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M Webb

Publications and source records attributed to M Webb.

At least 55 records · Page 3Linked to original sources
PubMed1986

The stimulation and inhibition of the exhalation of volatile selenium.

Administration of methylmercury (1.5-24 mumol kg-1; s.c.) to female rats simultaneously with Na2 75SO3 (0.25 or 24 mumol kg-1; s.c.) causes a dose-dependent increase in the exhalation of dimethylselenide. At the low selenite dose level, exhalation of 75Se over a 24 hr period is about fourfold greater after treatment with 24 mumol kg-1 methylmercury than that (approximately 0.75% of the dose) in the controls, but excretion by other routes (urine, faeces) and the liver and kidney contents of 75Se are not affected significantly. At the higher selenite dose level (24 mumol kg-1) exhalation of 75Se is correlated with the log dose of methylmercury. The faecal and urinary excretion remains essentially unaffected, and in rats treated with 24 mumol kg-1 methylmercury the 75Se contents of the liver, kidneys and blood are reduced by 78%, 86% and 18% respectively. The effects of the alkylmercurial are not specific since, at this selenite dose level, ethylmercury increases the exhalation and decreases the liver and kidney contents of 75Se approximately to the same extent as an equimolar dose of methylmercury. In methylmercury-treated and control animals dosed with 24 mumol kg-1 Na 75SeO3 the exhalation of 75Se is inhibited to the same extent by periodate-oxidized adenosine (PAD; 15 mumol kg-1, i.p.) in the first 6 hr. Later inhibition is less pronounced in methylmercury-treated rats. Under these conditions PAD has little effect on the renal content, but increases the hepatic content of 75Se. It seems, therefore, that the methylation of selenite occurs mainly in the liver and in both control and methylmercury-treated animals, S-adenosylmethionine is the major methyl donor. It is possible that methylmercury does not affect directly the methylation enzyme system but, by competition for protein sulphydryl groups, increases the availability of the intermediary selenide anion.

Animals↗
PubMed1986

Steroid receptor activation: the glucocorticoid receptor as a model system.

The glucocorticoid receptor has been used as a model for steroid receptor activation. Because of recent evidence for the essentially nuclear location of the unoccupied receptors of 1,25-dihydroxycholecalciferol and 17 beta-estradiol, the significance of the activation mechanism converting unactivated receptor complexes to DNA-binding forms is unclear for some receptors. Up to now the weight of evidence favors a cytoplasmic location of the unactivated glucocorticoid receptor. In this article we describe studies on the nature of the activation mechanism and of regulatory factors.

Animals↗
PubMed1986

The toxicity and teratogenicity of mercuric mercury in the pregnant rat.

Mercuric mercury (Hg2+), when injected IV into the pregnant Wistar rat, is retained mainly in the maternal compartment and uptake by the conceptuses is small. Thus if the dose is based on total body weight, the maternal body burden, particularly in late gestation, is greater than the whole body burden in the non-pregnant animal. The LD50 of Hg2+ (mg/kg total body weight), however, remains essentially constant (1.0-1.2 mg Hg2+/kg) throughout pregnancy. It seems, therefore, that the rat becomes more resistant to Hg2+ with increasing gestational age. This increased resistance does not correlate with differences in (a) the uptake of Hg2+ by the kidneys, the target organs of toxicity, (b) the severity of the histopathologically detected renal damage and (c) the inhibition of glomerular filtration. Biochemical measurements, however, suggest that kidney function may become less susceptible to Hg2+ as pregnancy advances from conception to near term. During mid-gestation the minimum effective teratogenic dose of Hg2+ (0.79 mg/kg total body weight) is high in relation to the maternal LD50 and the incidence of foetal malformations, mainly brain defects (23% in all live foetuses), is low. In rats of different gestational ages uptake of Hg2+ by the embryo/foetus at this dose level decreases sharply between day 12 and day 13. The teratogenic effects in the foetus and both the structural and functional damage to the maternal kidneys, however, are essentially the same in animals that are dosed with Hg2+ either immediately before, or immediately after these gestational ages.(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormalities, Drug-Induced↗
PubMed1986

Comparison of some biochemical effects of teratogenic doses of mercuric mercury and cadmium in the pregnant rat.

