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Centre for Environmental Health, University of Victoria, Victoria, British Columbia, Canada
3To whom correspondence should be addressed. E-mail: jdboer{at}uvic.ca
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONThe lacI transgenic system...Advantages of an animal...Mutation and its modulationLITERATURE CITED |
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KEY WORDS: • chemoprevention • mutation • transgenic • diet
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONThe lacI transgenic system...Advantages of an animal...Mutation and its modulationLITERATURE CITED |
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,2
). The measurement of mutagenic activity may therefore be an important and convenient way of determining the carcinogenic potential of a treatment. Several mutagenesis assays are in use, including bacterial and cell culture assays (3
,4
). A suitable animal system in which mutation can be assessed would be useful for such measurement and could also be used to determine the modulating effect of compounds on the mutagenicity of other agents, opening up the possibility of studying the efficacy and mechanism of chemoprevention. Many compounds that show promise in protecting us against cancer have been identified in our diet and in plant-based material. The prevention of cancer is an attractive approach to health management and the advantages are many (5
). However, a need exists for an evaluation in an animal system of the efficacy of many compounds, especially those derived from natural products and plants. Many natural products, often with unknown qualities, are used by many individuals. Indeed, some of these preparations have been demonstrated to be carcinogenic (6
). One advantage of using a real animal model for such studies is that the entire physiology and tissue-specific metabolism of carcinogens is an important part of the assay. Most carcinogens go through a cascade of activation and detoxification pathways in one or more tissues before exercising their carcinogenic potential. Such pathways cannot truly be mimicked in a cell-based assay. The recent advent of transgenic technology has made it possible to study mutation in animals rather than simply in bacteria or cell cultures.
There are a number of transgenic rodents available that use different mutation target genes. The best known are those that use the bacterial lacI gene (the Big Blue mouse) (7
,8
) and the bacterial lacZ gene (the Muta mouse) (9
). Other systems use the bacterial genes for supF (10
) and rpsL (11
), the 
bacteriophage cII gene (included in Big Blue and Muta mouse) (12
) and the genes for spi selection of deletions (13
). This review will concentrate on the lacI transgenic mice because of our experience with this well-studied system.
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The lacI transgenic system |
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TOPABSTRACTINTRODUCTIONThe lacI transgenic system...Advantages of an animal...Mutation and its modulationLITERATURE CITED |
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–21
) provided a wealth of information on both the sensitivity of the gene to mutation and the mutational specificity of many mutagenic compounds and treatments. The product of the lacI gene, which is the Lac protein, binds to the operator of the lacZ gene as a tetrameric protein and prevents the expression of the lacZ gene. Mutations in the lacI gene, therefore, can result in constitutive lacZ expression and the formation of ß-galactosidase. ß-Galactosidase can cleave the chromogenic compound 5-bromo-4-chloro-3 indolyl-ß-D-galactoside (X-gal),4
which results in a blue color. Mutants in the lacI gene can, therefore, be detected by the blue color of the bacterial colonies or bacteriophage plaques.
A plasmid containing the lacI gene is inserted into a bacteriophage vector (7
) and introduced into an embryonic cell of C57Bl/6 mice by microinjection, creating the Big Blue mouse. This Big Blue mouse was subsequently crossed with a C3H mouse to obtain mice of the same genetic background (B6C3F1) as those used in the National Toxicology Program bioassays (22
). The Big Blue mice have 
40 copies of the transgene integrated in a linear tandem array at a single locus on chromosome 4 (23
). The same construct was used to develop the lacI transgenic Fischer 344 rat (23
) in which 30–40 copies of the transgene are integrated at a single locus. The availability of both mice and rats makes a comparison between species possible.
The protocol for determining mutation frequency in tissues of these animals has been standardized (24
–26
). Animals are divided into groups, usually five per group, and subjected to a treatment. A control group that receives no treatment, or vehicle only, is included. Treatment can be done by oral gavage, intraperitoneal injection, topical application, or inhalation or by mixing the compound into the feed or drinking water. After exposure, a period of 14 d allows DNA damage to be converted into mutations. After this period, the animals are killed and all relevant tissues are removed, flash frozen in liquid nitrogen and stored at -80°C. High-molecular-weight DNA is isolated from the tissues and added to a bacteriophage packaging extract. This extract excises the bacteriophage genomes from the animal’s genomic DNA and packages them into viable phage particles. These particles are plated on E. coli SCS-8, a modification-restriction–deficient host bacterium that allows the formation of bacteriophage plaque. In the presence of X-gal, particles with a mutated lacI gene will form a blue plaque against a background of clear colorless plaques. The mutant frequency is calculated as the ratio of blue plaques to the total number of plaques.
