Outdoor air pollution and DNA damage.
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Air Pollutants↗
Biomedical subjects
D M DeMarini
Publications and source records attributed to D M DeMarini.
The DeltauvrB mutations in the Ames strains of Salmonella span 15 to 119 genes.
The DeltauvrB mutations present in strains of Salmonella enterica Typhimurium used commonly in the Salmonella (Ames) mutagenicity assay were isolated independently for at least five different his mutants. These deletions all involved the galactose operon, biotin operon, nucleotide-excision-repair uvrB gene, and chlorate-resistance genes. Beyond this, the size of the deletions and the number and type of genes deleted have remained unknown for nearly 30 years. Here, we have used genomic hybridization to a Typhimurium microarray to characterize these five DeltauvrB deletions. The number of genes (and amount of DNA) deleted due to the DeltauvrB mutations are 15 (16kb) each in TA97 and TA104, 47 (50kb) in TA100, 87 (96kb) in TA1537, and 119 (125kb) in TA98, accounting for 0.3, 0.3, 1.0, 1.9, and 2.6% of the genome, respectively. In addition, TA97 and TA104 contain an identical three-gene deletion elsewhere in their genomes, and, most remarkably, TA104 contains a 282-gene amplification, representing 7% of the genome. Missing genes include mfdA and mdaA, encoding a multi-drug translocase and a major nitroreductase, respectively, both absent in TA98; dps, encoding a DNA-binding protein absent in TA1537 and TA98; and dinG, encoding a lexA-regulated repair enzyme, absent in three DeltauvrB lineages. Genes involved in molybdenum cofactor biosynthesis and a number of ORFs of unknown functions are missing in all DeltauvrB strains investigated. Studies in DeltauvrB strains of Escherichia coli have found that the enhanced mutagenesis of some base analogues was due to the deletion of genes involved in molybdenum cofactor biosynthesis rather than to deletion of uvrB. These discoveries do not diminish the value of the data generated in the Ames strains. However, absence of genes other than uvrB may account for the enhanced mutagenicity of some compounds in DeltauvrB Ames strains. In general, microarrays will be useful for characterizing the extent and nature of deletion and amplification mutations.
DNA Helicases↗
Lung tumor KRAS and TP53 mutations in nonsmokers reflect exposure to PAH-rich coal combustion emissions.
We determined the TP53 and codon 12 KRAS mutations in lung tumors from 24 nonsmokers whose tumors were associated with exposure to smoky coal. Among any tumors studied previously, these showed the highest percentage of mutations that (a) were G --> T transversions at either KRAS (86%) or TP53 (76%), (b) clustered at the G-rich codons 153-158 of TP53 (33%), and (c) had 100% of the guanines of the G --> T transversions on the nontranscribed strand. This mutation spectrum is consistent with an exposure to polycyclic aromatic hydrocarbons, which are the primary component of the smoky coal emissions. These results show that mutations in the TP53 and KRAS genes can reflect a specific environmental exposure.
Air Pollution, Indoor↗
The antimutagenic effect of vanillin and cinnamaldehyde on spontaneous mutation in Salmonella TA104 is due to a reduction in mutations at GC but not AT sites.
Vanillin (VAN) and cinnamaldehyde (CIN) are dietary antimutagens that, when added to assay plates, reduced the spontaneous mutant frequency in Salmonella typhimurium strain TA104 (hisG428, rfa, uvrB, pKM101) by 50%. To date, no study has demonstrated whether or not the antimutagenic effects of an agent are due to a reduction in all classes of mutations or to a reduction in selective classes of mutations. To explore this issue, we have determined the spontaneous mutation spectrum in TA104 as well as the mutation spectrum after treatment of cells with antimutagens at concentrations that produced approximately a 50% reduction in mutant frequency but only a 10% reduction in survival. Statistical analysis revealed no significant difference between the mutation spectra of VAN- and CIN-treated cells. Relative to untreated cells, treatment with either VAN or CIN produced a significant reduction in mutations at GC sites, whereas neither compound produced a significant reduction in mutations at AT sites. Antimutagenesis experiments in hisG428 strains of Salmonella with varying DNA repair backgrounds showed that VAN and CIN require SOS repair genes to produce an antimutagenic effect against spontaneous mutagenesis. Studies evaluating the effect of VAN and CIN on growth rate showed that neither compound suppressed growth relative to untreated cells. To our knowledge, this is the first study to examine if an antimutagen reduced all or just some classes of mutations that were available for reduction.
