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Biomedical subjects

U H Ehling

Publications and source records attributed to U H Ehling.

At least 55 records · Page 3Linked to original sources
PubMed1985

Induction and manifestation of hereditary cataracts.

A cataract is an opacity of the lens causing a reduction of visual function. The organogenesis of the lens in various mammals is similar. Therefore, a cataract mutation in mice can be directly compared with cataracts in man. Screening for dominant cataracts in mice was combined with the scoring of specific locus mutations. This combination increases the number of scorable loci, allows the comparison of unselected and selected loci and makes possible a systematic comparison of dominant and recessive mutations. In a combined experiment, dominant cataract and specific locus mutations were scored in the same offspring of mice after treatment of spermatogonia. In radiation experiments the induced frequency of dominant cataracts in spermatogonia was after single exposure 4.5 - 5.5 X 10(-5) mutations/gamete/Gy and for specific locus mutations 1.6 - 2.8 X 10(-5) mutations/locus/Gy. In experiments with ethylnitrosourea (ENU) the induced frequency of dominant cataracts was 0.7 - 1.3 X 10(-5) (mutations/gamete)/(mg ENU/kg body weight) and for specific locus mutations 2.6 - 3.3 X 10(-6) (mutations/locus)/(mg ENU/kg body weight). The radiation-induced mutation rate can be used for the direct estimation of the genetic risk in humans. The genetically significant population dose for 19 000 offspring in Hiroshima and Nagasaki was estimated to be 1.1 X 10(6) man-rem, absorbed at high dose rate. For the 19 000 offspring one would expect less than 1 radiation-induced dominant cataract and a total of 20 - 25 dominant mutations. If the number of dominant and recessive loci are equal one would expect in addition the induction of 250 recessive mutations in this population. Chemically induced dominant cataract mutations could be used to determine the allowable level of exposure for a single compound. The genetically characterized mutations will be an ideal source for studies in the field of developmental genetics. The investigation of alpha-, beta-, and gamma-crystallins by electrophoretic methods, the activity determinations of enzymes and the systematic use of cDNA hybridization may lead to an understanding of the genesis of dominant cataracts in mice and man.

Animals↗
PubMed1985

Quantitative comparison of genetic effects of ethylating agents on the basis of DNA adduct formation. Use of O6-ethylguanine as molecular dosimeter for extrapolation from cells in culture to the mouse.

DNA-adduct formation and induction of gene mutations were determined simultaneously after treatment with the four ethylating agents, ethyl methanesulfonate (EMS), ethylnitrosourea (ENU), diethyl sulfate (DES), and N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG). Both, in E. coli K-12 (NAL-resistance) and in V79 Chinese hamster cells in culture (HPRT-deficiency), the frequencies of mutation induction by all chemicals were the same when plotted against the amount of O6-ethylguanine formed in DNA, suggesting that this DNA adduct can be used as a common dosimeter for the comparisons of the frequencies of gene mutations induced by ethylating agents in various mutagenicity assay systems. Using ENU, such a comparison was performed between mutation induction in V79 cells in vitro and in the specific-locus assay in the mouse. The data indicate that at equal levels of O6-ethylguanine in the DNA of V79 cells and in testicular DNA from male mice treated with ENU, the frequencies of induced mutants in both assay systems were quite similar. These results support the concept that the determination of premutagenic DNA adducts in vivo can be used to monitor exposure to chemical mutagens and that genetic risk estimations may ultimately be performed on the basis of such measurements and of comparative mutagenesis in vitro and in vivo.

Alkylating Agents↗
PubMed1982

Dominant cataract mutations and specific-locus mutations in mice induced by radiation or ethylnitrosourea.

