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H V Malling

Publications and source records attributed to H V Malling.

18 recordsLinked to original sources
PubMed1979

Action of N-isopropyl-alpha-(2-methylhydrazino)-p-toluamide hydrochloride (procarbazine hydrochloride) in the germ tissue of mice: dominant lethal effects.

A study was carried out on the effects of N-isopropyl-alpha-(2-methylhydrazino)-p-toluamide (procarbazine, Natulan) in the dominant lethal test in the mouse. Male mice were dosed once and mated with fresh virgin females each week. The utilization of sperm, treated as spermatids or testicular sperm with 100-800 mg/kg, resulted in significant post- and pre-implantation death of embryos. Fertility was markedly reduced after the injection of 200 mg/kg of procarbazine and over. This is probably due to a cell killing effect, the most sensitive stages being differentiating spermatogonia, type A sermatogonia and resting primary spermatocytes. Total sterility was induced for several weeks with doses of 600 and 800 mg/kg. Up to 12 weeks after treatment the number of females with implants was still significantly lower than controls indicating a severe depletion of spermatogonial cells. The spectrum of effects correlates well with the drug's effect on nucleic acid and protein synthesis.

Animals↗
PubMed1979

Influence of subcellular fractions of mammalian testes on the mutagenic activity of nitrofurans toward Escherichia coli; presence of a co-mutagen-like factor.

The activation of nitrofurans to mutagenic intermediates by testicular tissue was investigated. AF-2 and nitrofurazone were tested in a microsomal suspension assay with strain E. coli K-12 343/113 as indicator and subcellular fractions from rabbit testes. Different mutation patterns were observed in the presence or absence of testicular homogenate, indicating the presence of different mutagenic intermediates. The frequency of arg+ reversion increased proportionally to the homogenate concentration suggesting that the nitrofurans were activated by testicular components to intermediates that induced base-pair substitutions. Other experiments showed that a component of low molecular weight, present in the soluble fraction of homogenates of testes from rabbits, rats and monkeys, was responsible for the increased mutation frequency. It is concluded that this "co-mutagen-like" factor either alters the metabolism of nitrofurans in E. coli and/or promotes the formation of base-pair substitution-type mutations. This direct interaction between a nonenzymic component of mammalian testes and the mutation induction/expression process in E. coli suggests the role of co-mutagen-like factors in the sensitivity of testes to nitrofurans.

Animals↗
PubMed1979

Rhesus monkey (Macaca mulatta) model in genetic toxicology mitomycin C clastogenicity in germ cells.

The value of rhesus monkeys (Macaca mulatta) as a genetic toxicology model is limited by their scarcity, expense, and impracticality of progeny testing. However, in some special circumstances, e.g., accidental exposure of humans to potential mutagens, rhesus monkeys or other primates may provide a superior animal model to help to cope with a difficult public health situation. Using the testis as a target organ we found that when primary spermatocytes were treated in pre-leptotene stage with 1 mg mitomycin C/kg body weight, the frequency of exchanges, fragments, sex-chromosome and autosomal univalents increased significantly at diakinesis-metaphase I. This response was absent in cells treated during diplotene, late pachytene or during spermatogonial stages. We suggested that animals should be evaluated not only for genetic toxicology parameters, but also toxicologically, histologically, behaviorally, for carcinogenesis and seminal cytology. Whenever possible, the animals should be recycled.

Animals↗
PubMed1979

Genetic toxicity of procarbazine in bacteria and yeast.

Procarbazine [N-isopropyl-alpha-(2-methylhydrazino)-p-toluamide hydrochloride] is used to treat Hodgkin's disease. This compound was tested in vitro without and with S10 fraction from mice liver (microsomal assay) using Saccharomyces cerevisiae strain D7, Salmonella typhimurium (strains TA98, TA100, TA1535) and in vivo in Swiss albino mice (host-mediated assay) using D7. Procarbazine, without S10 fraction, is highly toxic and induced mitotic crossover, gene conversion, and reverse mutation in D7. It had a toxic effect on all the Salmonella strains; but did not induce reverse mutations at the histidine loci. Procarbazine, with S10 fraction, was less toxic and did not induce genetic effects in yeast or Salmonella. In the host-mediated assay, no genetic effects were seen.

Drug Evaluation, Preclinical↗
PubMed1979

Literature survey of bacterial, fungal, and Drosophila assay systems used in the evaluation of selected chemical compounds for mutagenic activity.

