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M F Festing

Publications and source records attributed to M F Festing.

At least 37 records · Page 2Linked to original sources
PubMed1995

DNA damage as assessed by 32P-postlabelling in three rat strains exposed to dietary tamoxifen: the relationship between cell proliferation and liver tumour formation.

Tamoxifen was administered in the diet (420 p.p.m.) to female F344 (Fischer), Wistar (LAC-P) and LEW (Lewis) rats to determine for each strain the early morphological and biochemical changes associated with the subsequent development of liver cancer. Hepatic DNA damage, as determined by 32P-postlabelling, showed a cumulative increase with time from 500 adducts/10(8) nucleotides at 30 days to almost 3000 adducts/10(8) nucleotides after 180 days, with little difference between strains at this time point. A significant strain difference was found in the number of adducts present in the Fischer rats at 90 days, compared to the Wistar and Lewis strains. There was a marked strain differences in the time to development of liver tumours. After 6 months treatment, both Wistar and Lewis rats had tumours while none were seen in the Fischer animals. After 11 months, all of the Wistar and Lewis rats had developed liver carcinoma, while the Fischer rats developed liver carcinoma by 20 months. Depression in cell proliferation, relative to age-matched controls, was seen in the livers of Fischer rats after six months of exposure to tamoxifen, in contrast to an increase in the Wistar and Lewis rats. This observation is consistent with the promotion of foci to tumours and the subsequent progression of tumours to carcinomas in the latter two strains. These data may assist in establishing the possible risk factors, such as extent of DNA damage and increased liver cell proliferation, to women with long-term prophylactic exposure to tamoxifen.

Animals↗
PubMed1995

Use of a multistrain assay could improve the NTP carcinogenesis bioassay.

There are often large strain differences in the response of laboratory animals to toxic chemicals and carcinogens, with some strains being totally resistant to dose levels that cause acute toxicity and/or cancer in other strains. The current National Toxicology Program carcinogenesis bioassay (NTP-CB) uses only a single isogenic strain of mice and rats and may therefore miss some carcinogens. New short-term tests to predict mutagenesis and possible carcinogenesis are validated using data from the NTP-CB. If the animal data are inaccurate, it may hinder this validation. The accuracy of the NTP-CB could be improved by using two or more strains of each species without increasing the total number of animals. It would be possible to continue to use sample sizes of 48-50 animals, but subdivide these into groups of 12 animals of 4 different strains (48 animals total) per dose/sex group, for example, instead of 48 identical animals. This would quadruple the number of genotypes without any substantial increase in cost. Such a multistrain "factorial" design would, on average, be statistically more powerful then the present design and should increase the chance of detecting carcinogens that currently may give equivocal results or go undetected because the test animal strains happen to be specifically resistant. When strains differ in response, studies of differences in metabolism, pharmacokinetics, DNA damage/repair, cellular responses, and in some cases identification of genetic loci governing sensitivity may provide biological information on toxic mechanisms that would help in assessing human risk and setting permissible exposure limits. The NTP may have made the world a safer place for F344 rats and B6C3F1 mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

At least four genes and sex are associated with susceptibility to urethane-induced pulmonary adenomas in mice.

Susceptibility to urethane-induced lung adenomas in mice has a polygenic mode of inheritance, with no obvious discontinuity in lung tumour counts among 37 AXB recombinant inbred strains. However, mean tumour counts were markedly higher in strains carrying the A/J allele at the Kras2 and H2 complex than in those carrying the C57BL/ allele. In 162 F2 hybrids and small numbers of both backcrosses between strain A/J (susceptible) and C57/BL/6 (resistant) mice, five factors influencing susceptibility were identified. Variation due to the 'major' Kras2 locus (chromosome 6) accounted for 60% of the total variation. 'Minor' loci linked to microsatellite markers Tnfb (in the H2 complex), D9Mit11 and D19Mit16 (on chromosomes 17, 9 and 19, respectively) accounted for a further 13% of the variation, and males had more tumours than females with sex differences accounting for 2% of the variation. No significant association with 32 other loci was detected. On a square-root transformed scale, heterozygotes at all marker loci were of intermediate susceptibility compared with homozygotes. The three minor loci and sex only affected lung tumour counts when at least one susceptible Kras2 allele was present.

