Commentary: paternal legacies.
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Abnormalities, Drug-Induced↗
Biomedical subjects
P C Jenkinson
Publications and source records attributed to P C Jenkinson.
Variability in chromosome aberrations, sister chromatid exchanges, and mitogen-induced blastogenesis in peripheral lymphocytes from control individuals.
Confidence in results from monitoring genetic end points in environmentally or occupationally exposed individuals can be improved with knowledge of the normal variability of changes in genetic end points in the general population. Confounding effects can be determined, and study interpretation can be improved by correlation of this variability with various lifestyle factors such as sex and age, smoking and drinking habits, viral infections, exposure to diagnostic X-rays, etc. Eight blood samples were taken from each of 24 male and 24 female volunteers over a period of 2 years. Questionnaires pertaining to lifestyle were completed at the time of each sampling. Whole blood was cultured and slides prepared for chromosome aberration (CA) or sister chromatid exchange (SCE) analysis. Separated mononuclear cells were cultured with a range of phytohemagglutinin concentrations, and the maximum level of mitogen-induced blastogenesis was determined by measurement of [3H]thymidine uptake. There was a significant effect of both year and season of sampling for all three end points. Because there was no consistent pattern in 2 successive years, effects were thought to be independent of season. No significant effects in any of the three end points were found with respect to sex or age nor any of the other lifestyle factors, although SCE frequency and mitogen-induced blastogenesis were nearly always higher in females than in males. These results point to the need for concurrent sampling of controls with exposed populations.
Cells, Cultured↗
Malformed foetuses and karyotype abnormalities in the offspring of cyclophosphamide and allyl alcohol-treated male rats.
Litters sired by male rats chronically treated with cyclophosphamide (CP) or allyl alcohol (AA), were evaluated for the incidence of foetal malformations and karyotype abnormalities. The male rats were also examined for the induction of deleterious effects on various parameters including those involved in reproductive performance. A highly significant and consistent increase in the numbers of malformed foetuses was seen in the litters from CP-treated male rats. Chromosome preparations revealed that a large proportion of the malformed foetuses carried karyotypic abnormalities. These effects were paralleled by a large increase in the number of post-implantation losses without significant differences in several sperm and semen characteristics including sperm abnormalities. No adverse reproductive effects were observed with allyl alcohol treatment.
1-Propanol↗
Tumours and malformations in the adult offspring of cyclophosphamide-treated and control male rats--preliminary communication.
Adult offspring aged 52-104 weeks, from male Sprague-Dawley rats treated chronically with cyclophosphamide (CP) were examined for tumours and gross abnormalities. Litter size at birth and at weaning was found to be greatly reduced as a result of paternal CP treatment. No unusual abnormalities were found at post-mortem examination but there was an increase in the incidence of hydronephrosis in offspring from CP-treated males compared with offspring from control males. This increase could have been indirectly caused by CP-treatment through reduced litter size. Histological examination of 26 tumours showed a variety of tumour types in the offspring of CP-treated and control males. Two of the four uterine tumours in offspring from CP-treated males were examined histologically; one was a sarcoma and the other an adenocarcinoma. Although no uterine tumours were found in offspring from control males, it is not clear whether this difference in frequency was treatment-related. The most common tumour site in female offspring from both CP-treated and control males was the mammary gland, and all six of these tumours which were examined histologically were adenofibromas. Abnormal karyotypes were observed in 2 out of 21 offspring showing abnormalities from CP-treated males and none out of 2 offspring with abnormalities from control males. These were not associated with tumours. It was concluded from this limited study that there was no clear evidence of increased tumour incidence in the offspring from CP-treated males. There was an indication that abnormal karyotypes may have been caused by the paternal CP treatment and these abnormalities persisted into adulthood.
Abnormalities, Drug-Induced↗
Analysis of chromosomal aberrations in workers exposed to low level benzene.