To establish a spectrum of mutational changes, blue mutant plaques are removed from the plate and the lacI gene is amplified by polymerase chain reaction and subsequently sequenced to determine the sequence of the entire coding portion of the gene. The classes of mutations (e.g. transversions, transitions, frameshifts or deletions) are tabulated for 50–100 mutants (a spectrum). Determination of the kinds of changes that were induced by the treatment may show details about the mechanism by which the treatment caused the mutations. In addition, when the induced changes are distinct from background mutations, even a small increase in frequency is detectable as a change in the spectrum. This can significantly increase the sensitivity of the assay. A second reason for sequencing is related to cell proliferation. Cell division can result in an initial lacI mutation being present in several daughter cells, increasing the mutant frequency. Removing the extra mutants from the collection changes the mutant frequency to a mutation frequency and in many cases improves the statistical significance of the results.
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Advantages of an animal system |
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TOPABSTRACTINTRODUCTIONThe lacI transgenic system...Advantages of an animal...Mutation and its modulationLITERATURE CITED |
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).
When a bacterial assay, such as the Ames test, is used, metabolic activation of mutagens necessitates the use of a rat liver microsomal extract (the "S9" extract), which mimics endogenous mammalian metabolic systems. However, the precise enzymes that were induced in the rat liver before the isolation of the extract will determine the activity of the extract. In addition, different tissues besides liver display different enzymatic activation profiles for different chemicals. The metabolism in various tissues may directly reflect tissue-specific carcinogenesis because most if not all carcinogens cause tumors only in specific tissues. For example, the polycyclic aromatic hydrocarbon 7,12-dimethylbenz[a]anthracene (DMBA) causes mammary carcinomas (28
) as well as skin tumors (29
). The heterocyclic amine 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) causes colon tumors in male rats, but mammary tumors in female rats (30
). This tissue-specific targeting makes whole-animal assays for mutation very different from bacterial mutagenesis tests such as the Ames test or cell culture assays.
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Mutation and its modulation |
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TOPABSTRACTINTRODUCTIONThe lacI transgenic system...Advantages of an animal...Mutation and its modulationLITERATURE CITED |
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4 x 10-5 (31
) (Table 1
). The largest class of background mutation is GC 
AT transition (50%), with 75% occurring at 5'-CpG-3' dinucleotide sequences (CpG sites) (33
). These transitions are thought to be caused by spontaneous deamination of methylated cytosines to thymine because the cytosines in 5'-CpG-3' sequences are frequently methylated in mammalian cells (34
). The second largest class of mutation is GC TA transversion. These mutations may be the result of oxidative damage caused by oxygen free radicals. We have found that the overall mutational spectrum is remarkably similar when different tissues of mice and rats are compared (32
). In contrast, the spectrum in the lacI gene in E. coli is significantly different (35
,36
) with a large fraction (75%) of the recovered mutants found at a single site (35
). This bacterial hotspot mutation is rarely found in animals, an important indication that the recovered spectrum is indeed of animal origin.
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–43
). Some examples of relevant alterations in the spectrum are shown in Table 2
. The important results of these studies are that each treatment yields a specific mutational response. Chemicals that form bulky DNA adducts, including aflatoxin-B1, benzo[a]pyrene and PhIP, generally cause GC > TA transversions. On the other hand, exposure to alkylating agents, including dimethylnitrosamine, generally results in GC AT transitions but not at 5'-CpG-'3 sites. These mutations can be sequence-context specific. More interestingly, mutations can be as tissue specific as tumorigenesis. In the remainder of the paper, we will discuss examples of modulation of mutation frequencies (Table 3
).
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). This increase is almost entirely due to an increase in GC TA transversions. Interestingly, mice are refractive to toxicity, carcinogenicity and mutagenicity of aflatoxin. This is attributed to a high level of glutathione S-transferase that detoxifies the P450-activated DNA-reactive aflatoxin metabolites (44
). We treated male and female rats with the dioxin 2,3,7,8-tetrachlorodibenzo[b,e] (1
,4
)dioxin (TCDD), a highly toxic and carcinogenic compound (45
). We did not see any TCDD-induced mutagenicity in the lacI gene, consistent with a nongenotoxic compound. However, when TCDD was given before an injection with aflatoxin, the aflatoxin-induced mutations were completely eliminated in female but not in male rats (Thornton, A., Stuart, G., Glickman, B.W., de Boer, J.G., University of Victoria, Victoria, BC, Canada, unpublished results, 2001). We attribute this to a TCDD-induced change in the balance of aflatoxin activation and detoxification, similar to the difference between mice and rats. Differences in hormones between male and female rats may modulate the effect of TCDD because estrogen affects the TCDD-mediated expression of cytochrome isozymes (46
). These results highlight the complexity of animal physiology and the importance of the Big Blue system for these studies.
