34 DNA or protein adducts. 1-Hydroxypyrene (1-OHP) is the comparable to the rest of the studies, and the fifth study 35 principal product of pyrene metabolism, representing 90% of focused on intra- and inter-individual variability of 1-OHP. its metabolites.20 Following inhalation, the half-life of 1-OHP Finally, we included 36 studies of DNA and/or protein is on average about 18–20 hours.21–23 Pyrene is the only adducts or metabolites of PAHs that referred to exposure to 3 7–9 11–13 15–17 27 36–61 known precursor of 1-OHP;24 it forms a consistent proportion PAHs through environmental air pollution. of higher molecular weight PAHs in the environment.25 The In the selected studies, biomarker levels were presented for two main analytical methods employed to measure 1-OHP non-smokers or were adjusted for smoking, except for two 12 38 are high performance liquid chromatography combined with studies that did not indicate if results were adjusted, and 49 fluorescence detection (HPLC/FD), and gas chromatography another study that did not adjust for smoking habits. with mass spectrometry (GC/MS). For HPLC/FD, the detec- Among the 19 studies analysing 1-OHP, 12 included non- tion limit is 0.05 mg/l, with a recovery rate of 85%,26 and for smoking individuals. Eight studies on DNA adducts recruited GC/MS it is around 0.1 mg/l with a higher recovery rate that only non-smokers, and five also had determinations on reaches more than 93%.27 PAH adducts have been mainly protein adducts. employed as a measure of PAHs linked to DNA in target tissues (biological effective dose), although protein adducts Statistical analysis have also occasionally been determined. The half-life of DNA We estimated between study differences and correlated mean adducts in lymphocytes is in the order of months, while for biomarker levels with mean levels of B(a)P or the sum of http://oem.bmj.com/ protein adducts it depends on the type of protein where the eight carcinogenic PAHs in air (including benzo(a)anthra- chemical is bound. In the case of albumin adducts, the half- cene, benzo(b)fluoranthene, benzo(k)fluoranthene, chrysene, life is around 20 days, while for haemoglobin adducts it is benzo(a)pyrene, dibenzo(ah)anthracene, indeno(1,2,3-cd)- around 120 days.
Load more

Recommended publications
  • Escherichia Coli Responses to a Single DNA Adduct
    JOURNAL OF BACTERIOLOGY, Dec. 2000, p. 6598–6604 Vol. 182, No. 23 0021-9193/00/$04.00ϩ0 Copyright © 2000, American Society for Microbiology. All Rights Reserved. Escherichia coli Responses to a Single DNA Adduct GAGAN A. PANDYA,† IN-YOUNG YANG, ARTHUR P. GROLLMAN, AND MASAAKI MORIYA* Laboratory of Chemical Biology, Department of Pharmacological Sciences, SUNY at Stony Brook, Stony Brook, New York 11794-8651 Received 14 June 2000/Accepted 12 September 2000 To study the mechanisms by which Escherichia coli modulates the genotoxic effects of DNA damage, a novel system has been developed which permits quantitative measurements of various E. coli pathways involved in mutagenesis and DNA repair. Events measured include fidelity and efficiency of translesion DNA synthesis, excision repair, and recombination repair. Our strategy involves heteroduplex plasmid DNA bearing a single site-specific DNA adduct and several mismatched regions. The plasmid replicates in a mismatch repair- deficient host with the mismatches serving as strand-specific markers. Analysis of progeny plasmid DNA for linkage of the strand-specific markers identifies the pathway from which the plasmid is derived. Using this approach, a single 1,N6-ethenodeoxyadenosine adduct was shown to be repaired inefficiently by excision repair, to inhibit DNA synthesis by approximately 80 to 90%, and to direct the incorporation of correct dTMP opposite this adduct. This approach is especially useful in analyzing the damage avoidance-tolerance mechanisms. Our results also show that (i) progeny derived from the damage avoidance-tolerance pathway(s) accounts for more than 15% of all progeny; (ii) this pathway(s) requires functional recA, recF, recO, and recR genes, suggesting the mechanism to be daughter strand gap repair; (iii) the ruvABC genes or the recG gene is also required; and (iv) the RecG pathway appears to be more active than the RuvABC pathway.
