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At least 19 recordsLinked to original sources
PubMed1978

Dominant lethal effects of triethylenemelamine in the guppy Poecilia reticulata.

The need to screen potential chemical pollutants for mutagenicity has increased with the increasing volume of such materials being introduced into natural water. The present study demonstrates the utility of a fish, the guppy (Poecilia reticulata), as a model test system in which water-borne chemical mutagens may be assayed for dominant lethal effects. Mature male guppies were injected with three doses of triethylenemelamine (0.1, 0.2 and 0.4 mg/kg) in addition to a control sham treatment. Each male was subsequently mated to virgin females. In an alternative test, male fish were allowed to swim in triethylenemelamine solutions of known concentration for a period of 24 h prior to being mated to virgin female guppies. 10 days following matings, females were dissected, and numbers of live and dead embryos were recorded. Significant dose effects were demonstrated by analysis of variance techniques in both the injection and the emersion tests with the results showing higher percentages of dead embryos and lower total number of embryos with increasing doses of TEM.

Animals↗
PubMed1992

Flow-cytometric analysis of the effects of triethylenemelamine on somatic and testicular tissues of the rat.

The effects of short-term (24 h) exposure to triethylenemelamine on cellular DNA in five tissues (bone marrow, spleen, kidney, large intestine, and testis) of the rat were studied using flow cytometry. Mean coefficients of variation of the G1 peaks were increased in both the low and high dosage groups relative to controls. Bone marrow exhibited the highest degree of effect, possibly due to the rapid rate of cell division in that tissue, and spleen was next highest. Thus, hematopoietic tissues are highly responsive to short-term, acute exposure to this mutagen. The results of the flow-cytometry assay closely paralleled a simultaneous chromosomal assay conducted on bone marrow of the same rats. These data are interpreted to be consistent with the hypothesis that the observed increase in mean coefficients of variation is due to the clastogenic effects of the mutagen and subsequent unequal distribution of DNA among the daughters of affected cells.

Animals↗
PubMed1994

Further flow cytometric studies of the effects of triethylenemelamine on somatic and testicular tissues of the rat.

Exposure to the mutagen triethylenemelamine on rat bone marrow, blood, and testis was studied using flow cytometry of DAPI-stained nuclei. Increased coefficients of variation (CVs) of the G1 peaks were observed in bone marrow and blood after both 1 d and 5 d exposures. After 5 d exposure and 7 d recovery both tissues had recovered, in some cases to significantly lower CVs. Increased CVs of the 1C peak of testis were observed only after 5 d exposure to the high dose with no subsequently observed recovery. Bone marrow cells also were stained with Hoechst 33258 and Propidium Iodide. No differences among dyes were observed indicating that increased CVs likely are due to DNA damage resulting from interactions with the mutagen rather than differences in how the dyes bind to DNA relative to mutagen binding. This study demonstrates that differences occur among tissues in how quickly they respond and recover from mutagen exposure. Increased CVs, cell cycle alterations, and decreased CVs after recovery are all potentially useful biomarkers of effect for laboratory and field studies in environmental toxicology.

Animals↗
PubMed1989

Initiating carcinogen, triethylenemelamine, induces micronuclei in skin target cells.

Keratinocytes from mouse skin were cultured for a short period in vitro following single or multiple treatments at low dose levels in vivo with the known chromosome-damaging agent triethylenemelamine (TEM). The chemical was applied to the skin of HRA/Skh hairless mice at concentrations corresponding to those reported to initiate cancer in initiation-promotion assays. A significant dose-related depression in keratinocyte cell recovery occurred over the dose range 0.3-1 mg TEM/mouse (single or multiple treatments). Under the same conditions, a dose-related induction of micronuclei was observed using the cytokinesis-block method with cytochalasin B. A similar frequency of micronuclei was detected in binucleate cells from mice treated with single or multiple applications of TEM. Mice held for 12-48 h post-treatment, before removal of skin for in vitro culture, yielded highest micronuclei frequencies. These results indicate that the same target cell population, skin keratinocytes, can be used to investigate both genotoxicity and carcinogenesis, and that micronucleus induction in these cells may be a sensitive signal of skin cancer initiation.