Literature reports were surveyed, with results noted from experiments in seven nonmammalian assay systems used for the detection of mutagenicity or other related genetic effects. A comparison was made of the activities of 54 selected noncarcinogens, procarcinogens, and ultimate carcinogens as revealed by these test systems. Of the compounds tested, 49 (91%) were active in one or more of the assays, and 42 (78%) were positive in at least one system without having to be metabolically activated. In one or more test systems, 17/17 (100%) of the ultimate carcinogens, 27/28 (96%) of the procarcinogens, and 6/9 (67%) of the noncarcinogens were positive. The Ames Salmonella-microsome assay responded with increased mutation frequency to 37/44 (84%) of the carcinogenic compounds but to only 2/8 (25%) of the noncarcinogens tested. The Drosophila system responded to 19/21 (90%) of the carcinogens and to 3/6 (50%) of the noncarcinogens. Prophages were induced when lysogenic bacteria were exposed to 12/21 (57%) of the carcinogens, but not enough tests were done with the noncarcinogens (1/3, or 33%) for a comparison. The other systems reviewed, such as the killing of repair-deficient bacteria, mutations in Escherichia coli and Neurospora crassa, and the host-mediated assay, were not challenged by enough of the compounds for valid comparisons.

Animals↗
PubMed1978

Genetic effects of crocidolite asbestos in Chinese hamster lung cells.

Chinese hamster lung cells cultured in the presence of crocidolite asbestos displayed inhibition of cell growth. Cell death was directly associated with the phagocytosis of larger fibres as observed with the aid of trypan blue. Water soluble components of crocidolite did not appear to inhibit cell growth. Chromosomal aberrations were induced by the asbestos. The aberrations were confined mainly to structural aberrations--breaks and fragments. Electron-microscopic preparation indicated that asbestos was readily contained in phagosomes. Phagocytosed asbestos appeared to be a weak mutagen in its ability to induce gene mutation at the hypoxanthine-guanine phosphoribosyl transferase locus.

Asbestos↗
PubMed1977

A biochemical specific locus mutation system in mice.

Two mouse strains DBA/2J and C57BL/6J are heteromorphic with respect to the electrophoretic mobility of at least 8 enzymes and the beta-hemoglobin chain. The genotype of DBA/2J for these markers is: Es-1, Es-3, Gpd-1, Gpi-1, Id-1, Mod-1, Pmg-1, Dip-1 and Hbb; and of C57B1/6J: Es-1, Es-3, Gpd-1, Gpi-1, Id-1, Mod-1, Pgm-1, Dip-1 and Hbb. Electrophoresis on tissues of interstrain hybrids will show the two parental bands and additional hybrid bands if the enzyme is a polymeric structure. In specific locus mutations which result in loss of activity (deletions, nonsense mutations), the hybrid resembles the non-mutated parent. In the mutation results in a change in electrophoretic mobility, some of the bands on the gel will either run faster or slower compared to the hybrid bands in a normal F1 animal. Fifty DBA/2J males were irradiated with gamma-rays from a Co60 source with two doses of 500 R at 24-h intervals at a dose rate of 95 R/min. After this irradiation the males were sterile for approximately 3 months. After the males regained their fertility, they were continuously mated to C57BL/6 females. Thus far somewhat over 2600 animals have been tested and four new mutations detected, giving a frequency of approximately 1.7 X 10(-4) mutations per locus per generation. The four mutations are: two independent mutations at Hbb, one at Mod-1 and one at Id-1.

Animals↗
PubMed1976

Bromodeoxyuridine resistance induced in mouse lymphoma cells by microsomal activation of dimethylnitrosamine.

Many chemicals are not mutagenic per se, but when metabolized by mammalian tissues yield mutagenic products. Dimethylnitrosamine (DMN) is such a promutagen. It has no effect on cell growth or mutant frequency when incubated alone with L5178Y mouse lymphoma cells, but exerts both mutagenic and toxic effects when incubated in a microsome reaction mixture. Microsomes were prepared from C3H/f We 16-wk-old male mice by the calcium preciptation technique. L5178Y continuously cultured mouse lymphoma cells heterozygous for thymidine kinase (TK+/-) were incubated for 15 min with calcium-precipitated microsomes and various concentrations of DMN in appropriate reaction mixtures. After a 48-hr expression time, treated cells were cloned in soft agar with and without bromodeoxyuridine (BUdR) (50 mug/ml); 10 days later colonies grown to greater than about 200 mum diameter were counted. The frequency of BUdR-resistant (mutant) colonies increased linearly with the DMN concentration. A reconstruction experiment showed that the assay conditions did not significantly alter the relationship between parent and BUdR-resistant cells in growth and cloning efficiency. The smallest dose of DMN used in these experiments was 100mumol/liter, the one-sided (100 mumol greater than control frequency) -p value is 0.036. The locus is extremely sensitive to mutagenesis by DMN compared with other known mutagens at similar levels of cell survival.

