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Biomedical subjects

I D Adler

Publications and source records attributed to I D Adler.

At least 91 records · Page 5Linked to original sources
PubMed1990

Bleomycin effects on mouse meiotic chromosomes.

The effects of a radiomimetic chemical, bleomycin (BLM), on meiotic chromosomes was evaluated in mice treated by intraperitoneal (i.p.) or intratesticular (i.t.) injection. Chromosome aberrations were analyzed at meiotic metaphase I, and damage to the synaptonemal complex (SC) was analyzed in meiotic prophase cells. In the metaphase aberration studies, an i.p. injection of 80 mg/kg BLM, timed to precede or coincide with pre-meiotic S phase, led to a significant increase in structural damage (P less than 0.01) in cells reaching metaphase I 12 days after treatment. However, no increases in clastogenic effects were observed at metaphase I after treatment of cells during various stages of prophase. SC analyses in pachytene cells following an i.p. or i.t. injection at S phase revealed various forms of synaptic errors and structural anomalies, including qualitative changes similar to those observed following irradiation. I.p. doses ranging from 25 to 100 mg/kg, and i.t. doses as low as 0.5 mg/kg, caused roughly 6-fold increases over control levels in the number of damaged cells. SC analyses in pachytene cells following BLM treatments 2 days earlier (at leptotene-zygotene) or 16 h earlier (at early-mid pachytene), also revealed induced structural and synaptic anomalies. Following the treatment at early-mid pachytene, there was some suggestion of interference with chiasma formation as evidenced by univalent-like configurations detected at diakinesis-metaphase. It was concluded that BLM is clastogenic for meiotic chromosomes; however, it does not reveal the strong S-independent clastogenic activity at meiosis that is characteristic of its activity at meiosis. SC analysis indicated that some damage is induced at meiotic prophase, although structurally aberrant cells are not recoverable at meiotic metaphase I. The results call forth various possible explanations for germ-line specific responses to BLM clastogenic activity.

Animals↗
PubMed1989

Clastogenic effects of benzo[a]pyrene in postimplantation embryos with different genetic background.

Certain strains of mice vary in their enzyme inducibility by polycyclic hydrocarbons, i.e., the strain C57 shows high and the strain DBA shows low inducibility of aryl hydrocarbon hydroxylase (AHH) by benzo[a]pyrene (BaP). The effect of this genetically determined difference on the clastogenic response to BaP was studied in 11 day old embryos after transplacental treatment. The four possible crosses, C57 and DBA inter se, C57 X DBA and DBA X C57, were used to determine the influence of the genetic background on the aberration yields in the embryos. Constitutive and induced AHH levels were measured in liver, bone marrow, and placenta of the pregnant females and in their embryos. Enzyme inducibility was high in tissues of C57 dams and in their homozygous or heterozygous embryos. In contrast, induction of AHH activity was low in tissues of DBA females and their homozygous embryos. The high BaP-induced AHH activity found in heterozygous embryos of DBA dams is in agreement with the dominant mode of inheritance for high AHH inducibility. The cytogenetic results showed that the clastogenic response was lowest in homozygous C57 embryos and highest in hybrid embryos independent of the genetic constitution of the dams. Homozygous DBA embryos showed an intermediate aberration yield. The AHH inducibility by BaP did not correlate quantitatively with the induced aberration rates. However, the data suggest that BaP activation in embryonic tissue on day 11 of pregnancy is sufficient to account for the clastogenicity in the fetuses. It is concluded that the genetic endpoint chromosomal breakage is not only determined by the formation of active BaP metabolites but also by genetically controlled detoxification of BaP, repair process, and the rate of transformation of primary DNA lesions into true DNA discontinuities.

Animals↗
PubMed1989

The present lack of evidence for unique rodent germ-cell mutagens.

Six chemicals, diethylhexyl phthalate (DEHP), ethanol, cyclohexylamine (CHA), sodium saccharin (NaS), cadmium chloride (CdCl2) and triflupromazine (TFP), were suggested to be unique germ-cell mutagens (Auletta and Ashby, 1988) by the GeneTox Workgroups of the U.S. Environmental Protection Agency (EPA). If this is a correct classification it would have major consequences when screening for mutagenicity and when labelling genotoxic substances. However, our re-evaluation of the GeneTox literature, including some more recent publications, has failed to find substantive evidence that any of these chemicals have been unequivocally established as having unique mutagenic activity in germ cells. For DEHP, NaS and TFP the evidence for genotoxic/mutagenic effects is questionable, in both germinal and somatic cells. Ethanol and CdCl2 showed clastogenic activity, but it was not restricted to germ cells. Both, ethanol and cadmium salts, appear to induce aneuploidy. The unconfirmed clastogenic effect of CHA was restricted to rats, but it occurred in both bone marrow and spermatogonia. Therefore, the general observation that rodent germ-cell mutagens are also genotoxic in somatic cells in vivo (Brusick, 1980; Holden, 1982) remains valid.