Animals↗
PubMed1989

Long-term effects of triethylenemelamine exposure on mouse testis cells and sperm chromatin structure assayed by flow cytometry.

The toxic and potentially mutagenic actions of triethylenemelamine (TEM) on mouse body and testis weights, testicular cell kinetics, sperm production, sperm head morphology, and sperm chromatin structure were assessed in two experiments. The first experiment examined effects of four dose levels of TEM, assayed 1, 4, and 10 wk after toxic exposure. In the second study, effects from five dosage levels were measured at 1, 4, and 10 wk, and the highest dosage level was evaluated over 44 wk. TEM produced an expected dose related loss of spermatogenic activity and subsequent recovery as determined by dual-parameter (DNA, RNA) flow cytometry (FCM) measurements of testicular cells. Both testicular weights and caudal sperm reserves remained generally below controls after 44 wk recovery following exposure to the highest (1.0 mg/kg daily x 5) dosage. Chromatin structure alterations, defined as increased susceptibility to DNA denaturation in situ, and sperm head morphology were highly correlated (.87-.93, P less than .001) with dose and with each other. Data obtained from the sperm chromatin structure essay (SCSA) on fresh sperm was highly correlated with measurements of aliquots of the same sample collected over 44 wk, frozen, and then measured on the same day. Sperm head morphology and sperm chromatin structure remained abnormal at 44 wk for the 1.0 mg/kg TEM dosage, suggesting that the abnormalities, present long after the initial toxic response, may be a result of mutation. This study demonstrates that flow cytometry provides a unique, rapid, and efficient means to measure effects of reproductive toxins and potential mutagens.

Animals↗
PubMed1979

Dominant lethality in frog embryos after paternal treatment with triethylenemelamine: cytogenetics, morphology, and swimming capability.

Male frogs (Rana pipiens) were injected intraperitoneally with triethylenemelamine (TEM). The injected males were held for seven days to permit TEM interaction with sperm. The TEM-treated males were then spermiated with human chorionic gonadotropin (HCG) and the ova of normal females were inseminated with the sperm. Direct observation was made of in vitro fertilized ova, cleavage, blastulation, and subsequent embryonic development. No differences were detected between the controls and treated animals from any experimental group for fertilization, cleavage, and blastulation. Dose-related morphologic abnormalities first became apparent at the time of gastrulation; the capability of hatched embryos to swim was affected by TEM. Metaphase chromosomes were studied from randomly selected embryos, and the prevalence of chromosomal structural abnormalities increased with dose over a range of 13--1,300 microgram TEM per kilogram frog.

Animals↗
PubMed1987

Effect of mode of administration of methyl methanesulfonate and triethylenemelamine on induction of unscheduled DNA synthesis in mouse germ cells.

The effect of route of administration on induction of unscheduled DNA synthesis (UDS) in mouse germ cells in vivo was studied using two germ cell mutagens, methyl methanesulfonate (MMS) and triethylenemelamine (TEM). The chemicals were administered to male mice (C3Hf X 101)F1 by IP injection or gavage using acute or 5-day subacute regimens. After completion of dosing, methyl-[3H]thymidine [( 3H]TdR) was injected into the testes, and spermatozoa were collected 16 days later. The sperm heads were isolated, and UDS was determined by the amount of [3H]TdR incorporated. Acute administration of MMS (2-100 mg/kg) induced a strong, dose-related UDS response. The response was slightly higher with IP injection than with gavage. The UDS response after five daily doses of 50 mg MMS/kg was 20-30% higher than that induced by a single IP or gavage dose. Acute administration of TEM (0.05-4.0 mg/kg) by IP injection or gavage induced weak and variable responses. Retesting TEM using inbred C3Hf mice produced weak but exposure-related responses with both acute IP and gavage treatments. There was a slight increase in UDS response with subacute IP injection but not with subacute gavage. Acute testicular injection of TEM produced a higher but more variable UDS response. The study showed that gavage, as well as IP injection, can be used for the administration of test chemicals and that the subacute 5-day regimen induced a higher UDS response than the acute regimen. Furthermore, the testicular route may enhance the detection of weak UDS inducers.

