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Biomedical subjects

E Zeiger

Publications and source records attributed to E Zeiger.

At least 55 records · Page 3Linked to original sources
PubMed1994

Genetic variability for stomatal conductance in Pima cotton and its relation to improvements of heat adaptation.

Responses of stomata to environment have been intensively studied, but little is known of genetic effects on stomatal conductance or their consequences. In Pima cotton (Gossypium barbadense L.), a crop that is bred for irrigated production in very hot environments, stomatal conductance varies genetically over a wide range and has increased with each release of new higher-yielding cultivars. A cross between heat-adapted (high-yielding) and unadapted genotypes produced F2 progeny cosegregating for stomatal conductance and leaf temperature. Within segregating populations in the field, conductance was negatively correlated with foliar temperature because of evaporative cooling. Plants were selected from the F2 generation specifically and solely for differing stomatal conductance. Among F3 and F4 populations derived from these selections, conductance and leaf cooling were significantly correlated with fruiting prolificacy during the hottest period of the year and with yield. Conductance was not associated with other factors that might have affected yield potential (single-leaf photosynthetic rate, leaf water potential). As breeders have increased the yield of this crop, genetic variability for conductance has allowed inadvertent selection for "heat avoidance" (evaporative cooling) in a hot environment.

Journal Article↗
PubMed1994

The effects of antioxidants and enzymes involved in glutathione metabolism on mutagenesis by glutathione and L-cysteine.

The effects of small molecular weight antioxidants and antioxidant enzymes on the mutagenicities of glutathione (GSH) and L-cysteine were studied in Salmonella typhimurium strain TA102. GSH and cysteine mutagenesis were inhibited by antioxidants and radical scavengers such as alpha-tocopherol, Trolox C, butylated hydroxyanisole (BHA), and retinyl acetate. Superoxide dismutase (SOD) had no effect, but catalase and horseradish peroxidase (HRP) inhibited mutagenesis. The heat-denatured enzymes had no effect on mutagenesis. Cysteine mutagenesis was enhanced by native and by heat-denatured rat-kidney post-mitochondrial supernatant, and by ferric ions. H2O2 and the H2O2-generating system of glucose-glucose oxidase (GOX) were mutagenic in TA102. Synergistic increases in mutagenesis were obtained in systems containing combinations of GSH or cysteine, with either H2O2 or the H2O2-generating system of glucose-GOX. GSH peroxidase (GPX) had no effect on mutagenesis of GSH or of H2O2, whereas the synergistic increase in mutagenesis by a combination of GSH and H2O2 was effectively inhibited by GPX. The results suggest strongly that, at least in biochemically-defined systems, GSH and cysteine mutagenesis are oxidative in nature, and involve reactive forms of oxygen and/or other radicals.

Animals↗
PubMed1994

Cytogenetic and germ cell effects of phosphine inhalation by rodents: II. Subacute exposures to rats and mice.

Phosphine (PH3) is a highly toxic grain fumigant to which there is significant human workplace exposure. To determine the in vivo cytogenetic effects of inhalation of PH3, male F344/N rats and B6C3F1 mice were exposed to target concentrations of 0, 1.25, 2.5, or 5 ppm PH3 for 6 hr/day for 9 days over an 11-day period. Approximately 20 hr after the termination of exposures, blood was removed from the mice and rats by cardiac puncture and the lymphocytes cultured for analyses of sister chromatid exchanges and chromosome aberrations in rats and mice, and micronuclei (MN) in cytochalasin B-induced binucleated lymphocytes from mice. In addition, bone marrow (rats) and peripheral blood (mice) smears were made for the analysis of MN in polychromatic and normochromatic erythrocytes. No significant increase in any of the cytogenetic endpoints was found at any of the concentrations examined. These results indicate that concentrations of PH3 up to 5 ppm are not genotoxic to rodents when administered by inhalation for 9 days during an 11-day period as measured by several cytogenetic assays. To evaluate the effects of PH3 on male germ cells, a dominant lethal test was conducted in male mice exposed to 5 ppm PH3 for 10 days over a 12-day period and mated to groups of untreated females (2 females/male) on each of 6 consecutive 4-day mating intervals. None of the 6 groups of females exhibited a significant increase in percent resorptions. These results indicate that exposure to 5 ppm PH3 by inhalation does not induce dominant lethality in male mouse germ cells at steps in spermatogenesis ranging from late differentiating spermatogonia/early primary spermatocytes through mature sperm.