Animals↗
PubMed1989

Clastogenic effects of cis-diamminedichloroplatinum. I. Induction of chromosomal aberrations in somatic and germinal cells of mice.

The clastogenicity of cisplatin, cis-diamminedichloroplatinum(II), an extensively used antitumor drug, has been studied employing (101/E1 X C3H/E1)F1 mice, aged 12-14 weeks. Chromosomal aberrations were assessed in mitotic divisions of bone marrow cells and differentiating spermatogonia. The drug was tested at 3 doses, 0.5, 1.0 and 2.5 mg/kg and 1.0, 2.5 and 5.0 mg/kg, respectively, for bone marrow and spermatogonia. Cisplatin had a clastogenic effect which was dose-dependent in both cell types. The frequencies of aberrant cells increased non-linearly in bone marrow and the dose-response relationship could be best described by a linear-quadratic equation. At the highest dose the affected cells carried multiple aberrations. An average of 2.7 aberrations per aberrant cell was observed 12 h after treatment of the mice with 2.5 mg/kg of cisplatin. In differentiating spermatogonia the dose response for aberrant cells could be described by a linear equation. The damage to the individual affected cell was less dramatic than in bone marrow, averaging 1.4 aberrations per damaged cell at the highest dose tested. Gaps were excluded from these considerations but they generally also showed a dose-related increase. A quantitative comparison of the clastogenic response to cisplatin was based on the dose-response relationships using 2 criteria, the doubling dose and the dose of unit increase (DUI). For both comparisons the general conclusion was that bone marrow cells were twice as sensitive as differentiating spermatogonia to the clastogenic action of cisplatin.

Animals↗
PubMed1989

Evaluation of chromosomal aberrations in bone marrow of 1C3F1 mice.

The chemical caprolactam (CAP) was tested for induction of chromosomal aberrations in bone marrow of male and female 1C3F1 mice at a single dose of 1000 mg/kg by oral intubation of an aqueous solution at a volume of 0.1 ml/10 g of body weight. Bone marrow was sampled from groups of 10 animals 24, 30 and 48 h after treatment. CAP did not produce chromosomal aberrations under the present experimental conditions. At the same time, benzo[a]pyrene, used as a positive control, significantly increased the aberration rates at a dose of 63 mg/kg.

Animals↗
PubMed1989

The influence of the Robertsonian translocation Rb(X.2)2Ad on anaphase I non-disjunction in male laboratory mice.

A Robertsonian translocation in the mouse between the X chromosome and chromosome 2 is described. The male and female carriers of the Rb(X.2)2Ad were fertile. A homozygous/hemizygous line was maintained. The influence of the X-autosomal Robertsonian translocation on anaphase I non-disjunction in male mice was studied by chromosome counts in cells at metaphase II of meiosis and by assessment of aneuploid progeny. The results conclusively show that the inclusion of Rb2Ad in the male genome induces non-disjunction at the first meoitic division. In second metaphase cells the frequency of sex-chromosomal aneuploidy was 10.8%, and secondary spermatocytes containing two or no sex chromosome were equally frequent. The Rb2Ad males sired 3.9% sex-chromosome aneuploid progeny. The difference in aneuploidy frequencies in the germ cells and among the progeny suggests that the viability of XO and XXY individuals is reduced. The pairing configurations of chromosomes 2, Rb2Ad and Y were studied during meiotic prophase by light and electron microscopy. Trivalent pairing was seen in all well spread nuclei. Complete pairing of the acrocentric autosome 2 with the corresponding segment of the Rb2Ad chromosome was only seen in 3.2% of the cells analysed in the electron microscope. The pairing between the X and Y chromosome in the Rb2Ad males corresponded to that in males with normal karyotype. Reasons for sex-chromosomal non-disjunction despite the normal pairing pattern between the sex chromosomes may be seen in the terminal chiasma location coupled with the asynchronous separation of the sex chromosomes and the autosomes.(ABSTRACT TRUNCATED AT 250 WORDS)

Anaphase↗
PubMed1989

Suspect spindle poisons: analysis of c-mitotic effects in mouse bone marrow cells.