Animals↗
PubMed1980

Dominant lethality in Xenopus laevis induced with triethylenemelamine (TEM).

Adult male South African clawed toads, Xenopus laevis, were injected intraperitoneally with triethylenemelamine (TEM) dissolved in water over a dose range of 13-1,300 micrograms/kg or with water (controls). Mating of the treated males with untreated females was induced seven days later by injection of human chorionic gonadotropic hormone (HCG). Accumulated lethality one week after fertilization among progeny was dose related. Morphological abnormalities among embryos that survived to hatching were similarly dose related. Because anatomically anomalous embryos may have impaired behavior, swimming capacity was tested, and anomalies in swimming behavior were also found to be dose related. Finally, short-term cell cultures were made on minced embryos to obtain chromosome spreads. Structural aberrations, rings, dicentrics, etc of somatic chromosomes were also dose related.

Animals↗
PubMed1992

Transplacental genotoxicity of triethylenemelamine, benzene, and vinblastine in mice.

Transplacental cytogenetic effects of triethylenemelamine (TEM), benzene, and vinblastine on maternal mice and their fetuses have been investigated using micronucleus and sister chromatid exchange (SCE) as genetic endpoints. CD-1 mice were treated on day 14 and 15 of gestation with TEM (0.125, 0.25, and 0.5 mg/kg), benzene (439,878, and 1,318 mg/kg), and vinblastine (0.5, 1, and 2 mg/kg) by intraperitoneal injection at 24 hr intervals, and sacrificed 40 hr after the first injection. Erythrocytic precursor cells in maternal bone marrow and fetal livers (2-4) from each pregnant mouse were used for the micronucleus and/or the SCE analyses. Significant dose-related increases in both micronuclei and SCE were found in maternal bone marrow and fetal liver following TEM treatment. Benzene at the highest dose (1,318 mg/kg) also caused a significant increase in micronuclei and SCE in both maternal bone marrow and fetal liver cells. The embryonic genotoxic effect of TEM was much higher than that of benzene for both genetic endpoints, and the frequency of micronuclei induced by benzene was higher in fetal liver than in maternal bone marrow cells. Vinblastine, a spindle poison, induced micronuclei but not SCE. Micronuclei induction by vinblastine was 7 fold greater in maternal bone marrow than in fetal liver cells. All three chemicals were cytotoxic in maternal bone marrow cells, but not in fetal liver cells except for TEM, which showed a weak cytotoxicity in fetal liver cells in the micronucleus assay. These results indicate that TEM, benzene, and vinblastine are transplacental genotoxicants in mice.

Animals↗
PubMed1995

Measurement of DNA integrity and structure in Xenopus embryos in the presence of hydroxyurea, actinomycin-D, and triethylenemelamine using the fluorescent probe Hoechst 33258.

Cell health assay of water quality (CHAWQ) is an assay using intracellular biomarkers measured by optical techniques. CHAWQ uses embryos of the South African clawed frog, Xenopus laevis, and optical transducers of intracellular biomarkers to obtain rapid assessment of toxicity to frog embryos. Since the biomarkers are common to all cells, CHAWQ can indicate toxicity of different classes of chemicals. Among the biomarkers used are 1) the change in synthesis rate, 2) the structure, or 3) the environment of DNA. Measurement of DNA to detect genotoxicants has previously used extracted DNA or flow cytometry to detect alterations in DNA content or configuration. We report the use of viable frog embryos and the fluorescent probe Hoechst 33258 to detect the effect of three DNA-active chemicals--actinomycin-D, hydroxyurea, and triethylenemelamine (TEM)--on DNA in intact embryos. We found that we can detect changes in the DNA in the presence of toxicants at concentrations comparable to longer-term assays but following a much shorter time of drug exposure. Actinomycin-D caused a fluorescence decrease, TEM caused a fluorescence increase, whereas hydroxyurea gave a biphasic response. Hydroxyurea caused a decrease at low concentrations and an increase at higher concentrations. Concentration-response data for TEM, hydroxyurea, and actinomycin-D generated EC50 values of 0.1 mg/ml, 1.4 mg/ml, and 6.34 micrograms/ml, respectively.