Administration, Inhalation↗
PubMed1994

Localization of oxidative damage by a glutathione-gamma-glutamyl transpeptidase system in preneoplastic lesions in sections of livers from carcinogen-treated rats.

Previous studies from our laboratories have shown that catabolism of glutathione (GSH) by gamma-glutamyl transpeptidase (GGT) in the presence of transition metals leads to oxidative damage (OD). This damage is exemplified in vitro by GGT-dependent GSH mutagenesis which involves reactive oxygen species and by GGT-dependent accumulation of lipid peroxidation (LPO) products in systems containing polyunsaturated fatty acid and GSH. In order to test whether catabolism of GSH by membranal GGT in enzyme-altered preneoplastic hepatic lesions can induce oxidative damage in situ, and to test whether the OD is localized in these lesions, 21 day old Fischer rats were treated with 12 mg/kg diethylnitrosamine (DEN) followed by 0.1% or 0.25% phenobarbital (PB) in the diet. Cryostat sections were examined histochemically for GGT-rich hepatic lesions. Adjacent sections were incubated with GSH and iron and examined for areas staining for lipid peroxidation. Distinct LPO-positive areas were shown to correspond well with the GGT-positive hepatic lesions. Promotion with 0.25% PB led to increasing proportions of LPO-positive lesions with time among GGT-positive lesions. The visualization of LPO in GGT-rich hepatic lesions depended on the presence of GSH and iron, and was not observed following chelation of iron by diethyl triaminopentaacetic acid (DTPA), in the presence of acivicin, an inhibitor of GGT, or in the presence of the radical scavenger butylated hydroxytoluene (BHT). The factors affecting GSH-GGT-dependent LPO in the GGT-rich foci were identical to those affecting GSH-GGT-driven LPO in vitro, and were similar to those affecting oxidative GSH-mutagenesis catalyzed by GGT. The results indicate that metabolism of GSH by GGT in preneoplastic liver foci can initiate an oxidative process leading to a radical-rich environment and to oxidative damage. Such damage may contribute to the processes by which cells within such foci progress to malignancy.

Animals↗
PubMed1994

Activation by caecal reduction of the azo dye D & C red no. 9 to a bacterial mutagen.

D & C Red No. 9 is a monoazo dye used for manufacturing printing inks, rubber and plastics, and as an additive in cosmetics and drugs. In an NTP carcinogenicity study in rats and mice it induced splenic sarcomas and liver nodules in male rats; no chemical-related tumours were induced in mice. On the basis of its contradictory responses in a range of in vitro tests and its inactivity in several in vivo genotoxicity assays, it has been suggested that the dye may act as a non-genotoxic carcinogen. We tested the dye in the Salmonella mutagenicity assay using several different protocols. The dye was not mutagenic when tested using the standard (aerobic) preincubation protocol. Variable responses were seen when the flavin mononucleotide (FMN) reduction protocol was used. A third protocol was provided by incubating the test compound overnight with a rat caecal preparation under anoxic conditions to reduce the azo bond. Ethyl acetate extracts of this incubation mixture, when tested in the standard preincubation protocol using induced rat liver S9, yielded dose-related mutagenic responses in TA100, and a weak response in TA98. The presuemed major reduction product, 1-amino-2-naphthol (1-A-2-N) was mutagenic to TA100, but not TA98, in standard protocols with S9. The results show that it is necessary to use a protocol in which D & C Red No. 9 is reduced in order to demonstrate the mutagenicity of this dye. The non-genotoxicity previously reported for D & C Red No. 9, may have been due to insufficient reductive cleavage.(ABSTRACT TRUNCATED AT 250 WORDS)

Aerobiosis↗
PubMed1994

Cytogenetic studies of sodium fluoride in mice.