Adenoma↗
PubMed1994

Reduction of animal use: experimental design and quality of experiments.

Poorly designed and analysed experiments can lead to a waste of scientific resources, and may even reach the wrong conclusions. Surveys of published papers by a number of authors have shown that many experiments are poorly analysed statistically, and one survey suggested that about a third of experiments may be unnecessarily large. Few toxicologists attempted to control variability using blocking or covariance analysis. In this study experimental design and statistical methods in 3 papers published in toxicological journals were used as case studies and were examined in detail. The first used dogs to study the effects of ethanol on blood and hepatic parameters following chronic alcohol consumption in a 2 x 4 factorial experimental design. However, the authors used mongrel dogs of both sexes and different ages with a wide range of body weights without any attempt to control the variation. They had also attempted to analyse a factorial design using Student's t-test rather than the analysis of variance. Means of 2 blood parameters presented with one decimal place had apparently been rounded to the nearest 5 units. It is suggested that this experiment could equally well have been done in 3 blocks using 24 instead of 46 dogs. The second case study was an investigation of the response of 2 strains of mice to a toxic agent causing bladder injury. The first experiment involved 40 treatment combinations (2 strains x 4 doses x 5 days) with 3-6 mice per combination. There was no explanation of how the experiment involving approximately 180 mice had actually been done, but unequal subclass numbers suggest that the experiment may have been done on an ad hoc basis rather than being properly designed. It is suggested that the experiment could have been done as 2 blocks involving 80 instead of about 180 mice. The third study again involved a factorial design with 4 dose levels of a compound and 2 sexes, with a total of 80 mice. Open field behaviour was examined. The author incorrectly used the t-test to analyse the data, and concluded that there was no dose effect, when a correct analysis showed this to be highly significant. In all case studies the scientists presented means +/- standard deviations or standard errors involving only the animals contributing to that mean, rather than the much better estimates that would be obtained with a pooled estimate of error. This is virtually a universal practice.(ABSTRACT TRUNCATED AT 400 WORDS)

Anesthetics↗
PubMed1993

Genetic variation in outbred rats and mice and its implications for toxicological screening.

There are two basic types of laboratory rodent used in toxicological screening. Isogenic (inbred) strains are rather like clones of genetically identical individuals whereas outbred stocks are usually more variable, though the amount of variability depends on the previous history of the colony. In some cases outbred stocks may be genetically quite uniform. Many different strains of both types are available. Both types and a variety of strains are used for toxicological screening. There is clear evidence of important genetic variation both in spontaneous disease and in response to toxic agents, yet little account is taken of this in choosing suitable animals. Three options appear to be available. The first is to ignore genetic variation and use a single isogenic strain. However, if the strain happens to be insensitive to the test chemical, a toxic chemical may be judged to be relatively safe. The second option would be to synthesize a genetically heterogeneous stock by crossing two or more strains. However, this could lead to both increased false positive and false negative results as experimental "noise" either obscures true treatment effects, or is mistaken for a treatment effect. The third option is to use more than one strain, but without increasing the total number of animals used. This would provide a broad range of genotypes, so reducing the chance that they are all insensitive, without increasing experimental noise. This appears to be the only sensible way of broadening the genetic base in toxicological screening. Where strain differences are found, they may provide a tool for studying toxic mechanisms, which may be helpful in extrapolating to human populations.

Animals↗
PubMed1993

DNA fingerprinting for genetic monitoring of inbred laboratory rats and mice.