Metaphase chromosome preparations were analysed as part of a larger study from a population occupationally exposed to benzene and compared with a control group. Forty eight of the 66 exposed individuals and 29 of the 33 controls had samples in which metaphase spreads could be evaluated. The incidence of chromosomal aberrations (particularly chromatid deletions and gaps) in the exposed group were slightly increased compared with the control group. This increase was of borderline significance in parametric statistical tests but was significant using Fisher's exact test. No lifestyle factors had any consistent effect on the incidence of chromosome aberrations, although there was a small reduction in gaps with increasing cigarette smoking. Older individuals had a higher incidence of chromosome exchanges and "other" aberrations. Individuals who reported a recent viral illness had a higher incidence of aberrations particularly gaps. There was no evidence of any correlation in the incidence of chromosome aberrations with any of the other biological parameters previously reported. The increased incidence of aberrations seen in the group exposed to benzene may result from a history of exposure to benzene. Nevertheless, other explanations such as sampling, interindividual variability, and unintentional bias in the selection of two groups cannot be excluded.
Benzene↗
The protective effects of L-ascorbic acid and DL-alpha-tocopherol on cultured rat embryos treated with xanthine/xanthine oxidase.
Abnormalities of the neural suture were observed in cultured rat embryos exposed to oxygen radicals generated by xanthine and xanthine oxidase. The distribution of the severity of these abnormalities was altered by the addition of L-ascorbic acid (AA) or DL-alpha-tocopherol (AT). The antioxidant effect of AA and AT were probably responsible for the protection of the embryos from the damaging effects of oxygen radicals.
Animals↗
Chromosome aberrations, mitogen-induced blastogenesis and proliferative rate index in peripheral lymphocytes from 106 control individuals of the U.K. population.
Blood samples were taken from 106 individuals (73 males and 33 females) and examined for chromosome aberrations, mitogen-induced blastogenesis and proliferative rate index (PRI). The values obtained were investigated in relation to sex, age, smoking, alcohol consumption and X-ray exposure. In all the parameters, there was shown to be a difference between the mean values for the males and females. The incidence of chromosome aberrations was greater in females than in the males, whereas the mean values of PRI and mitogen-induced blastogenesis were lower in females than in the males. A sex difference has been reported previously in the same population, in that the females were shown to have a higher rate of sister-chromatid exchanges than the males (Anderson et al., 1986; Dewdney et al., 1986). Contraceptive pill usage was not considered to be of importance in the sex difference seen and there was shown to be no significant influence due to age, smoking or alcohol consumption on any of the parameters except that smoking reduced lymphocyte PRI. Males with previous X-ray exposure also showed a lower response to mitogen-induced blastogenesis and had a reduced PRI.
Age Factors↗
Genotoxic effects in peripheral blood and urine of workers exposed to low level benzene.
Blood samples were obtained from a population of refinery workers representing different age groups. Sixty six men with low average exposure to benzene and 33 male controls were investigated. An examination of cell cycle kinetics and sister chromatid exchange was carried out on control and exposed individuals. No significant differences were found between groups of individuals varying in their drinking and smoking habits or their exposure to diagnostic x rays. Individuals with the lowest and highest phenol values were examined for urine mutagenicity, with urinary phenol used here as an indicator of benzene exposure. There was no difference in the number of revertant colonies in strains TA98 and 100 between the high and low urinary phenol groups. There were also no differences in any of the biochemical measures or haematological parameters investigated in all the individuals except that higher values for mean corpuscular volume were found in exposed than in control individuals. These values, however, were within the normal clinical range.
Adult↗
Chromosomal aberrations and sister chromatid exchanges in lymphocytes and urine mutagenicity of migraine patients: a comparison of chronic feverfew users and matched non-users.
1. Thirty migraine patients who had taken the leaves, tablets or capsules of feverfew daily for more than 11 consecutive months were compared to 30 feverfew non-user migraine patients who had been individually age- and sex-matched. 2. The frequency of chromosomal aberrations and sister chromatid exchanges (SCE) were determined from lymphocyte cultures established from blood samples taken over a period of several months. Matched pairs were sampled on the same date for two-thirds of the cases, and the greatest difference in sampling time of the remainder was 20 days. Also, the mutagenicity of urine samples from 10 feverfew user migraine patients was compared to that from 10 matched non-user migraine patients using the Ames Salmonella mutagenicity test system. Paired samples were given on the same date. 3. The mean frequency of chromosomal aberrations in the feverfew user group was lower than that in the non-user group both in terms of cells with breaks (2.13% vs 2.76%) and in terms of cells with all aberrations (4.34% vs 5.11%). However, this difference was small and not significant. 4. The mean frequency of SCE in the feverfew exposed group was lower than that in the control group (8.78 vs 8.80 SCE/cell), but, this difference was not significant as determined by factorial analysis of variance (P = 0.897). There was a highly significant variance between the frequencies of SCE in the matched pairs of migraine patients but this was not related to age, sex or feverfew exposure.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Studies of the 'adaptive' repair response in human lymphocytes and V79 cells after treatment with MNNG and MNU.