In the coordinated programme to study aneuploidy induction, sponsored by the Commission of the European Communities, 10 known or suspect spindle poisons (colchicine, econazole, chloralhydrate, hydroquinone, diazepam, thiabendazole, cadmium chloride, pyrimethamine, vincristine and thimerosal) were tested in mouse bone marrow cells for the induction of c-mitotic effects. Three criteria were chosen: changes of the mitotic index, induction of chromatid contraction and spreading and decrease of anaphase frequencies. Among the chemicals tested colchicine, econazole, chloralhydrate, hydroquinone and vincristine were found positive. Diazepam, thiabendazole, cadmium chloride, pyrimethamine and thimerosal revealed no induction of c-mitotic effects under the conditions tested. Mitotic block and subsequent chromosome malsegregation (non-disjunction) are related phenomena. The three criteria chosen are considered as an indicative pre-screening test for the aneuploidy inducing potency of a chemical in mitotic, but not in meiotic cells. The present experiments were also regarded as a dose-finding exercise for further in vivo studies.

Anaphase↗
PubMed1988

Radiation-induced translocations in spermatogonial stem cells of Macaca fascicularis and Macaca mulatta.

3 adult monkeys, one Macaca fascicularis and two Macaca mulatta, were whole-body irradiated with 1 Gy gamma-rays (60 Co). Reciprocal translocations induced in spermatogonial stem cells were scored as translocation multivalents in primary spermatocytes from 7.5 to 27.5 months after exposure. The translocation yields ranged from 4.1% at the earliest to 1.8% at the latest sampling interval. No significant differences were observed in the responses of the individual animals. A decline in the translocation frequencies with time after treatment was found in all 3 animals. The present data are different from those reported for testicular X-irradiation of the rhesus monkey Macaca mulatta (van Buul, 1980; Lyon et al., 1976) in that the translocation yields are higher. They are consistent with the results reported for testicular gamma-irradiation of the crab-eating monkey Macaca fascicularis (Matsuda et al., 1984, 1985). In view of the present results it appears unlikely that a species difference exists within the genus Macaca in the sensitivity of spermatogonial stem cells to the induction of translocations by ionizing radiation.

Animals↗
PubMed1988

Clastogenic effects of acrylamide in mouse bone marrow cells.

Acrylamide, known to induce dominant-lethal mutations (Shelby et al., 1986; Smith et al., 1986) and heritable translocations (Shelby et al., 1987) in rodent germ cells, was hitherto a questionable clastogen in rodent bone marrow (Shiraishi, 1978). Therefore, it was tested for chromosomal aberrations in mouse bone marrow cells, spermatogonia and by the micronucleus test. The intraperitoneally injected doses ranged from 50 to 150 mg/kg. In the chromosomal bone marrow test and the micronucleus assay positive results were obtained with acrylamide, and in the latter test the effect increased linearly with dose. Chromosomal aberrations were not induced in differentiating spermatogonia by the acute acrylamide treatment. Cisplatin was used as a positive control and gave the expected positive response in all 3 tests. The present results demonstrate that acrylamide is no exception among clastogens. It breaks chromosomes not only in mammalian germ cells but also in somatic cells.

Acrylamide↗
PubMed1987

Micronucleus test in bone marrow of mice treated with 1-nitropropane, 2-nitropropane and cisplatin.

Micronucleus tests were carried out in bone marrow of mice treated with 1-nitropropane, 2-nitropropane and cisplatin. For 1-nitropropane and 2-nitropropane the results were negative. With cisplatin a dose-dependent increase in the number of polychromatic erythrocytes with micronuclei was observed. The lowest positive dose was 0.1 mg/kg (P less than 0.001, Mann-Whitney-Wilcoxon test). The hepatocarcinogen 2-nitropropane showed clastogenic activity in human lymphocytes in vitro in the presence of S9 (Bauchinger et al., 1987). The negative results in bone marrow suggest that short-lived genotoxic metabolites may be formed in the liver but do not reach the bone marrow.

Alkanes↗
PubMed1983

New approaches to mutagenicity studies in animals for carcinogenic and mutagenic agents. II. Clastogenic effects determined in transplacentally treated mouse embryos.