AT Rich Sequence↗
Spontaneous and MNNG-induced reversion of an EGFP construct in HeLa cells: an assay for observing mutations in living cells by fluorescent microscopy.
A HeLa cell line stably expressing the enhanced green fluorescence protein (EGFP) gene, interrupted by the HBB IVS2-654 intron, was studied without treatment and after treatment with a single standard dose of 15 microM of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). This assay was done in order to prove that such a construct can revert by a variety of mechanisms and that it produces a visible phenotype, i.e., green fluorescence. The system permits visual detection of living mutant cells among a background of non-mutant cells and does not require a selective medium. The results show that the construct reverts by large deletions (-62, -100, and -162 bp), small insertions (+4 bp), small rearrangements (19 bp duplication), base substitutions at purines (G652, G653, A655, G579), and a pyrimidine (T654) between nucleotide positions 579 and 837. Splice-site mutations were recovered, and some of the mechanisms underlying these mutations are discussed. Because of the ease of detection of revertant cells under fluorescent light and the wide variety of mutations that can be recovered, further development of this system could make it a useful new mammalian cell mutagenicity assay.
Base Sequence↗
Mutagenicity in lung of big Blue((R)) mice and induction of tandem-base substitutions in Salmonella by the air pollutant peroxyacetyl nitrate (PAN): predicted formation of intrastrand cross-links.
Peroxyacetyl nitrate (PAN) is a ubiquitous air pollutant formed from NO(2) reacting with acetoxy radicals generated from ambient aldehydes in the presence of sunlight and ozone. It contributes to eye irritation associated with photochemical smog and is present in most urban air. PAN was generated in a chamber containing open petri dishes of Salmonella TA100 (gas-phase exposure). After subtraction of the background mutation spectrum, the spectrum of PAN-induced mutants selected at 3.1-fold above the background mutant yield was 59% GC-->TA, 29% GC-->AT, 2% GC-->CG, and 10% multiple mutations - primarily GG-->TT tandem-base substitutions. Using computational molecular modeling methods, a mechanism was developed for producing this unusual tandem-base substitution. The mechanism depends on the protonation of PAN near the polyanionic DNA to release NO(2)(+) resulting in intrastrand dimer formation. Insertion of AA opposite the dimerized GG would account for the tandem GG-->TT transversions. Nose-only exposure of Big Blue((R)) mice to PAN at 78ppm (near the MTD) was mutagenic at the lacI gene in the lung (mutant frequency +/-S.E. of 6.16+/-0.58/10(5) for controls versus 8.24+/-0.30/10(5) for PAN, P=0.016). No tandem-base mutations were detected among the 40 lacI mutants sequenced. Dosimetry with 3H-PAN showed that 24h after exposure, 3.9% of the radiolabel was in the nasal tissue, and only 0.3% was in the lung. However, based on the molecular modeling considerations, the labeled portion of the molecule would not have been expected to have been bound covalently to DNA. Our results indicate that PAN is weakly mutagenic in the lungs of mice and in Salmonella and that PAN produces a unique signature mutation (a tandem GG-->TT transversion) in Salmonella that is likely due to a GG intrastrand cross-link. Thus, PAN may pose a mutagenic and possible carcinogenic risk to humans, especially at the high concentrations at which it is present in some urban environments.
Air Pollutants↗
Mutation spectra in Salmonella of analogues of MX: implications of chemical structure for mutational mechanisms.