In bacteria, there is evidence that a damage inducible repair response system known as the adaptive response exists since pretreatment with low doses of a simple monofunctional alkylating agent leads to a decrease in both the lethal and mutagenic effects of a subsequent challenge dose of the agent. The evidence for an analogous system in mammalian cells has proved to be inconsistent to date. The induction of chromosome repair mechanisms in human cells by low-dose radiation from tritiated thymidine has been shown to make the cells refractory to the induction of chromosome aberrations by X-rays. The present communication investigates the induction of an adaptive response in human lymphocytes from four donors and V79 cells using SCE and mutation as endpoints and MNNG and MNU for the adapting and challenging treatment. It is clear that a reproducible model of the adaptive response in human lymphocytes is difficult to establish because of the variability between different donors and different culture times. In V79 cells, assays with much larger cell numbers are required to detect a reproducible response with such small changes in mutant frequency. To demonstrate an adaptive response conclusively in mammalian cells will probably require the use of more sensitive experimental protocols and alternative methods of administration of adaptive doses of mutagen.
Animals↗
Effect of ethylene glycol monomethyl ether on spermatogenesis, dominant lethality, and F1 abnormalities in the rat and the mouse after treatment of F0 males.
Adult male CD rats and CD-1 mice were given a single oral dose of ethylene glycol monomethyl ether (EGM) at 0, 500, 750, 1,000, or 1500 mg/kg. Groups of 10 were killed at weekly intervals after dosing for analysis of sperm counts and morphology or testicular histology; further groups of 10 were sequentially mated to pairs of virgin females to test for dominant lethality or gross foetal malformations in the F1 generation (F1 abnormalities). EGM was found to deplete the spermatocytes of both species severely, principally pachytene cells, but with other stages affected with increasing dose. A delay in the progression of spermatogenesis may account for a discrepancy between the apparent stage-specificity of damage deduced from lowered sperm counts and that observed histologically. In the rat, morphological abnormalities were observed in sperm that had been exposed as spermatocytes; in the mouse, however, the sensitive cells were the late spermatocytes and early spermatids. In all these parameters there was an indication of a dose-response relationship in both rats and mice. In the mating studies EGM induced a dose-related decrease in fertility 5 weeks after dosing in the rat, but complete sterility in all but the lowest dose after 6 weeks. In contrast, EGM had no effect on the reproductive capacity of the mouse. There was no statistically significant evidence for the induction of dominant lethal mutations or F1 abnormalities in either species. A single oral dose of cyclophosphamide (CTX) at 100 mg/kg induced a significant increase in dominant lethality in both species. CTX reduced the number of total implants in the rat and induced a nonsignificant increase in the number of abnormal offspring sired by treated male mice.
Abnormalities, Drug-Induced↗
The use of a battery of strains of mice in a factorial design to study the induction of dominant lethal mutations.
The induction of dominant lethality following oral dosing of males with 200 mg/kg of cyclophosphamide was investigated using a factorial experimental design. Males from 3 genotypes, BALB/c, CBA/Ca and CBA/Ca X C57BL/6JF1 hybrid (CBB6F1) were mated to 6 females of the same genotype as the males over 3 weeks. Cyclophosphamide reduced the mating frequency of the BALB/c and CBA/Ca males. The total number of implants/female was reduced in all 3 genotypes with the greatest effect in the first 2 weeks after the males were treated. The proportion of early deaths/litter was significantly increased in CBA/Ca and CBB6F1 but the increase was smaller and non-significant with BALB/c. There was a high incidence (29.8%) of early deaths in the control BALB/c females. Statistical analysis of the ratio of early deaths to total implants in a litter using either the Freeman-Tukey binomial or the arc-sine transformation gave similar and satisfactory results. Analysis of early death data rather then the ratio of early deaths: total implants would have led to misleading conclusions. The implications of the use of a factorial design in dominant lethal assays for the detection of strain variation in mutagenic response without an increase in animal usage is discussed.