    [Show full text]
  • 1 INTRODUCTION DNA Damage and Types of Repair DNA Is Subject to Various Types of Damage That Can Impair Cellular Function Leadin
    INTRODUCTION DNA damage and types of repair DNA is subject to various types of damage that can impair cellular function leading to cell death or carcinogenesis. DNA damage blocks normal cellular processes such as replication and transcription [1, 2]. Should DNA damage persist it can have catastrophic consequences for the cell and for the organism including mutagenesis, cancer, and cell death (i.e. in neurons). DNA damage may come from internal as well as external sources and is associated with various types of genetic diseases and cancers. Therefore DNA repair provides a mechanism to restore DNA nucleotide sequences to the native state. Several DNA repair pathways have been identified including base excision repair (BER), mismatch repair (MMR) and nucleotide excision repair (NER). The type of lesion will dictate which pathway is utilized for repair. For example an N7-methyl guanine residue can only be removed by BER, while a benzopyrene guanine adduct residue can only be removed by NER [3]. Nucleotide Excision Repair Nucleotide Excision Repair (NER) is a versatile DNA repair pathway because of its ability to repair a wide range of nucleotide adducts [4]. NER is responsible for the repair of bulky DNA damage lesions including cyclobutane pyrimidine dimers (CPDs) and 6-4 pyrimidine pyrimidone photoproducts (6-4PPs) caused by UV radiation [3, 5]. NER repairs platinum DNA adducts that are formed by cancer chemotherapeutic drugs such as cisplatin and carboplatin [1, 6, 7]. UV radiation and platinum compounds cause covalent linkage of adjacent thymine or guanine residues respectively. Aromatic 1 hydrocarbons, as found in cigarette smoke, cause guanine adducts that also require NER for their removal.
    [Show full text]
  • Slow Repair of Bulky DNA Adducts Along the Nontranscribed Strand of the Human P53 Gene May Explain the Strand Bias of Transversion Mutations in Cancers
    Oncogene (1998) 16, 1241 ± 1247 1998 Stockton Press All rights reserved 0950 ± 9232/98 $12.00 Slow repair of bulky DNA adducts along the nontranscribed strand of the human p53 gene may explain the strand bias of transversion mutations in cancers Mikhail F Denissenko1, Annie Pao2, Gerd P Pfeifer1 and Moon-shong Tang2 1Beckman Research Institute, City of Hope, Duarte, California 91010; 2University of Texas MD Anderson Cancer Center, Science Park-Research Division, Smithville, Texas 78957, USA Using UvrABC incision in combination with ligation- cancer development (Hollstein et al., 1991, 1996; Jones mediated PCR (LMPCR) we have previously shown that et al., 1991; Harris and Hollstein, 1993; Greenblatt et benzo(a)pyrene diol epoxide (BPDE) adduct formation al., 1994; Harris, 1996; Ruddon, 1995). along the nontranscribed strand of the human p53 gene is The p53 mutations found in human cancers are of highly selective; the preferential binding sites coincide various types, and occur at dierent sequences with the major mutation hotspots found in human lung (Greenblatt et al., 1994; Hollstein et al., 1996). More cancers. Both sequence-dependent adduct formation and than 200 mutated codons of the p53 gene have been repair may contribute to these mutation hotspots in identi®ed in various human cancers, and the types of tumor tissues. To test this possibility, we have extended mutations often seem to bear the signature of the our previous studies by mapping the BPDE adduct etiological agent (Greenblatt et al., 1994; Hollstein et distribution in the transcribed strand of the p53 gene and al., 1996). One of the most notable examples is lung quantifying the rates of repair for individual damaged cancer.