The cytogenetic effects of sodium fluoride (NaF) were measured in mice following administration in the drinking water for 6 weeks. Bone fluoride levels were determined and showed a dose-related incorporation of fluoride. Micronuclei were measured in peripheral blood erythrocytes following 1 and 6 weeks of NaF administration. Bone marrow cell preparations were examined for the presence of chromosome aberrations following 6 weeks of treatment; metaphase and anaphase cells were examined. Anaphase cells were scored in three independent laboratories, two of which also scored metaphase cells from the same slides. No increases in micronuclei were seen in peripheral erythrocytes at either time point, and no increases in chromosome aberrations were seen in bone marrow cells when metaphase or anaphase cells were examined. A concurrent positive control, cyclophosphamide, produced significant increases in peripheral blood cell micronuclei and in chromosome aberrations in bone marrow cells in metaphase. No increases in aberrations were seen in the same cyclophosphamide-treated mice when anaphase cells were examined.

Anaphase↗
PubMed1994

Summary of the National Toxicology Program benzidine dye initiative.

The benzidine dye initiative is a research program established by the National Toxicology Program to generate an integrated body of scientific information regarding the potential health risks associated with exposure to benzidine- and benzidine-congener-derived dyes. Because an in-depth evaluation of each of the hundreds of benzidine-congener-derived dyes was considered impractical, the research program was designed to study the metabolism and disposition, genetic toxicity, and in vivo toxicity and carcinogenicity of two primary benzidine congeners, 3,3'-dimethylbenzidine and 3,3'-dimethoxybenzidine, and a select group of prototypical dyes derived from those amines. It was anticipated that by applying the basic information generated in these extensive studies, it would be possible to make regulatory decisions about other dyes after conducting only a minimal number of experiments such as studies of disposition and metabolism, and in vitro mutagenicity. This paper summarizes the results of studies conducted to evaluate the metabolism, disposition, mutagenicity, toxicity, and carcinogenicity of representative benzidine congeners and derived dyes.

Animals↗
PubMed1994

Some comments on potency measures in mutagenicity research.

In this article, the measurement of the potency of a chemical or mixture from its dose response in a particular assay is addressed. Attention is focused on data from the Ames Salmonella assay. Three measures of potency are explored and shown to be highly correlated. The presentation then discusses specific areas of research that might benefit from a study of potency.

Dose-Response Relationship, Drug↗
PubMed1993

Mutagenicity of the human carcinogen treosulphan, and its hydrolysis product, dl-1,2:3,4-diepoxybutane in mammalian cells.

The cytotoxicity and mutagenicity of the human carcinogen, treosulphan, and its hydrolysis product, dl-1,2:3,4-diepoxybutane (DEB), were studied in Chinese hamster ovary, AS52, cells. Treosulphan (0.1-1.0 mM) is toxic and mutagenic at the gpt locus. A strong pH dependence was noted. DEB is cytotoxic and mutagenic at a much lower dose (0.025 mM), but these effects were not affected by pH. The results suggest that the toxic and mutagenic effects of treosulphan are mediated by its hydrolysis product DEB, and that the conversion of treosulphan to DEB is highly pH-dependent.

Analysis of Variance↗
PubMed1993

Genetic toxicity of fluoride.