Animals↗
Increased incidence of abnormal foetuses in the offspring of cyclophosphamide-treated male mice.
The incidence of morphologically abnormal foetuses in the litters of cyclophosphamide (CP)-treated male mice was investigated and compared with control values. In two experiments (100 mg/kg) CP was shown to increase the incidence of grossly abnormal foetuses over that seen in the controls, although neither was statistically significant in isolation. When the probabilities from the two tests of significance were combined using the method of Fisher the result was significant (P = 0.02). These results suggest that an acute exposure to a mutagen in male mice can cause genetic damage that results in an increased incidence of phenotypically abnormal offspring. However, the large numbers of animals required and the variable control level of abnormalities, indicate that this dosing regimen is an inefficient method of studying the genetic mechanisms responsible for the effects seen.
Abnormalities, Drug-Induced↗
Investigation of possible genetoxic effects of feverfew in migraine patients.
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Chromosome Aberrations↗
Malformations induced in cultured rat embryos by enzymically generated active oxygen species.
Day 9.5 rat embryos were exposed in culture to xanthine/xanthine oxidase generated active oxygen species. Growth and development were assessed after 46 hr of culture. The treatment induced abnormalities of the neural suture, the severity of which increased in a dose-related manner with the concentration of substrate or enzyme. Glutathione (10 mM) or catalase (50 micrograms/ml) either partially or completely abolished the effects of xanthine/xanthine oxidase, whereas the addition of superoxide dismutase (50 micrograms/ml) or desferrioxamine (1mM) did not reduce the number of malformed embryos. These findings suggest that hydrogen peroxide and/or hydroxyl radicals are responsible for the effects of xanthine and xanthine oxidase.
Abnormalities, Drug-Induced↗
Variation in sister-chromatid exchange among 106 members of the general U.K. population.
SCE scores of lymphocytes from 106 people revealed that the majority of background variation in SCE was between cells within individuals. Highly significant differences existed between individuals. Lesser, but still highly significant differences also existed between replicate cultures. Inter-individual variation was contributed to by each person's sex and their smoking habits. SCE frequency was not influenced by any of the other factors considered, age, drinking habits and diagnostic X-ray exposure of persons or lymphocyte number and proliferation rate in cultures.
Age Factors↗
Sister chromatid exchange (SCE) analysis in 106 control individuals.
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Age Factors↗
Chromosome aberrations (CA), sister-chromatid exchanges (SCE) and mitogen-induced blastogenesis in cultured peripheral lymphocytes from 48 control individuals sampled 8 times over 2 years.
Confidence in the measurement of positive effects determined by monitoring of environmentally or occupationally exposed individuals can be enhanced by a knowledge of the normal variability in these endpoints in the general population. Confounding effects can be determined and study interpretation improved by correlation of this variability with various lifestyle factors such as sex and age of donor, smoking and drinking habits, viral infections, exposure to diagnostic X-rays, etc. 8 blood samples were taken from each of 24 male and 24 female volunteers over a period of 2 years. Questionnaires pertaining to lifestyle were completed at the time of each sampling. Whole blood was cultured and slides prepared for CA or SCE analysis. Separated mononuclear cells were cultured with a range of phytohaemagglutinin concentrations and the maximum level of mitogen-induced blastogenesis was determined by measurements of [3H]thymidine uptake. There was a significant effect of both year and season of sampling for all 3 endpoints. No significant effects in any of the 3 endpoints were found with respect to sex or age of donor nor any of the other lifestyle factors, although SCE frequency and mitogen-induced blastogenesis were nearly always higher in females than males. These results point to the need for concurrent sampling of controls with exposed populations.
Adolescent↗