Cell suspensions from whole embryos were obtained on the 12th day of gestation from treated pregnant female mice. For the present experiments five model mutagens-BaP, bleomycin, mitomycin C, procarbazine, and TEM--were chosen for their different modes of action in inducing chromosomal aberrations. Time-response and dose-response were studied for chromosomal aberrations induced by transplacental treatment of mouse embryos. All five known mutagens gave a positive response in the present system. The maximum time of response varied from compound to compound and was found as early as 3h after treatment with the G2-clastogen bleomycin or as late as 18 h after treatment with the bifunctional alkylating agent TEM. Chromatid breaks and exchanges increased with dose in all instances. The correlations between clastogenic, carcinogenic, and teratogenic effects are discussed. It is concluded that the transplacental cytogenetic test may be applicable to identify chemicals that exhibit all three properties.

Animals↗
PubMed1983

Comparison of types of chemically induced genetic changes in mammals.

The present paper reviews the currently available in vivo systems for detection of chemically induced mutations and chromosome aberrations and summarizes the data of the relevant tests for mammalian germ-cell mutations (specific-locus test and heritable translocation test). The value of in vivo screening tests (somatic mutations and sperm abnormalities) for predicting specific-locus mutations is illustrated by comparing doubling doses. The results from the mammalian germ-cell mutation tests (specific-locus test and heritable translocation test) constitute the base-line for an assessment of predictability. Radiation and chemically induced specific-locus mutations differ in a number of respects, suggesting a need for caution in making risk estimates for chemical mutagen exposures in terms of radiation-equivalent doses. In vivo nondisjunction tests are discussed. Finally, unsolved problems and difficulties in generalizing qualitative and quantitative correlations between test systems are outlined. It is concluded that even qualitative predictions from data on somatic cells to germ cells are at best insecure because germ-cell specificity cannot be foretold, not to mention the fact that quantitative extrapolations from the results of in vivo screening tests, in general, are fraught with even more uncertainties. There is an acute need for collection of more data from studies involving germ cells.

Animals↗
PubMed1982

Studies on the mutagenic potential of the pesticide chlordimeforme and its principal metabolites in the mouse heritable translocation assay.

Chlordimeforme and its 2 principal metabolites, N-formyl-4-chloro-o-toluidine and 4-chloro-o-toluidine, were studied for induction of heritable translocations. Maximal tolerated doses of the compounds were given daily by gavage for 7 consecutive weeks. After mating with untreated females, about 1000 F1 male offspring per group--including vehicle control and positive control (Tretamine, TEM)--were tested for their reproductive performance by use of a sequential decision procedure on litter sizes to select males with translocation heterozygosity. Partially sterile, sterile and non-classifiable F1 males were examined cytogenetically by scoring meiotic chromosomes for translocation multivalents or analysing mitotic divisions for marker chromosomes. The 3 compounds tested at dose levels showing toxic effects did not induce translocation heterozygosity. Tretamine, the positive control, gave the expected mutagenic response.

Amidines↗
PubMed1982

Mouse spermatogonia and spermatocyte sensitivity to chemical mutagens.

Twenty-one chemicals have been tested for the induction of chromatid aberrations in differentiating spermatogonia, and 14 of them gave a positive response. However, when spermatocytes derived from treated As-spermatogonia were analyzed for reciprocal translocations, the results were negative for 10 out of 17 chemicals tested. For the remaining 7 chemicals, either conflicting results or no dose dependency has been reported. The difference between aberrations in differentiating spermatogonia and the lack of translocations in spermatocytes after treatment of stem-cell spermatogonia was most obvious with mitomycin C. Reasons for this difference are discussed. In meiotic prophase, mitomycin C and TEM caused aberrations observable at diakinesis only after treatment of spermatocytes in S-phase. In contrast, ionizing radiation produces its main effect during pachytene. Translocation heterozygotes were recovered among progeny of mitomycin C- and TEM-treated spermatocytes. Conclusions for human health hazards are: (1) chromosomal aberrations induced by chemical mutagens in spermatogonia do not pose a considerable risk because they do not sufficiently survive germinal selection; (2) chemical treatment of spermatocytes can result in chromosomally abnormal offspring. The quantification of human ill health based on translocation yields obtained in animal experiments poses great difficulties that have not been resolved.

Animals↗