Animals↗
PubMed1975

Premature chromosome condensation, structural chromosome aberrations, and micronuclei in early mouse embryos after treatment of paternal postmeiotic germ cells with triethylenemelamine: possible mechanisms for chemically induced dominant-lethal mutatiions.

Cytogenetic effects in preimplantation 4-8-cell mouse embryos have been investigated after treating paternal postmeiotic germ cells with triethylenemelamine (TEM). Dose-levels of TEM which do not affect fertilization but yield high incidence of dominant-lethal mutations in sperm and spermatids were shown to produce relatively high frequencies of (a) premature chromosome condensation (PCC), (b) structural chromosome anomalies (breakage-reunion phenomena), and (c) micronuclei in these embryos. The results indicate that genetic death of embryos is mainly due to imbalance (i.e. loss) of genetic material, either from breaks leading to lagging fragments and micronuclei, or from the segregation of various types of exchange figures (dicentrics, rings etc.) resulting in mechanical disturbances of cleavage division. It is suggested that PCC, to some extent, is an expression of TEM-induced long-lived lesions which, transmitted into the egg, prevent the chromosomes in question from replicating and/or condensing normally. This phenomenon could well be associated with loss of chromosome material resulting in embryonic death.

Animals↗
PubMed1975

[Investigations on the mutagenic effect of triethylenemelamine (TEM) on early embryonic tissue and bone marrow of the rat by chromosome analysis (author's transl)].

Female rats were treated with triethylenemelamine (Tretamine; TEM) with a dose of 0.4 mg/kg body weight and 0.6 mg/kg body weight respectively on days 1, 2, 3; 3, 4, 5 or 6, 7, 8 post coitum. The animals were slaughtered on day 9 or pregnancy. Corpora lutea and living and dead embryos were counted to estimate embryonic loss. Thereafter chromosome-analysis of bone marrow cells and embryonic tissue took place. Highter TEM dosage increased the rate of embryonic loss. It increased from 28.1% with a dose of 3 X 0.4 mg TEM to 75.7% with 3 X 0.6 mg TEM. The level of embryonic loss depends on the time of treatment during different stages of early gestation. It was highest on the first 3 days and lowest on days 6-8 of gestation (0.4 mg TEM on -ays 1, 2, 3 p.c., 71.8%; 0.4 mg TEM on days 6, 7, 8 p.c., 2.9%). By the chromosome analysis, early embryonic tissue seemed to be more sensitive to TEM than bone marrow cells. The highest rates of numerical (35.7%) and (3 X 0.4 mg TEM). A higher dose induced a negative dose-effect, the frequency of aberrations decreased (3 X 0.6 mg TEM, 29% NUMERICAL AND 1.2% STRUCTURal aberrations). With increased embryonic loss (from 28.1% to 75%) structural aberrations decreased (from 5.7% to 1.2%). The time of treatment p.c. was highly correlated with the frequency of aberrations. It was highest with TEM application on days 6, 7, 8 of pregnancy; at the same time the mortality rate was lowest. The same tendencies were noted in the investigation of the chromosomes from bone marrow cells.

Animals↗
PubMed1975

An evaluation of the micronuclei test using triethylenemelamine, trimethylphosphate, hycanthone and niridazole.