    [Show full text]
  • Chapter 1 Introduction
    The Cytotoxic Effects of Malondialdehyde on Human Lung Fibroblast Cells Sally Ann Yates A thesis submitted in partial fulfilment of the requirements of Liverpool John Moores University for the degree of Doctor of Philosophy March 2015 Abstract ABSTRACT Malondialdehyde (MDA) is a mutagenic and carcinogenic product of lipid peroxidation which has also been found at elevated levels in smokers. MDA reacts with nucleic acid bases to form pyrimidopurinone DNA adducts, of which 3-(2-deoxy-β-D-erythro- pentofuranosyl)pyrimidol[1,2-α]purin-10(3H)-one (M1dG) is the most abundant and has been linked to smoking. Mutations in the TP53 tumour suppressor gene are associated with half of all cancers. This research applied a multidisciplinary approach to investigate the toxic effects of MDA on the human lung fibroblasts MRC5, which have an intact p53 response, and their SV40 transformed counterpart, MRC5 SV2, which have a sequestered p53 response. Both cell lines were treated with MDA (0-1000 µM) for 24 and 48 h and subjected to a variety of analyses to examine cell proliferation, cell viability, cellular and nuclear morphology, apoptosis, p53 protein expression, DNA topography and M1dG adduct detection. For the first time, mutation sequencing of the 5’ untranslated region (UTR) of the TP53 gene in response to MDA treatment was carried out. The main findings were that both cell lines showed reduced proliferation and viability with increasing concentrations of MDA, the cell surface and nuclear morphology were altered, and levels of apoptosis and p53 protein expression appeared to increase. A LC-MS-MS method for detection of M1dG adducts was developed and adducts were detected in CT-DNA treated with MDA in a dose-dependent manner.
    [Show full text]
  • Targeted Mutations Induced by a Single Acetylaminofluorene DNA
    Proc. Nati. Acad. Sci. USA Vol. 85, pp. 1586-1589, March 1988 Genetics Targeted mutations induced by a single acetylaminofluorene DNA adduct in mammalian cells and bacteria (shuttle vector/mutagenesis) MASAAKI MORIYA*, MASARU TAKESHITA*, FRANCIS JOHNSON*, KEITH PEDENt, STEPHEN WILL*, AND ARTHUR P. GROLLMAN *Department of Pharmacological Sciences, State University of New York at Stony Brook, Stony Brook, NY 11794; and tHoward Hughes Medical Institute Laboratory, Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205 Communicated by Richard B. Setlow, November 2, 1987 ABSTRACT Mutagenic specificity of 2-acetylamino- lems were obviated by initiating mutagenesis with a defined fluorene (AAF) has been established in mammalian cells and DNA adduct introduced at a specific site in the genome and several strains of bacteria by using a shuttle plasmid vector by detecting the full spectrum of mutations by oligodeoxy- containing a single N-(deoxyguanosin-8-yl)acetylaminofluo- nucleotide hybridization. rene (C8-dG-AAF) adduct. The nucleotide sequence of the Viral and plasmid vectors containing specifically located gene conferring tetracycline resistance was modified by con- DNA adducts have been described (5-8); some ofthese have servative codon replacement so as to accommodate the se- been tested for mutagenic properties in bacteria (8-10). We quence d(CCTTCGCTAC) flanked by two restriction sites, have constructed a shuttle plasmid containing a single Bsm I and Xho I. The corresponding synthetic oligodeoxynu- "bulky" adduct, N-(deoxyguanosin-8-yl)acetylaminofluo- cleotide underwent reaction with 2-(N-acetoxy-N-acetylamino)- rene (C8-dG-AAF). This modified plasmid was allowed to fluorene (AAAF), forming a single dG-AAF adduct.
    [Show full text]
  • Health Effects of Chemical Mixtures: Benzo(A)Pyrene and Arsenic
    Health Effects of Chemical Mixtures: Benzo[a]pyrene and Arsenic Hasmik Hakobyan, Elizabeth Vaccaro and Hollie Migdol Department of Environmental & Occupational Health, California State University, Northridge Abstract Routes of Exposure Metabolism of Benzo[a]pyrene and Arsenic Arsenic and benzo[a]pyrene (BaP) are ubiquitous compounds commonly found throughout the environment. This poster is a review of the current literature examining the combined effects of arsenic and BaP to determine the mechanism of their synergistic qualities. Being exposed to both arsenic and BaP simultaneously in the environment is very likely. Vehicle exhaust, volcanoes, cigarette smoke, air pollution, industrial processes contaminated water and charred meats can contribute to the co-exposure to arsenic and BaP. The carcinogenicity of BaP occurs subsequent to the metabolic activation of the compound resulting in DNA damage via DNA-adduct formation. The literature indicates that the co-exposure to arsenic and BaP causes a synergistic reaction between to the two compounds, as arsenic potentiates BaP-DNA adducts. BaP DNA adduct formation. [18] Introduction Arsenic occurs in the environment naturally and it is Arsenic manmade. Arsenic sources are algaecides, mechanical cotton harvesting, glass manufacturing, herbicides, and nonferrous Dermal: Dermal exposure may lead to illness, but to a lesser extent alloys [2]. Arsenic trioxide may be found in pesticides and than ingestion or inhalation. [4] [9] defoliants and as a contaminant of moonshine whiskey [2]. Presently, arsenic is widely used in the electronics industry in Ingestion: Main intake of arsenic is through ingestion of food the form of gallium arsenide and arsine gas as components in containing arsenic.