Epidemiologic studies have indicated that green tea may have a beneficial effect on health, including prevention against cancer. Yang and Wang (47
) reviewed >50 studies and, although many yielded inconclusive results, several studies suggested a modest protective effect of tea consumption. Mortality from stomach cancer in several tea-producing areas in Japan is only one fifth (men) and one third (women) that of the national rate (48
). Sadakata et al. (49
) found that the mortality rate in Japanese tea ceremony teachers is significantly lower than that of other women living in the same area. Skin tumors caused by DMBA or ultraviolet light were inhibited by either topical or oral administration of epigallocatechol gallate, the main active ingredient of tea (50
). We (51
) recently showed that green tea infusions reduce mutations in Big Blue mice. Two groups of mice were fed either water or green tea as their source of liquid. After several weeks, all mice received an injection of benzo[a]pyrene. In the water group, the average mutation frequency increased twofold over the background. The increase was due mainly to induced GC TA transversions, typical of benzo[a]pyrene mutagenesis (41
). The increase in the group that was provided green tea, on the other hand, was only 50% of that seen in the water group. The reduction was due to a lower induction of GC TA transversions. This indicates a significant protective effect of green tea consumption against benzo[a]pyrene–specific mutagenesis, in agreement with findings of epidemiologic and tumor studies.
Conjugated derivatives of linoleic acid (CLA) occur naturally in dairy products and cooked meat (52
,53
). These compounds are formed as part of the metabolism of linoleic acid by bacteria in the rumen. Although pork and chicken meat contain CLA, meat from ruminants generally contains more CLA than does that of nonruminants. Fatty tissue contains from 1 to 6 mg CLA/g, but cooking can increase its concentration as much as fivefold. CLA is present in dairy products such as cheese at 3–9 mg/g fat. Human consumption is estimated at nearly 1 g CLA/d (53
). CLA was shown to have anticarcinogenic properties against topical application of DMBA in the mouse epidermal papilloma carcinogenesis system (53
) and to be an effective anticancer agent in mice and rats against a broad range of carcinogens in a variety of target tissues, including mammary gland (54
,55
). The efficacy of CLA in cancer prevention is manifest at concentrations close to the levels consumed by humans in their diet (54
).
We investigated the protective effect of CLA against the mutagenicity of the dietary heterocyclic amine PhIP in tissues of the Big Blue rat. The addition of PhIP in the diet increases the mutant frequency in several tissues, including the distal colon (20-fold increase over background) and prostate (10-fold). When CLA was given in the diet together with PhIP, a reduction in the recovery of mutations was seen in the distal part of the colon as well as in the prostate, ranging from 25 to 45% (56
). These findings are in agreement with earlier findings that PhIP adduct formation is inhibited by dietary CLA (57
). Most interestingly, a change in the mutational spectrum of recovered PhIP-induced mutants after CLA treatment revealed that CLA might act through alterations in a DNA repair pathway (56
).
The importance of an animal system rather than a cell culture or bacterial assay is also evident from the ability to measure mutation in distinct histological regions. When we assayed the flame retardant tris-(2,3-dibromopropyl)phosphate, a kidney carcinogen, for mutagenicity in the kidney, we sectioned the kidney into renal cortex and inner and outer medulla. We found that the highest levels of mutation occurred in the cortex with a gradient in frequency from cortex through outer medulla to inner medulla, a nearly threefold difference (38
). Carcinogenicity, however, was limited to the outer medulla in which cell proliferation was found upon treatment (58
). We suspect, therefore, that the combination of mutation induction and cell proliferation was responsible for the induced tumors in the outer medulla. These findings show the high level of spatial discrimination possible in mutation detection.
Our results show that the lacI transgenic mouse provides a useful model system to investigate the protective effects of potential chemopreventive compounds. The tissue-specific mutation induction and the ability to detect changes in the mutational spectrum make it a sensitive assay that can measure prevention in target tissues in a real animal.
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FOOTNOTES |
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2 Supported in part by the National Cancer Institute of Canada, the Cancer Research Society and the National Institutes of Health (USA).
4 Abbreviations used: CLA, conjugated linoleic acid; CYP450, cytochrome P450 (phase I) enzymes; DMBA, 7,12-dimethylbenz[a]anthracene; PhIP, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine; TCDD, 2,3,7,8-tetrachlorodibenzo[b,e][1,4]dioxin; X-gal, 5-bromo-4-chloro-3 indolyl-ß-D-galactoside.
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LITERATURE CITED |
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TOPABSTRACTINTRODUCTIONThe lacI transgenic system...Advantages of an animal...Mutation and its modulationLITERATURE CITED |
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