DNA fingerprinting using a nonisotopically labeled minisatellite probe provided a valuable technique for genetic monitoring/quality control of laboratory rodents. Each of 12 inbred rat strains had a unique fingerprint pattern, and colonies separated for over 20 years had identical or nearly identical patterns. Strain LOU/Iap, which is known to have been genetically contaminated in the past, was clearly different from strain LOU/CN, supporting previous findings of studies using biochemical markers. Inbred strains of mice were also found to differ from each other. The F1 hybrid between C57BL/6 and CBA/Ca could not be distinguished from C57BL/6 by using DNA fingerprints, although they could be distinguished by using biochemical markers. Some congenic strains differed from their inbred partner. A suspected genetic contamination of MRL/Mp-lpr mice could not be detected in a sample of the breeding colony by using biochemical markers; however, DNA fingerprints from the suspect animals clearly demonstrated genetic segregation. DNA fingerprinting will be of particular value in investigating suspected problems as only a small sample of fresh, frozen, or ethanol-preserved tissue is needed. Thus, the actual suspect animals can be studied, rather than samples from a breeding colony from which contaminated animals may already have been eliminated.

Animals↗
PubMed1993

FRAR course on laboratory approaches to aging. Genetic quality control in laboratory rodents.

Laboratory rodents are widely used in gerontological research. Many different strains are available, and superficially there is little to distinguish them (many are albino), although they may differ markedly in life span and pattern of spontaneous disease, as well as for a whole range of biochemical, immunological, behavioural and physiological characteristics. As experience has shown that strains can easily become muddled, some form of genetic quality control is essential. There is no single method of genetic quality control which can be recommended for all occasions. Methods based on identification of Mendelian genetic markers, such as biochemical and immunological polymorphisms can be sensitive, but may be expensive and require considerable expertise. Methods based on simultaneous study of several markers, such as skin grafting and polyvalent strain-specific antisera, may be cheaper but less flexible. DNA fingerprinting and the use of microsatellite markers appear to be the methods of choice in the future, though these are still expensive and require considerable expertise.

Animals↗
PubMed1992

The scope for improving the design of laboratory animal experiments.

The factors which need to be taken into account in designing a 'good' experiment are reviewed. Such an experiment should be unbiased, have high precision, a wide range of applicability, it should be simple, and there should be a means of quantifying uncertainty (Cox 1958). The relative precision due to the use of randomized block designs was found to range from 96% to 543% in 5 experiments involving 30 variables. However, a survey of 78 papers published in two toxicology journals showed that such designs were hardly used. Similarly, designs in which more than one factor was varied simultaneously ('factorial designs') were only used in 9% of studies, though interactions between variables such as dose and strain of animal may be common, so that single factor experiments could be misleading. The consequences of increased within-group variability due to infection and genetic segregation were quantified using data published by Gärtner (1990). Both substantially reduced precision, but toxicologists continue to use non-isogenic laboratory animals, leading to experiments with a lower level of precision than is necessary. It is concluded that there is scope for improving the design of animal experiments, which could lead to a reduction in animal use. People using animals should be required to take formal training courses which include sessions on experimental design in order to minimize animal use and to increase experimental efficiency.

Analysis of Variance↗
PubMed1991

Genetic factors in neurotoxicology and neuropharmacology: a critical evaluation of the use of genetics as a research tool.

Animals have evolved a detoxication system to enable them to survive in a hostile chemical environment in which foods contain many non-nutrient chemicals. Detoxication depends on enzymes which are often genetically polymorphic. As a result, inter-individual variation is common, and in humans several Mendelian loci have been identified. However, most variation in response is probably due to the action of several genes. Genetic variation in response to the neurotoxin MPTP and to chemically and physically-induced seizures is reviewed. In the former case, differences between pigmented and white mouse strains have been noted which are consistent with the hypothesis that humans are more sensitive than mice or rats because of the presence of melanin in human brains. However, variation in sensitivity probably also depends on other genes. In the case of audiogenic seizures, a single locus has been identified and mapped, but its relationship with seizures induced by other agents is not clear. Genetic variation in response to alcohol is also discussed. The failure of most toxicologists to consider genetic variation as a potentially confounding variable, and as a powerful research tool, is discussed critically in relation to non-repeatability of research on the neurotoxic effects of lead, and in relation to the genetic variation in MPTP, seizures, and alcohol response already noted. It seems clear that genetic methods provide a powerful research tool which is largely being ignored by toxicologists.