To determine the feasibility of the micronuclei procedure for cytogenetic studies, a comparatively weak chromosome breaking agent, trimethylphosphate (TMP) and the potent alkylating agent, triethylenemelamine (TEM) were evaluated. The procedure followed was that of Matter and Schmid with the following modifications: (a) direct flushing of bone marrow with 0.2 ml calf fetal serum. (b) air drying slides for a period of only I h, and (c) the use of pH 6.0 phosphate buffer to dilute both Wright and Giemsa stains. With this technique a dose response curve was generated for both TMP and TEM, using mice as the experimental animal. With TMP, a doubling over background was found when a concentration of 0.5 g/kg per day for five days was administered. To establish a statistically significant doubling dose over the control, a minimum of five animals must be used with 2000 polychromatic cells being analyzed per animal. Of the two antischistosomal agents tested, hycanthone yielded an increase of 20-fold in the number of micronuclei over control at 40 mg/kg administered i.p. for five days, while with niridazole no increase in micronuclei at several concentrations tested both by single and multiple injection was found. The results obtained with these compounds compare favorably with what has been reported for the standard in vivo metaphase analysis.

Alkylating Agents↗
PubMed1977

Triethylenemelamine induced dominant lethals in mice--comparisons of oral versus intraperitoneal injection.

We have compared the relative effectiveness of oral and i.p. injections of triethylenemelamine (TEM) in inducing dominant lethality in male mice. The standard dominant lethal protocol was used in these experiments. TEM, when injected i.p. resulted in significant increased in fetal mortality during the first three weeks post-treatment. Decreases in the number of implants per pregnant female were noted during this same period, with only minor decreases in fertility. In contrast, oral injections of TEM resulted in only fluctuations in the percent of fetal mortality. In addition, oral injections of TEM did not result in significant differences in either total implants or percent fertility. Possible causes of the observed differences between these two routes of administration are discussed.

Administration, Oral↗
PubMed1978

Heritable translocation test on random-bred mice after prolonged triethylenemelamine treatment.

Heritable translocation and dominant lethal tests were conducted with random-bred Swiss albino male mice. The animals were provided drinking water containing triethylenemelamine (TEM) for 4 weeks, and were then mated for 3 successive weeks for analysis of dominant lethality and production of F1 progeny. Potential translocation carriers among F1 males were selected after two breedings and confirmed by cytogenetic analysis. Translocation heterozygotes were obtained in offspring of the TEM-treated groups, but not in the control groups. In F1 males produced from the first week of mating, the frequencies of translocations were 0, 1.78 6.2 and 10.0% for the control group and groups receiving TEM at 0.0125, 0.025 and 0.050 mg/kg/day, respectively, and in those produced from the third week of mating, the values were 0 and 2.1%, respectively, for the control group and the group receiving TEM at 0.050 mg/kg/day. F1 males from the second week of mating were not studied for the induction of heritable translocations. TEM-induced dominant lethality and heritable translocations were most prominent in the first week of mating after 4 weeks of treatment. In addition, heritable translocations appeared to be a more sensitive endpoint than dominant lethal mutations for the measurement of mutagenic effects of TEM.

Animals↗
PubMed1995

Triethylenemelamine: induction of specific-locus mutations in the ad-3 region of heterokaryon 12 of Neurospora crassa.