We determined the mutation spectra in Salmonella of four chlorinated butenoic acid analogues (BA-1 through BA-4) of the drinking water mutagen 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) and compared the results with those generated previously by us for MX and a related compound, MCF. We then considered relationships between the properties of mutagenic potency and mutational specificity for these six chlorinated butenoic acid analogues. In TA98, the three most potent mutagens, BA-3, BA-4, MX, and the organic extract, all induced large percentages of complex frameshifts (33-67%), which distinguish these agents from any other class of compound studied previously. In TA100, which has only GC sites for mutation recovery, >71% of the mutations induced by all of the agents were GC-->TA transversions. The availability of both GC and TA sites for mutation in TA104 resulted in greater distinctions in mutational specificity than in TA100. MX targeted GC sites almost exclusively (98%); the structurally similar BA-4 and BA-2 produced mutations at similar frequencies at both GC and AT sites; and the structurally similar BA-3 and BA-1 induced most mutations at AT sites (69%). Thus, large variations in structural properties influencing relative mutagenic potency appeared to be distinct from the more localized similar structural features influencing mutagenic specificity in TA104. Among a set of physicochemical properties examined for the six butenoic acids, a significant correlation was found between pK(a) and mutagenic potency in TA100, even when the unionized fraction of the activity dose was considered. In addition, a correlation in CLOGP for BA-1 to BA-4 suggested a role for bioavailability in determining mutagenic potency. These results illustrate the potential value of structural analyses for exploring the relationship between chemical structure and mutational mechanisms. To our knowledge, this is the first study in which such analyses have been applied to structural analogues for which both mutagenic potency and mutation spectra date were available.
Base Sequence↗
Influence of DNA repair on mutation spectra in Salmonella.
This paper reviews the influence of DNA repair on spontaneous and mutagen-induced mutation spectra at the base-substitution (hisG46) and -1 frameshift (hisD3052) alleles present in strains of the Salmonella (Ames) mutagenicity assay. At the frameshift allele (mostly a CGCGCGCG target), DeltauvrB influences the frequency of spontaneous hotspot mutations (-CG), duplications, and deletions, and it also shifts the sites of deletions and duplications. Cells with pKM101+DeltauvrB spontaneously produce complex frameshifts (frameshifts with an adjacent base substitution). The spontaneous frequency of 1-base insertions or concerted (templated) mutations is unaffected by DNA repair, and neither mutation is inducible by mutagens. Glu-P-1, 1-nitropyrene (1NP), and 2-acetylaminofluorene (2AAF) induce only hotspot mutations and are unaffected by pKM101, whereas benzo(a)pyrene and 4-aminobiphenyl induce only hotspot in pKM101(-), and hotspot plus complex in pKM101(+). At the base-substitution allele (mostly a CC/GG target), the DeltauvrB allele increases spontaneous transitions in the absence of pKM101 and increases transversions in its presence. The frequency of suppressor mutations is decreased 4x by DeltauvrB, but increased 7. 5x by pKM101. Both repair factors cause a shift in the proportion of mutations to the second position of the CC/GG target. With UV light and gamma-rays, the DeltauvrB allele increases the proportion of transitions relative to transversions. pKM101 is required for mutagenesis by Glu-P-1 and 4-AB, and the types and positions of the substitutions are not altered by the addition of the DeltauvrB allele. Changes in DNA repair appear to cause more changes in spontaneous than in mutagen-induced mutation spectra at both alleles. There is a high correlation (r(2)=0.8) between a mutagen's ability to induce complex frameshifts and its relative base-substitution/frameshift mutagenic potency. A mutagen induces the same primary class of base substitution in TA100 (DeltauvrB, pKM101) as it does in Escherichia coli, mammalian cells, or rodents as well as in the p53 gene of human tumors associated with exposure to that mutagen. Thus, a mutagen induces the same primary class of base substitution in most organisms, reflecting the conserved nature of DNA replication and repair processes.