Animals↗
PubMed1975

Mutagenicity of actinomycin D in Neurospora crassa.

Actinomycin D is known to bind to native DNA and is widely used as an antineoplastic agent and inhibitor of DNA-dependent RNA and protein synthesis. We report here the induction by actinomycin D of purple adenine-requiring mutants (ad-3) in wild-type Neurospora crassa. A significant increase in the frequency of ad-3 mutants was evident when the organism was grown vegetatively in the presence of actinomycin D; the mutation frequency was at least 3.6 per 106 survivors. The actinomycin D-induced ad-3 mutants were 29% ad-3A and 71% ad-3B. The ad-3B mutants were classed by complementation pattern as 25% nonpolarized complementing; 14% polarized complementing; and 61% noncomplementing. The spectrum of complementation types of the actinomycin D-induced mutants most closely parallels that of mutants induced by ICR-170, known to induce base-pair insertions or deletions, or that of X ray-induced or spontaneous mutants. It is significantly different from spectra seen following treatment with nitrous acid or N-methyl-N'-nitro-N-nitrosoguanidine, agents known to induce mainly base-pair substitutions.

Adenine↗
PubMed1975

Azaguanine-resistant mutants induced by several mutagens in a neurospora heterokaryon.

This paper reports the development of a new system for the detection of forward mutations in a heterokaryon of Neurospora crassa. This system, designed to detect a wide variety of genetic alterations, is based upon the detection of 8-azaguanine-resistant mutants in an adenine-requiring heterokaryon carrying the aza-3 gene. Induction of mutations in the aza-3 gene was detected after treatment of conidia with ultraviolet light, X-rays, ethyl methanesulfonate (EMS), or the acridine mustard, ICR-170. The pattern of appearance of mutant colonies and various factors in mutant selection are discussed.

Acridines↗
PubMed1975

Factors affecting metabolism and mutagenicity of dimethylnitrosamine and diethylnitrosamine.

For exploration of the factors affecting dimethylnitrosamine (DMN) mutagenicity, for gathering of information on the metabolism of DMN, a frequently used and relatively well-understood carcinogen, and for explanation of metabolic variations in DMN carcinogenicity, parallel in vitro assays of the microsomal activation of DMN to a mutagen and of DMN demethylation were performed. Salmonella typhimurium G46 reversions to histidine independence increase linearly with time of incubation for 30 min. At low concentrations of microsomal protein, increases in protein yield a more than proportional increase in mutations. Increasing DMN concentration saturates the enzyme, yielding less demethylation and fewer mutations proportionately. Mutagenesis is completely inhibited by 1 mM 2-diethyl-aminoethyl-2,2-diphenylvalerate. When both DMN and microsomal protein are varied at high concentrations, there is a simple linear relationship between mutagenicity and DMN demethylase activity. Thus DMN demethylase activity may be the primary controlling factor in the metabolism of DMN to a mutagen, and probably to a carcinogen; other simultaneous pathways of DMN metabolism proportional to demethylation have not been ruled out. Induction with both phenobarbital and 3-methylcholanthrene (3-MC) increased rat and mouse liver DMN demethylase activity. Mouse liver microsomes from the C57BL/6 strain demethylate DMN at a markedly lower rate than do microsomes from the C3H strain, but after 3-MC induction the relationship is reversed. Strain differences in activation of DMN were not found in the activation of diethylnitrosamine to a mutagen. Hepatic dealkylation of DMN and diethylnitrosamine to active mutagenic metabolites is increased in both rats and mice by both 3-MC and phenobarbital induction, which is in contrast to the findings of others that 3-MC and phenobarbital induction, which is in contrast to the findings of others that 3-MC decreases the incidence of DMN-induced hepatic tumors in rats, and phenobarbital decreases the incidence of diethylnitrosamine-induced hepatic tumors in mice.

Animals↗