In a combined experiment, dominant cataract mutations and specific-locus mutations were scored in the same offspring. In radiation experiments, a total of 15 dominant cataract and 38 specific-locus mutations was scored in 29396 offspring. In experiments with ethylnitrosourea (ENU), a total of 12 dominant cataracts and 54 specific-locus mutations was observed in 12712 offspring. The control frequency for dominant cataracts was 0 in 9954 offspring and for specific-locus mutations 11 in 169955 offspring. The ratio of radiation-induced recessive visible to dominant mutations was about 2.5:1. The difference was even more pronounced for ENU-induced mutations. The ratio of recessive visibles to dominant cataracts for chemically induced mutations in spermatogonia was about 5.4:1. The two characteristic features of radiation-induced specific-locus mutations--the augmenting effect of dose fractionation and the quantitative differences in the mutation rates between spermatogonial and post-spermatogonial stages--can also be demonstrated for the induction of dominant cataracts. The dominant cataract mutations recovered can be categorized into 7 phenotypic classes: total opacity, nuclear and zonular cataract, nuclear cataract, anterior pyramidal cataract, anterior polar cataract, anterior capsular cataract, and vacuolated lens. The largest class of mutations, a total of 11, affected the anterior polar region, while the number of total opacities in both experiments was 5. The only noteworthy difference observed between the radiation- and ENU-induced mutations recovered was that, of the 2 radiation-induced total lens opacities, both were associated with an iris anomaly and microphthalmia whereas the ENU-induced total opacities were not.

Animals↗
PubMed1982

Induction of unscheduled DNA synthesis in the germ cells of male mice after treatment with hydrazine or procarbazine.

The induction of unscheduled DNA synthesis (UDS) in early spermatid stages of mice was studied after treatment with hydrazine or procarbazine (Natulan). The UDS response was assayed by measuring the levels of [3H]dThd in the nuclei of sperm cells derived from treated and untreated early spermatid stages. The radioactivity present in these nuclei was measured by liquid scintillation counting. Mice were also treated with 100 mg/kg of MMS in order to compare the UDS level induced by this chemical with that induced by hydrazine or procarbazine. The level of UDS induced by hydrazine was not significantly different from that of the untreated controls in any of the 5 doses tested (10-120 mg/kg). Procarbazine, on the contrary, induced UDS in all the 5 doses tested, from 50 to 600 mg/kg. The increase in the UDS response was positively correlated with the increasing dose. The present results with hydrazine indicate either that this compound does not reach the germ cells in sufficient amounts to produce DNA damage or that the repair system in early spermatid stages does not recognize the type of DNA damage produced by this compound. The sensitivity of detection of UDS in the germ cells of male mice is compared with that of the rabbit. At equivalent germ-cell stages and dosage the mouse UDS assay is more sensitive, by a factor of 2 to 3, than the rabbit assay for the induction of UDS by procarbazine and MMS.

Animals↗
PubMed1979

Induction of dominant lethal mutations in male mice by fosfestrol.

Using the dominant lethal assay, the ability of fosfestrol, a diethylstilboestrol derivate, to induce mutations in male mice was tested and confirmed. Up to 300 mg/kg of fosfestrol the induction of mutations occurs exclusively in spermatozoa. A dose of 600 mg/kg of fosfestrol induces dominant lethal mutations up to 10 days posttreatment. The majority of induced dominant lethal mutations in all dose groups are expressed as loss after implantation.

Animals↗
PubMed1979

Procarbazine-induced specific-locus mutations in male mice.

Procarbazine is used in drug-combination treatment of Hodgkin's disease. The specific locus method was used to test and confirm the ability of procarbazine to induce gene mutations in pre- and post-meiotic germ cells of male mice. The lowest dose of procarbazine that significantly increased the mutation frequency in As spermatogonia over the control frequency was 400 mg/kg (P = 0.003). The corresponding dose for the post-spermatogonial germ-cell stages was 600 mg/kg (P = 0.009). The dose--response was linear for the point estimates of the mutation frequencies after treatment of As spermatogonia with 0, 200, 400 and 600 mg/kg. The point estimate of the mutation frequency at the 800 mg/kg level was one-third of that expected from a linear extrapolation. Variation in mutation rates among the 7 loci between the lowest (a locus) and the highest (p locus) was 12-fold. Only 24% of procarbazine-induced specific locus mutations in As spermatogonia were lethal in the homozygous condition. From the mutation spectra and the viability tests, it is concluded that procarbazine-induced mutations may be mainly due to base-pair changes. Procarbazine-induced specific-locus mutations fulfilled the criteria for the estimation of the doubling dose, the dose necessary to induce as many mutations as occur spontaneously. The doubling dose of procarbazine in As spermatogonia of mice was 114 mg/kg. The therapeutic dose for procarbazine is about 215 mg/kg. If man and mouse were equally sensitive, this dose would induce 1.9 times as many mutations as arise spontaneously. From the incidence of patients with Hodgkin's disease (1 : 42 000) the calculated population dose of procarbazine is 5.12 micrograms/kg. Assuming equal sensitivity between the sexes we can calculate, for an estimated number of 30 000 genes, the induction of about 22 mutations per million children due to procarbazine treatment. The same number of induced mutations can be calculated if the risk of patients is used for the estimation of the genetic hazard.