Alleles↗
Mutation spectra of the drinking water mutagen 3-chloro-4-methyl-5-hydroxy-2(5H)-furanone (MCF) in Salmonella TA100 and TA104: comparison to MX.
The chlorinated drinking water mutagen 3-chloro-4-methyl-5-hydroxy-2(5H)-furanone (MCF) occurs at concentrations similar to or greater than that of the related furanone 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX). MCF and MX differ structurally only by replacement of a 3-methyl in MCF with a 3-dichloromethyl in MX; yet, MCF is significantly less mutagenic than MX and produces different adducts when reacted with nucleosides or DNA. To explore further the effects that these structural differences might have on the biological activity of MCF and MX, we determined the mutation spectra of MCF in Salmonella strains TA100 and TA104 and of MX in strain TA104; the spectrum of MX in TA100 had been determined previously. In TA100, which presents only GC targets for mutagenesis, MCF induced primarily (75%) GC --> TA transversions, with most of the remaining revertants (20%) being GC --> AT transitions. This spectrum was not significantly different from that of MX in TA100 (P = 0.07). In TA104, which presents both GC and AT targets, MCF induced a lower percentage (57%) of GC --> TA transversions, with most of the remaining revertants (33%) being AT --> TA transversions. In contrast, MX induced almost only (98%) GC --> TA transversions in TA104, with the remaining revertants (2%) being AT --> TA transversions. Thus, almost all (98%) of the MX mutations were targeted at GC sites in TA104, whereas only 63% of the MCF mutations were so targeted. These results are consistent with the published findings that MX: (1) forms an adduct on guanosine when reacted with guanosine, (2) induces apurinic sites in DNA, and (3) forms a minor adduct on adenosine when reacted with adenosine or DNA. The results are also consistent with evidence that MCF forms adenosine adducts when reacted with adenosine. Our results show that the replacement of the 4-methyl in MCF with a 4-dichloromethyl to form MX not only increases dramatically the mutagenic potency but also shifts significantly the mutagenic specificity from almost equal targeting of GC and AT sites by MCF to almost exclusive targeting of GC sites by MX. Environ. Mol. Mutagen. 35:106-113, 2000 Published 2000 Wiley-Liss, Inc.
Alleles↗
Induction of sister chromatid exchanges in human peripheral blood lymphocytes by bromoform: investigation of the role of GSTT1-1 polymorphism.
Brominated trihalomethanes (THMs) are disinfection by-products present frequently in chlorinated drinking water. Brominated THMs are mutagenic in a variety of systems and are carcinogenic in rodents. The metabolism of brominated THMs is thought to involve a GSH conjugation reaction leading either to formaldehyde or DNA-reactive intermediates via glutathione S-transferase-theta (GSTT1-1), which is polymorphic in humans. In the present study, we have determined the genotoxicity of one of the brominated THMs, bromoform (BF), by measuring its ability to induce sister chromatid exchanges (SCEs) in whole-blood (WB) cultures of human peripheral blood lymphocytes from GSTT1-1+ and GSTT1-1- donors. The results showed no differences in SCEs per cell by BF between GSTT1-1+ and GSTT1-1- individuals when the cells were exposed to 5 x 10(-3) M BF at the beginning of cell culturing (10.8+/-0.85 vs. 10.57+/-0.47, respectively), at the 16th (9.66+/-0.91 vs. 9.57+/-0.07), or the 24th h (8.21+/-0.61 vs. 8.29+/-0.24) of cell growth. Although GSTT1-1 is expressed in the erythrocytes, the lack of expression of the GSTT1-1 gene in the target cells (lymphocytes) may account for this observation.
Adult↗
Mutation spectra in Salmonella TA98, TA100, and TA104 of two phenylbenzotriazole mutagens (PBTA-1 and PBTA-2) detected in the Nishitakase River in Kyoto, Japan.