    [Show full text]
  • Processed Meat Grilled Meat Bacon Air Pollution Car Exhaust
    Diet and Lifestyle Factors in Cancer Risk Robert J. Turesky, Ph.D. Professor Masonic Chair in Cancer Causation Masonic Cancer Center Department of Medicinal Chemistry Disclosure ⚫ I have no actual or potential conflict of interest in relation to this program/presentation. A lot of research focuses on agents that can cause cancer Drug Safety "Alle Dinge sind Gift und nichts ist ohne Gift; allein die Dosis macht, dass ein Ding kein Gift ist.” ( "All things are poison and nothing is without poison; only the dose makes a thing not a poison.” ) Paracelsus 1493-1541 Paracelsus (born Philippus Aureolus Theophrastus Bombastus von Hohenheim) Swiss physician, alchemist Diet and cancer: many cancers are caused by lifestyle factors, not genetics • Change in phyto- N-nitroso compounds estrogen profiles from from salted fish, plants, soy? pickled vegetables (nitrates) • Exposures to “new” carcinogens What are carcinogens? Carcinogens generally cause damage after repeated or long-duration exposure. They may not have immediate apparent harmful effects, with cancer developing only after a long latency period. Dose: amount and duration of exposure. The lower the dose the least likely you are to develop cancer or related diseases. Carcinogens increase the risk of cancer by altering cellular metabolism or damaging DNA directly in cells, by forming DNA adducts, which interfere with biological processes, and induce mutations resulting in the uncontrolled, malignant division, ultimately leading to the formation of tumors. Chemicals formed endogenously, i.e.
    [Show full text]
  • Excision of Oxidatively Generated Guanine Lesions by Competitive DNA Repair Pathways
    International Journal of Molecular Sciences Review Excision of Oxidatively Generated Guanine Lesions by Competitive DNA Repair Pathways Vladimir Shafirovich * and Nicholas E. Geacintov Chemistry Department, New York University, New York, NY 10003-5180, USA; [email protected] * Correspondence: [email protected] Abstract: The base and nucleotide excision repair pathways (BER and NER, respectively) are two major mechanisms that remove DNA lesions formed by the reactions of genotoxic intermediates with cellular DNA. It is generally believed that small non-bulky oxidatively generated DNA base modifi- cations are removed by BER pathways, whereas DNA helix-distorting bulky lesions derived from the attack of chemical carcinogens or UV irradiation are repaired by the NER machinery. However, existing and growing experimental evidence indicates that oxidatively generated DNA lesions can be repaired by competitive BER and NER pathways in human cell extracts and intact human cells. Here, we focus on the interplay and competition of BER and NER pathways in excising oxidatively generated guanine lesions site-specifically positioned in plasmid DNA templates constructed by a gapped-vector technology. These experiments demonstrate a significant enhancement of the NER yields in covalently closed circular DNA plasmids (relative to the same, but linearized form of the same plasmid) harboring certain oxidatively generated guanine lesions. The interplay between the BER and NER pathways that remove oxidatively generated guanine lesions are reviewed and discussed in terms of competitive binding of the BER proteins and the DNA damage-sensing NER Citation: Shafirovich, V.; Geacintov, factor XPC-RAD23B to these lesions. N.E. Excision of Oxidatively Generated Guanine Lesions by Keywords: DNA damage; base excision repair; nucleotide excision repair; oxidative stress; reactive Competitive DNA Repair Pathways.