Animals↗
PubMed1991

Tich: a mutant causing disproportional growth in the mouse.

A spontaneous mutation 'tich' (gene symbol tch) appeared as a recessive mutation in inbred mice of strain A. TL. Homozygotes are rather dumpy mice of approximately normal weight but with short limbs and tail. Skeletal measurements on backcross siblings show that the mandible bones are almost normal but long bones and some parts of the pelvic and pectoral girdles are short. Although tich resembles brachypodism phenotypically it is not linked to agouti, and does not match the description of any other skeletal mutation. There was some evidence for weak linkage with albinism on chromosome 7. The mutation has reappeared amongst the A. TL mice of a UK commercial breeder and may have been accepted as the norm for A. TL amongst some European users of this mouse.

Animals↗
PubMed1990

Mouse strain differences in resident peritoneal cells: a flow cytometric analysis.

A flow-cytometric study of resident peritoneal cells among 8 mouse strains showed a more than twofold variation in the ratio of macrophages to macrophages plus lymphocytes, ranging from 27% in A/J to 62% in C57B/L10, with significant strain differences in a number of other cellular parameters. There was a particular deficiency of lymphocytes in strain CBA/N, which carries the xid mutation. Studies of the phagocytosis of fluorescent beads also revealed large differences in the number of beads taken up, ranging from 0.99 per cell in MFI to 1.64 per cell in BALB/c mice in a 20-min period. The total number of peritoneal cells collected also varied between strains, ranging from 2.75 x 10(6) in CBA/Ca to 5.85 x 10(6) in MF1. The total yield of macrophages per mouse ranged from 0.93 x 10(6) in A/J to 3.16 x 10(6) in C57BL/10. These differences should be taken into account when designing experiments which use resident peritoneal cells.

Animals↗
PubMed1989

Correlation between genetic distances based on single loci and on skeletal morphology in inbred mice.

Genetic and morphometric distances between 12 inbred strains of mice ranging from closely related substrains to a sub-species were estimated using published data on single locus polymorphisms, and on the basis of up to 44 measurements on seven different bones, respectively. Simulation was also used to investigate sampling effects for the single loci. There were strong and statistically highly significant correlations among all measures of genetic distance ranging from 0.58 for the comparison of single loci with the logarithm of the Mahalanobis distance based on 24 measurements on four bones, to 0.72 for estimates of genetic distance based on single loci and the morphology of the mandible. These findings are in sharp contrast with those of Wayne & O'Brien (1986) who claimed that 'structural gene and morphometric variation of mandible traits are uncoupled between mouse strains'. Their failure to find such a correlation is probably because their sample of inbred strains included only a single pair of closely related substrains, and no substrains separated for less than 40 years, and because they failed to correct for non-linearity between morphometric and single-locus measurement scales. Simulations and regression analysis suggested that genetic distances could be estimated with approximately equal precision using morphological data on bone measurements or about 10 cladistically informative single loci, which would usually involve sampling about 50 loci. Data based on single-gene markers is usually more informative than morphometric data for studying the similarity of independently-derived strains. However, similarities among closely related populations such as sublines of an inbred strain can usually be studied more efficiently using morphometry.

Animals↗
PubMed1989

CBXC: a set of recombinant inbred strains between CBA/Ca and BALB/c.

A new set of nine recombinant inbred strains designated CBXC-1 to CBXC-9 has been developed from a cross between CBA/Ca female and BALB/c male mice. All of the strains have been brother x sister mated for more than 20 generations, and have been characterized at eight electrophoretic, one immunological and two coat colour loci at which the progenitor strains differ. This set of strains should be useful in investigating the genetics of any characters which differ between the two progenitor strains.

Animal Husbandry↗