Previous studies have identified two potent aromatic amine mutagens in the Nishitakase River, a tributary of the Yodo River, which serves as the main drinking water supply for the Osaka area in Japan. The two potent mutagens are 2-[2-(acetylamino)-4-[bis(2-methoxyethyl)amino]-5-methoxyphenyl]-5-am ino-7-bromo-4-chloro-2H-benzotriazole (PBTA-1) and 2-[2-(acetylamino)-4-[N-(2-cyanoethyl)ethylamino]-5-methoxyphenyl]-5- amino-7-bromo-4-chloro-2H-benzotriazole (PBTA-2). PBTA-1 and PBTA-2 are presumed to be formed from azo dyes discharged in a reduced form from dye factories to sewage treatment plants where they become chlorinated and are then discharged into the river. PBTA-1 and PBTA-2 account for 21% and 17% of the mutagenic activity of the Nishitakase River, respectively. Here we determined the mutation spectra induced by these two mutagens in TA98, TA100, and TA104 at 30-35, 8-10, and 2x, respectively, above the background. In TA98, the PBTA compounds produced identical mutation spectra, with 100% of the revertants containing the hotspot 2-base deletion of CG within the (CG)(4) sequence. In TA100, 73% of the revertants were GC-->TA transversions, with most of the remaining being GC-->AT transitions; the spectra produced by the two compounds in TA100 were not significantly different (p=0.8). In TA104, as in TA100, the majority (83%-87%) of the revertants were GC-->TA transversions, with most of the remaining revertants (11%-13%) being AT-->TA transversions. Thus, 83%-87% of the mutations induced by the PBTA compounds in TA104 were at G/C sites. The mutation spectra produced by the two compounds in TA104 were not significantly different (p0.08). PBTA-1 and PBTA-2 are structurally similar and have similar mutagenic potencies and mutation spectra in the respective strains. The mutation spectra produced by the PBTA compounds (100% hotspot deletion in TA98 and primarily GC-->TA transversions in TA100 and TA104) are similar to those produced by other potent aromatic amines, which is the class of compounds from which the PBTA mutagens derive.
Base Pairing↗
Comparison of cytogenetic effects of 3,4-epoxy-1-butene and 1,2:3, 4-diepoxybutane in mouse, rat and human lymphocytes following in vitro G0 exposures.
To understand better the species differences in carcinogenicity caused by 1,3-butadiene (BD), we exposed G0 lymphocytes (either splenic or peripheral blood) from rats, mice and humans to 3, 4-epoxy-1-butene (EB) (20 to 931 microM) or 1,2:3,4-diepoxybutane (DEB) (2.5 to 320 uM), two of the suspected active metabolites of BD. Short EB exposures induced little measurable cytogenetic damage in either rat, mouse, or human G0 lymphocytes as measured by either sister chromatid exchange (SCE) or chromosome aberration (CA) analyses. However, DEB was a potent inducer of both SCEs and CAs in G0 splenic and peripheral blood lymphocytes. A comparison of the responses among species showed that the rat and mouse were approximately equisensitive to the cytogenetic damaging effects of DEB, but the situation for the human subjects was more complex. The presence of the GSTT1-1 gene (expressed in the erythrocytes) reduced the relative sensitivity of the lymphocytes to the SCE-inducing effects of DEB. However, additional factors also appear to influence the genotoxic response of humans to DEB. This study is the first direct comparison of the genotoxicity of EB and DEB in the cells from all three species.
Animals↗
Ionizing radiation-induced mutagenesis: radiation studies in Neurospora predictive for results in mammalian cells.