Animals↗
PubMed1977

Dominant lethal mutations in male mice.

Dominant lethal mutations are due to chromosome aberrations as demonstrated by analysis of first cleavage. With a sample size of 40-45 mice per dose the induction of dominant lethal mutations by 10 mg/kg of methyl methanesulfonat (MMS) can be detected in spermatids in the mating interval 9-12 days posttreatment (6-11%). In the same mating interval a dose of 150 mg/kg of MMS induces 100% dominant lethal mutations. MMS and other chemical mutagens can be characterized by their different spermatogenic response. The germ cell stage specific induction of dominant lethal mutations by chemical agents is very likely due to their different pathways and therefore, to different effects on the structural and macromolecular changes during spermatogenesis. The feasibility of standardizing test protocol for the dominant lethal assay in mice, based on collaborative studies, is discussed. The reproducibility of results and the sensitivity of the induction of dominant lethal mutations in the collaborative studies demonstrate the usefullness of the method for mutagenicity screening.

Animals↗
PubMed1976

Mutagenicity testing and risk estimation with mammals.

Mammalian test systems are currently used for mutagenicity screening. The necessity and the limitations of standardizing these methods are discussed for dominant-lethal assay. In addition to the refinement of standard methods, the development of new systems in mammals is emphasized. One promising approach is the detection of presumed somatic mutations. Another new development takes advantage of electrophoretic methods for detecting induced structural alterations of gene products. Mammalian experiments will be essential for the assessment of risks from chemical mutagens. The development of standards for the controlled use of chemical mutagens should be guided by the experience accumulated in radiation genetics. Two methods, the measurement of specific-locus mutation rates in mice and the direct determination of the phenotypic damage of dominant genes affecting the skeleton of mice, are recommended for the assessment of the hazard of chemical mutagens.

Animals↗
PubMed1976

[Genetic hazards in a technological age (author's transl)].

The maximal tolerable risk for mankind due to radiation and chemically induced mutations has been accepted as an increased mutation rate of 25%. A linear dose-effect relationship has been assumed and from the experimentally obtained mutation rate due to irradiation of mouse spermatogonia, the following risk factors were obtained: 1. The doubling dose for specific locus in the mouse is representative of recessive conditions. 2. The mutation rate depends on dose rate and fractionation of the irradiation. 3. The extrapolation factor for using these mammalial results in man is about 1.2. 4. The results of specific locus investigations are representative of all the mutation-types in a mouse that have been investigated. 5. Both sexes are similarly affected. On the above premises, a radiation dose of approximately 75 mrem per annum would increase the spontaneous mutation rate in man by about 9% per generation. The risk due to chemical mutagens should not exceed that due to radiation. Methods similar to those used for radiation risks are able to estimate the chemical risk to the population. The tolerable risk to the population from chemical mutagens depends partly on the radiation burden, but the extent of the chemical burden is unknown. This can only be estimated if the law provides for measurements of mutagenicity for drugs, food additives, biocydal agents and industrial chemicals. A risk analysis should be carried out for those chemo-mutagens which are essential. The chemical burden of all permitted mutagens should not exceed the spontaneous mutation rate by 10% per generation at the most. The human hereditory stock can be protected from irreparable damage only if one succeeds in establishing norms for the controlled use of chemical mutagens similar to the regulations which already exist for radiation protection.

Animals↗