    [Show full text]
  • Oxaliplatin–DNA Adducts As Predictive Biomarkers of FOLFOX
    Published OnlineFirst February 6, 2020; DOI: 10.1158/1535-7163.MCT-19-0133 MOLECULAR CANCER THERAPEUTICS | COMPANION DIAGNOSTIC, PHARMACOGENOMIC, AND CANCER BIOMARKERS Oxaliplatin–DNA Adducts as Predictive Biomarkers of FOLFOX Response in Colorectal Cancer: A Potential Treatment Optimization Strategy Maike Zimmermann1,2, Tao Li1, Thomas J. Semrad1,3, Chun-Yi Wu4, Aiming Yu4, George Cimino2, Michael Malfatti5, Kurt Haack5, Kenneth W. Turteltaub5, Chong-xian Pan1,6,7, May Cho1, Edward J. Kim1, and Paul T. Henderson1,2 ABSTRACT ◥ FOLFOX is one of the most effective treatments for advanced enabled quantification of oxaliplatin–DNA adduct level with accel- colorectal cancer. However, cumulative oxaliplatin neurotoxicity erator mass spectrometry (AMS). Oxaliplatin–DNA adduct forma- often results in halting the therapy. Oxaliplatin functions predom- tion was correlated with oxaliplatin cytotoxicity for each cell line as inantly via the formation of toxic covalent drug–DNA adducts. We measured by the MTT viability assay. Six colorectal cancer hypothesize that oxaliplatin–DNA adduct levels formed in vivo in patients received by intravenous route a diagnostic microdose peripheral blood mononuclear cells (PBMC) are proportional to containing [14C]oxaliplatin prior to treatment, as well as a second tumor shrinkage caused by FOLFOX therapy. We further hypoth- [14C]oxaliplatin dose during FOLFOX chemotherapy, termed a esize that adducts induced by subtherapeutic “diagnostic micro- “therapeutic dose.” Oxaliplatin–DNA adduct levels from PBMC doses” are proportional to those induced by therapeutic doses correlated significantly to mean tumor volume change of evaluable and are also predictive of response to FOLFOX therapy. These target lesions (5 of the 6 patients had measurable disease). Oxali- hypotheses were tested in colorectal cancer cell lines and a pilot platin–DNA adduct levels were linearly proportional between clinical study.
    [Show full text]
  • Polycyclic Aromatic Hydrocarbon-DNA Adducts in Human Lung and Cancer Susceptibility Genes P
    (CANCER RESEARCH 53, 3486-3492, August 1. 19931 Polycyclic Aromatic Hydrocarbon-DNA Adducts in Human Lung and Cancer Susceptibility Genes P. G. Shields,1 E. D. Bowman, A. M. Harrington, V. T. Doan, and A. Weston Laboratory- of Human Carcinogenesis, Division of Cancer Etiology, National Cancer Institute. Bethesda, Mailand 20892 ABSTRACT tency in laboratory animal studies exists (9). Human studies have associated PAH exposure, which typically occurs as complex mix Molecular dosimetry for polycyclic aromatic hydrocarbon-DNA ad- tures, with skin and lung cancers (7). Increased sister chromatid ex ducts, genetic predisposition to cancer, and their interrelationships are change frequency also occurs (10). PAHs form DNA adducts via a under study in numerous laboratories. This report describes a modified •¿"P-postlabelingassayfor the detection of polycyclic aromatic hydrocar complex metabolic activation pathway that includes CYP1A1, ep- bon-DNA adducts that uses immunoaffmity chromatography to enhance oxide hydroxylase, CYP3A4, and other enzymes (11). However, in chemical specificity and quantitative reliability. The assay incorporates termediate metabolites can be detoxified through pathways beginning internal standards to determine direct molar ratios of adducts to unmod with GST/x. Thus, the measurement of PAH-DNA adducts would ified nucleotides and to assess T4 polynucleotide kinase labeling efficiency. provide indications of exposure as well as the net success of compet High performance liquid chromatography is used to assure adequacy of ing metabolic and detoxification pathways. DNA enzymatic digestion. The assay was validated using radiolabeled The 32P-postlabeling assay is considered to be one of the most benzoloIpyrene-diol-epoxide modified DNA (r = 0.76, P < 0.05) thereby sensitive procedures for the detection of carcinogen-DNA adducts assessing all variables from enzymatic digestion to detection.