Ionizing radiation was the first mutagen discovered and was used to develop the first mutagenicity assay. In the ensuing 70+ years, ionizing radiation became a fundamental tool in understanding mutagenesis and is still a subject of intensive research. Frederick de Serres et al. developed and used the Neurospora crassa ad-3 system initially to explore the mutagenic effects of ionizing radiation. Using this system, de Serres et al. demonstrated the dependence of the frequency and spectra of mutations induced by ionizing radiation on the dose, dose rate, radiation quality, repair capabilities of the cells, and the target gene employed. This work in Neurospora predicted the subsequent observations of the mutagenic effects of ionizing radiation in mammalian cells. Modeled originally on the mouse specific-locus system developed by William L. Russell, the N. crassa ad-3 system developed by de Serres has itself served as a model for interpreting the results in subsequent systems in mammalian cells. This review describes the primary findings on the nature of ionizing radiation-induced mutagenesis in the N. crassa ad-3 system and the parallel observations made years later in mammalian cells.
Animals↗
Cytosol is required for the modulation by dietary casein of the hepatic microsomal activation of aflatoxin B1 to mutagenic metabolites detectable in Salmonella.
We have shown previously that dietary protein (casein) levels can affect the ability of rat liver S9 to metabolize aflatoxin B1 (AFB) as well as other promutagens detectable in Salmonella strain TA98 [Mutat. Res. (1997), 360, 115-126 and 127-143]. The mutagenic potency of AFB was greatest when metabolized by the Aroclor 1254-induced hepatic S9 prepared from F344 male rats that consumed an isocaloric, semisynthetic diet for 6 weeks that contained an adequate (12%) level of methionine-supplemented casein as the sole protein source, compared with S9s from rats fed diets that contained nominally deficient (8%) or high (22%) levels of casein. Here we have extended this observation by performing (i) mutagenicity studies with microsomes, cytosols and reconstituted S9s (recombinations of microsomes and cytosols across dietary groups), and (ii) in vitro incubations followed by analysis of metabolites by fluorescence high-pressure liquid chromatography. Microsomes, but not cytosols, activated AFB; however, activation to the level observed with S9 occurred only when microsomes from the rats fed 12% casein were combined with cytosols from any dietary group. Consistent with the mutagenicity results, the greatest metabolism of the AFB parent compound and the highest level of the glutathione conjugate of the presumptively identified AFB-exo-8,9-epoxide (the ultimate mutagenic form of AFB) were produced by S9s from the rats fed the 12% casein diet. The levels of these metabolites and the mutagenicity of AFB changed in parallel with changes in dietary casein levels. In summary, cytosolic elements, which are not affected by dietary casein levels, interact with microsomal enzymes, which are modulated by dietary casein levels, to influence the ability of hepatic S9 to activate AFB to a mutagen.
Aflatoxin B1↗
Induction of genetic damage in human lymphocytes and mutations in Salmonella by trihalomethanes: role of red blood cells and GSTT1-1 polymorphism.
The brominated trihalomethanes (THMs) are mutagenic and carcinogenic disinfection by-products frequently found in chlorinated drinking water. They can be activated to mutagens by the product of the glutathione S-transferase-Theta (GSTT1++-1) gene in Salmonella RSJ100, which has been transfected with this gene. To evaluate this phenomenon in humans, we have examined the genotoxicity of a brominated THM, bromoform (BF), using the Comet assay in human whole blood cultures exposed in vitro. No differences were found in the comet tail length between cultures from GSTT1-1(+) versus GSTT1-1(-) individuals (1.67 +/- 0.40 and 0.74 +/- 0.54 microm/mM, respectively, P = 0.28). The high variability was due to the relatively weak induction of comets by BF. Combining the data from both genotypic groups, the genotoxic potency of BF was 1.20 +/- 0.34 microm/mM (P = 0.003). GSTT1-1 is expressed in red blood cells but not in the target cells (lymphocytes), and expression within the target cell (as in Salmonella RSJ100) may be necessary for enhanced mutagenesis in GSTT1-1(+) relative to GSTT1-1(-) cultures. To examine this, we exposed Salmonella RSJ100 and a control strain not expressing the gene (TPT100) to the most mutagenic brominated THM detected in Salmonella, dibromochloromethane (DBCM), either in the presence or absence of S9 or red blood cells from GSTT1-1(+) or GSTT1-1(-) individuals. S9 did not activate DBCM in the non-expressing strain TPT100, and it did not affect the ability of the expressing strain RSJ100 to activate DBCM. As with S9, red cells from either genotypic group were unable to activate DBCM in TPT100. However, red cells (whole or lysed) from both genotypic groups completely repressed the ability of the expressing strain RSJ100 to activate DBCM to a mutagen. Such results suggest a model in which exposure to brominated THMs may pose an excess genotoxic risk in GSTT1-1(+) individuals to those organs and tissues that both express this gene and come into direct contact with the brominated THM, such as the colon. In contrast, those organs to which brominated THMs would be transported via the blood might be protected by erythrocytes. Such a proposal is reasonably consistent with the organ specificity of drinking water-associated cancer in humans, which shows slightly elevated risks for cancer of the colon and bladder but not of the liver.