F- is not mutagenic in standard bacterial systems, but produces chromosome aberrations and gene mutations in cultured mammalian cells. Although there is disagreement in the literature concerning the ability of F- to induce chromosome aberrations in cultured human and rodent cells, the weight of the evidence leads to the conclusion that F- exposure results in increased chromosome aberrations in these test systems. NaF induced primarily chromatid gaps and chromatid breaks, indicating that the rodent cells are responsive in the G2 stage of the cell cycle. In contrast, studies with synchronized human cells indicated that the S phase was the most sensitive. If F- does have a cell cycle-specific effect, it could be expected that differences in the cell treatment and harvest protocols could lead to conflicting results for the induction of chromosome aberrations. Gene mutations were produced in cultured rodent and human cells in the majority of the studies. Unfortunately, a number of the in vitro and in vivo cytogenetic studies are of questionable utility because of the protocols used, the quality of the responses reported, or the interpretations of the data. The conflicting results in the in vivo cytogenetic studies are difficult to reconcile. There are reports of increased chromosome aberrations in rat bone marrow and testes, but other studies, using similar protocols and dose ranges, have reported no induced chromosome damage. Although some of the studies were performed at toxic levels of F-, other studies, including those that showed positive results, were at F- concentrations (1-5 ppm) equivalent to human exposure levels. In the majority of studies that were reported to be positive, there were high background frequencies, or the investigators reported categories of nuclear or chromosome damage that are difficult to interpret. Interestingly, many of the positive results were obtained when anaphase cells were scored, whereas similar treatment protocols in other laboratories yielded negative results when metaphase cells were the only cell type examined. It is difficult, without additional data, to determine the reasons for finding chromosome breaks in anaphase, but not metaphase, cells. Other reports have presented insufficient information to allow adequate evaluations. Therefore, at this time, the question of whether F- produces chromosome damage in vivo should be considered unresolved.

Animals↗
PubMed1993

Inhalation toxicity of 1,6-hexanediamine dihydrochloride in F344/N rats and B6C3F1 mice.

1,6-Hexanediamine (HDA) is a high production volume chemical which is used as an intermediate in the synthesis of paints, resins, inks, and textiles and as a corrosion inhibitor in lubricants. Two- and 13-week studies of the toxicity of the dihydrochloride salt of HDA (HDDC) were conducted in male and female Fischer 344/N rats and B6C3F1 mice using whole-body inhalation exposure. Both species were evaluated for histopathologic and reproductive effects, and rats were examined for clinical chemistry and hematologic changes. In the 2-week inhalation studies, animals were exposed to 10-800 mg HDDC/m3, 6 hr per day. All rats, all female mice, and two of five male mice in the high-exposure group died before the end of the study. Surviving mice in this group had a dose-dependent depression in body weight gain. Clinical signs were primarily related to upper respiratory tract irritation and included dyspnea and nasal discharge in both species. Treatment-related histopathologic lesions included inflammation and necrosis of the laryngeal epithelium of both species and the tracheal epithelium of mice, as well as focal inflammation and ulceration of the respiratory and olfactory nasal mucosa. In the 13-week inhalation studies, animals were exposed to HDDC at concentrations of 1.6-160 mg/m3 for 6 hr per day, 5 days per week. In addition to the base study groups, a supplemental group of rats at each exposure level was included to assess the effect of HDDC on reproduction. No treatment-related changes in organ weights or organ-to-body-weight ratios occurred in rats, and no treatment-related clinical signs or gross lesions were seen in either species. Chemical-related microscopic lesions were limited to the upper respiratory tract (larynx and nasal passages) in the two highest exposure groups and were similar in both species. These lesions included minimal to mild focal erosion, ulceration, inflammation, and hyperplasia of the laryngeal epithelium, in addition to degeneration of the olfactory and respiratory nasal epithelium. HDDC caused no significant changes in sperm morphology or vaginal cytology and no significant adverse effects on reproduction in rats or mice. Hematologic and clinical chemistry changes in rats were minor and sporadic and were not accompanied by related histologic findings. HDDC did not increase the frequency of micronucleated erythrocytes in mice.(ABSTRACT TRUNCATED AT 400 WORDS)

Administration, Inhalation↗
PubMed1993

Mutagenicity of chemicals added to foods.