    [Show full text]
  • Chemical Biology of 6-Nitrochrysene Induced Deoxyadenosine DNA Adduct and Formamidopyrimidine DNA Lesion: Mutagenesis and Genotoxicity in E
    University of Connecticut OpenCommons@UConn Doctoral Dissertations University of Connecticut Graduate School 1-7-2020 Chemical Biology of 6-Nitrochrysene Induced Deoxyadenosine DNA Adduct and Formamidopyrimidine DNA Lesion: Mutagenesis and Genotoxicity in E. coli and Human Cells Brent V. Powell University of Connecticut, [email protected] Follow this and additional works at: https://opencommons.uconn.edu/dissertations Recommended Citation Powell, Brent V., "Chemical Biology of 6-Nitrochrysene Induced Deoxyadenosine DNA Adduct and Formamidopyrimidine DNA Lesion: Mutagenesis and Genotoxicity in E. coli and Human Cells" (2020). Doctoral Dissertations. 2398. https://opencommons.uconn.edu/dissertations/2398 Chemical Biology of 6-Nitrochrysene Induced Deoxyadenosine DNA Adduct and Formamidopyrimidine DNA Lesion: Mutagenesis and Genotoxicity in E. coli and Human Cells Brent Valentine Powell, Ph.D. University of Connecticut, 2020 The environmental pollutant, 6-nitrochrysene (6-NC) is the most potent carcinogen evaluated by the newborn mouse assay. The genotoxicity of 6-NC is derived from its ability to form electrophilic species in cells which can react with nucleophilic sites of 2'-deoxyguanosine (dG) and 2’-deoxyadenosine (dA) in DNA to generate DNA-carcinogen adducts. DNA lesions derived from 6-NC can play important roles in the development of human cancer by inducing mutations in crucial genes resulting in the disruption of gene expression. Mutations in an oncogene, a tumor- suppressor gene such as p53, or a gene that controls the cell cycle can lead to uncontrolled cell growth, resulting in carcinogenesis, a process which ultimately gives rise to human cancer. Most of these mutations arise through error-prone mutagenic bypass of the lesions which is enabled by low fidelity translesion synthesis (TLS) DNA polymerases.
    [Show full text]
  • Genotoxicity of Adduct Forming Mutagen Benzo(A)Pyrene in Tradescantia B
    PL9700249 10 Section VII 3. A. Cebulska-Wasilewska, S. Macugowski, H. Pluciennik, R. Smoliiiski. Report IFJ No 1511/B, 7-27, 1990; 4. A. Cebulska-Wasilewska, J. Smagala, Raport IFJ No 1511/B, 53-63, 1990; 5. W. Wajda, A. Cebulska-Wasilewska, (in Polish), in: Are Chemicals More Hazardous to Environ- ment than Radiation?, Ed.: A. Cebulska-Wasilewska, Raport IF.] No 1511/B, 63-Hl, 1990; 6. A. Cebulska-Wasilewska, J. Huczkowski H. Pluciennik, (in Polish), in: Are Chemicals More Ha- zardous to Environment than Radiation?, Ed.: A. Cebulska-Wasilewska, Raport IF.J No 1511/B. 93-98, 1990; 7. A. Cebulska-Wasilewska, H. Pluciennik, A. Wierzewska, E. Kasper, B. Krzykwa, Annual Rep. 1NP, Cracow, p. 311-313 (1992); 8. A. Cebulska-Wasilewska, H. Pluciennik, A. Wierzewska, Proc. of Conf. on Env. Mutagenesis in Human Populations at Risk, Cairo, p. 41 (1992); 9. E, Carbonell, N. Xamena, A. Creus, R. Marcos, Mutagenesis 8, 511-517 (1993); 10. J. Major, G. Kemeny, A. Tompa, Acta Medica Hungarica 49, 79-90 (1993). Genotoxicity of Adduct Forming Mutagen Benzo(a)pyrene in Tradescantia B. Paika, M. Litwiniszyn, and A. Cebulska-Wasilewska Polycyclic aromatic hydrocarbons (PAH) are present among other by-products of combus- tion processes and they are ubiquitous pollutants of our environment. Benzo(a)pyrene (BaP) belonging to this class of compounds is a widely distributed environmental carcinogen that has DNA-damaging and mutagenic properties. Mutations that are formed as a consequence of induced DNA damage are very important for the process of cancer development. Since the relationship between DNA damage and mutation fixation is not always clear, there is a need to investigate a correlation between genotoxic effects on molecular and cellular levels.
    [Show full text]