Adult↗
Multifocal accumulation of p53 protein in esophageal carcinoma: evidence for field cancerization.
A systematic characterization of the cancerization field of esophageal carcinoma based on p53 protein accumulation has not been reported previously. The present report presents such a study based on 50 specimens of esophageal squamous-cell carcinoma from northern China. To gain insight into the etiology of this disease among the 50 subjects, DNA was analyzed for a polymorphism of the aldehyde dehydrogenase-2 (ALDH2) gene, which has been associated with increased risk for esophageal cancer among alcohol-consuming patients in Japan. However, the frequency of this polymorphism among our subjects, 30% (15/50), was within published control frequencies for this allele, suggesting that this allele may not play a role in the etiology of esophageal cancer in this northern Chinese population. Immuno-histochemical staining showed that 66% of the tumors were p53+. Of 420 pieces near or adjacent to p53+ tumors, p53+ cells were present among 64% of basal-cell hyperplasia (BCH), 70% of dysplasia (DYS) and 88% of carcinoma in situ (CIS). Of 216 pieces near or adjacent to p53- tumors, p53+ frequencies were 25% of BCH, 25% of DYS and 0% of CIS. The proportion of BCH cells that were p53+ decreased at increasing distance from the tumor (p = 0.006). The sporadic distribution of p53+ cells and the distribution and frequency of p53+ precursor lesions support the view that accumulation of p53 protein is multifocal and occurs in precursor lesions in early stages of esophageal carcinogenesis.
Adult↗
Dietary interventions of human carcinogenesis.
The diet is a complex mixture that is associated with approximately 30% of human cancer in the U.S. Extensive laboratory studies indicate that the diet is composed of many mutagens/carcinogens as well as antimutagens/anticarcinogens. Overwhelming evidence from epidemiological studies indicates that a diverse diet that is high in fruits and vegetables and low in certain fats, along with moderate caloric intake and exercise, is most closely associated with reduced cancer risk. Dietary intervention studies using complex food items (fruits, vegetables, and fats) support these epidemiological observations; dietary interventions using single compounds (vitamins, antioxidants, etc.) have generally not. Estimates suggest that appropriate dietary changes could reduce the percentage of deaths due to prostate, colorectal, pancreatic, and breast cancer by >/=50%.
Anticarcinogenic Agents↗
Mutation spectra resulting from carcinogenic exposure: from model systems to cancer-related genes.
The events leading to cancer are complex and interactive. Alteration of cancer genes, such as the tumor suppressor gene p53, plays a central role in this process. Analysis of the frequency, type and site of mutations in important cancer-related genes may provide clues to the identification of etiological factors and sources of exposure. In this chapter we have selected a few examples of environmental human carcinogens and have attempted to use the knowledge of their mechanisms of mutagenesis, as derived from in vitro cell systems, as a key to understanding the complexity of p53 mutation spectra in tumors arising at the putative target organ. The analysis will focus on environmental exposure to UV radiation. The examples of tobacco smoke, dietary aflatoxin and vinyl chloride will be also briefly discussed.
Aflatoxin B1↗