The mutagenicity of the trifunctional alkylating (or cross-linking) agent TEM (triethylenemelamine or 2,4,6-tris(1-aziridinyl)-1,3,5-triazine) in the adenine-3 (ad-3) region was studied with a two-component heterokaryon (H-12) of Neurospora crassa. The objective was to characterize the genetic damage produced by this chemical to determine the spectrum of specific-locus mutations induced in a lower eukaryotic organism and to compare this spectrum with that induced in the mouse. Specific-locus mutations in the ad-3 region of strain H-12 result from gene/point mutations, multiple-locus mutations, and multilocus deletion mutations at the closely linked ad-3A and ad-3B loci. These loci control two sequential biochemical reactions in the purine biosynthetic pathway. A 0.1 M solution of TEM was used to treat conidial suspensions of H-12 for 20, 40, 80, 120, or 170 min to obtain dose-response curves for (1) inactivation of conidia, and (2) the induction of specific-locus mutations in the ad-3 region. These experiments demonstrated that TEM is a strong mutagen (maximum forward-mutation frequency between 100 and 1000 ad-3 mutations per 10(6) survivors) for the induction of specific-locus mutations in the ad-3 region. Both biochemical and classical genetic tests were used to characterize the TEM-induced ad-3 mutations from each of the five treatment groups to distinguish between the different genotypic classes and subclasses. The overall data base from these genetic studies demonstrates that TEM-induced ad-3 mutations result predominantly (95.5% [769/805]) from gene/point mutations at the ad-3A and ad-3B loci, and from a low percentage (4.5% [36/805) of multilocus deletion mutations. In addition, TEM induces an unusually high frequency of multiple-locus mutations with sites of recessive lethal damage closely linked with the ad-3 region. Comparison of the dose-response curves for the major classes and subclasses of TEM-induced ad-3 mutations demonstrates (1) that gene/point mutations and multilocus deletion mutations increase as the 1.4 power of TEM treatment time, and (2) that the two classes of TEM-induced multiple-locus ad-3 mutations consisting of gene/point mutations with separate sites of recessive lethal damage increase at about the 1.96 power of TEM treatment time. When the data from the present specific-locus studies are compared with those in the mouse, we find, insofar as such comparisons are possible, that a similar spectrum of specific-locus mutations has been induced by TEM in each assay system.

Animals↗
PubMed1995

Comparison of the mutagenicity and mutagen specificity of ethylenimine with triethylenemelamine in the ad-3 region of heterokaryon 12 of Neurospora crassa.

Studies have been performed to compare the mutagenicity and mutagenic specificity of the trifunctional alkylating agent, triethylenemelamine (TEM), and a closely related monofunctional agent, ethylenimine (EI), in the adenine-3 (ad-3) region of a 2-component heterokaryon (H-12) of Neurospora crassa. The primary objective of our studies was to characterize the genetic damage produced by each agent with regard to (1) mutagenic potency, and (2) the spectrum of specific-locus mutations induced in a lower eukaryotic organism. As in higher eukaryotes, specific-locus mutations in the ad-3 region of H-12 result from gene/point mutations, multilocus deletion mutations, and multiple-locus mutations. Specific-locus mutations resulting from gene/point mutation and multilocus deletion mutation can be detected in higher eukaryotes, but multiple-locus mutations can be detected only with difficulty or not at all. Our experiments with the ad-3 forward-mutation assay have demonstrated that TEM is a strong mutagen (maximum forward-mutation frequency between 100 and 1000 ad-3 mutations per 10(6) survivors) and EI is a moderate mutagen (maximum forward-mutation frequency between 10 and 100 ad-3 mutations per 10(6) survivors) for the induction of specific-locus mutations in the ad-3 region. Classical genetic tests were used to identify the different genotypic classes and subclasses among the EI- and TEM-induced ad-3 mutations from each experiment. The overall data base demonstrates that both EI- and TEM-induced ad-3 mutations result predominantly from gene/point mutations at the ad-3A and ad-3B loci (97.3% and 95.5%, respectively), and infrequently from multilocus deletion mutations (2.7% and 4.5%, respectively). Heterokaryon tests for allelic complementation on TEM- and EI-induced ad-3B mutations, however, have revealed a difference between the percentages showing allelic complementation (63.1% and 40.9%, respectively). Based on the specific revertibility of complementing and noncomplementing ad-3B mutations induced by other agents, this difference in the percentages of ad-3B mutations showing allelic complementation results from a difference between the spectrum of genetic alterations at the molecular level. In addition, comparison of the ratio of TEM-induced ad-3A and ad-3B mutations with those induced by EI has revealed a difference between the ad-3B/ad-3A ratios. Additional comparisons are made of the mutagenic effects of TEM and EI with those of other chemical mutagens and carcinogens in the ad-3 specific-locus assay in Neurospora.

Adenine↗