Much attention has recently been brought to the fact that many natural components of the diet are mutagenic and/or carcinogenic. Approximately 2700 distinct chemical entities, chemical mixtures, and plant extracts are allowed as direct food additives by the US F.D.A. These include chemicals found in the body, natural components of foods, and synthetic chemicals. In addition to the chemicals among these additives that are mutagenic, there are a number of mutagens that are normally present in the plant products that are consumed as part of the normal diets. The mutagenicity in Salmonella of these food additives was identified using the National Toxicology Program and US E.P.A. Gene-Tox databases. Relatively few of the chemicals deliberately added to foods have been tested for mutagenicity. Among the chemicals tested, approximately 15% were mutagenic in Salmonella. The mutagens include both organic and inorganic substances. Many of the natural plant components, such as flavonoids, hydrazides, and tannins also have been shown to be mutagenic. However, these natural components are not considered as food additives. A large proportion of the mutagenic food additives appear to act through the generation of oxygen- or free radicals. Although the relationships between mutagenicity and carcinogenicity of electrophilic chemicals has been well studied, the potential hazard of low-level increases in free-radical generating substances on tumor incidences is unknown.

Animals↗
PubMed1993

Glutathione metabolism by gamma-glutamyltranspeptidase leads to lipid peroxidation: characterization of the system and relevance to hepatocarcinogenesis.

Glutathione (GSH)-driven lipid peroxidation (LPO) in vitro was catalyzed by gamma-glutamyltranspeptidase (GGT; EC 2.3.2.2.). The reaction required iron, iron chelators and oxygen, was accelerated by glycylglycine (gly)2, a GGT enhancer, and was inhibited by the GGT inhibitors serine--borate and acivicin. LPO occurred at rat plasma concentrations of GSH and transferrin, and in the presence of putative physiological chelators such as citrate and ADP. GSH-driven LPO was inhibited by butylated hydroxytoluene, but not by catalase, peroxidase or superoxide dismutase. These results suggest that metabolism of GSH initiated by GGT may lead to oxidative damage. Such oxidative damage may be induced in vivo by GSH in proximity to GGT-rich preneoplastic foci in rat liver.

Animals↗
PubMed1993

Genetic toxicology: current status of methods of carcinogen identification.

A critical aspect of the efforts to relate the results of short-term genetic toxicity tests with those from long-term rodent tests for carcinogens is the quality and consistency of the studies conducted by the National Toxicology Program. Analysis of the results in relationship to chemical structure has shown that mutagenic potential is a primary risk factor for carcinogen identification. Chemicals positive in the Salmonella assay-generally possess "structural alerts" for electrophilic interactions, are predominantly represented among chemicals producing trans-species carcinogenic effects in rodents, and among those identified as carcinogenic to humans. Current efforts are aimed at defining toxicological, structural, and mechanistic properties of nonmutagens that are carcinogenic in rodents.

Animals↗
PubMed1992

Conditions for detecting the mutagenicity of divalent metals in Salmonella typhimurium.

The mutagenesis of metals in bacteria, as reported in the literature, can best be described as inconsistent. We report that cobalt chloride (Co++), ferrous sulfate (Fe++), manganese sulfate (Mn++), cadmium chloride (Cd++), and zinc chloride (Zn++) could be reproducibly detected as mutagens in Salmonella strain TA97 when preincubation exposures were made in sterile, distilled, deionized water, or in Hepes buffer in NaCl2/KCl2, rather than the standard sodium phosphate buffer. Co++ was also mutagenic under standard preincubation conditions. The individual components of Vogel-Bonner medium, i.e., potassium and ammonium phosphate, citrate, and magnesium sulfate, inhibit mutagenesis by these metals. The phosphates and the citrate probably inhibit by chelating the metals, while data are presented to suggest that Mg++ inhibition of metal mutagenesis is due to competitive inhibition for active transport via the magnesium active transport system in Salmonella. The chelator, diethyldithiocarbamate, inhibited the mutagenicity of Co++, Fe++, Zn++, and Mn++, but enhanced the mutagenicity of Cd++. The results presented show that divalent metals can be detected as mutagens in Salmonella, and that their lack of detection as mutagens is not due to an inherent insensitivity of Salmonella but to their interaction with media components and/or passive and active transport processes.

Agar↗