Mercuric mercury (Hg2+), like cadmium (Cd2+), interferes with the transport of certain essential metals to the conceptus in the pregnant Wistar rat and, at 48 h after the IV injection of a teratogenic dose (0.79 mg Hg2+/kg body weight) on day 12 of gestation, the foetal concentrations of Zn2+, Cu2+ and Fe3+, but not of Mg2+, are reduced significantly. Both Hg2+ and Cd2+, at teratogenic dose levels, inhibit the placental and foetal uptake of 65Zn2+ and 67Cu2+, but possibly by different mechanisms. In addition, the effects of Hg2+, at different times after dosing, on the uptake of these labelled tracers and of 59Fe3+, administered as 15-min pulses, do not parallel the changes in the placental and foetal concentrations and contents of the endogenous, stable metallic ions. The teratogenic dose of Hg2+ inhibits the placental and foetal uptake of L-[4,5-3H]-leucine, but not the incorporation of the labelled amino acid into foetal protein. In contrast, the corresponding dose of Cd2+ inhibits both leucine uptake and protein synthesis in the placenta and foetus. Similarly, Cd2+ inhibits the uptake of [2-14C]-thymidine and its incorporation into foetal DNA, whereas Hg2+ reduces the placental and foetal uptake, but has little or no effect on the utilization of the nucleoside. Since both Cd2+ and Hg2+ reduce the foetal uptake of 65Zn and the foetal concentration of Zn, but only Cd2+ interferes with DNA synthesis, it is unlikely that the inhibition of the metabolism of thymidine can be attributed to reduction in thymidine kinase activity in consequence of foetal Zn deficiency.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Neuronal differentiation of cloned human teratoma cells in response to retinoic acid in vitro.

We have analysed immunocytochemically the differentiation in vitro of clones of the human teratoma cell line Tera-2. The proliferating stem cells expressed Thy-1 and N-CAM/D2-CAM antigens. On treatment with 5 X 10(-5) M retinoic acid in either monolayer or aggregate cultures they began to express receptors for tetanus toxin and McAb A2B5. Three weeks after initiating retinoic acid treatment, the cultures contained a variety of cell morphologies, including about 3% of cells with a neuron-like morphology. These cells were reactive with tetanus toxin, McAb A2B5, and antibodies against Thy-1 and N-CAM/D2-CAM. They also expressed 55 000 and 210 000 Da neurofilament subunits.

Animals↗
PubMed1986

Intestinal uptake and retention of copper in the suckling rat, Rattus rattus--III. Effects of closure.

The ileum of suckling rats contains a high level of copper, most of which is concentrated within cytoplasmic vesicles of the enterocytes. Intestinal closure, 20-21 days after birth, results in the replacement of enterocytes by cells devoid of these vesicles and there is a concomitant fall in the level of copper in the ileum. Administration of cortisone acetate (0.5 mg/g body wt) to 5-day-old rats results in premature loss of copper-laden ileal enterocytes and an 80-90% decrease in the ileal copper concentration. The loss of copper is mainly from the soluble fraction of the tissue and is proportionally greater from the high molecular weight-protein fraction rather than from the copper complex.

Animals↗
PubMed1986

Intestinal uptake and retention of copper in the suckling rat, Rattus rattus--I. Distribution and binding.

The distribution of the heterogeneous copper (Cu)-complex in the intestine of the neonatal rat parallels that of total Cu and is maximal in the ileum. In the ileum the total Cu concentration exceeds 400 micrograms/g wet wt at 14 days of age and then falls to about 20 micrograms/g wet wt in the 20-day-old pup. The apoproteins (apopeptides) of the Cu-complex, which are absent from the late-foetal intestine, vary in number and proportion with postnatal age and nutritional status.

Aging↗
PubMed1986

Intestinal uptake and retention of copper in the suckling rat, Rattus rattus--II. Copper accumulation in the ileum and distal jejunum.

High concentrations of copper were demonstrated histochemically in the enterocytes lining the ileum and distal jejunum of suckling rats. Copper was not detected in cells from the duodenum or proximal jejunum of these rats or from any region of the small intestine of rats in which "closure" had taken place. X-Ray microanalysis demonstrated copper, in equi-atomic association with sulphur, within discrete vesicles in the supranuclear cytoplasm of the enterocytes. Despite the high concentrations of these two elements no biochemical evidence was found for the presence of significant amounts of copper-binding metallothionein. The highest concentrations of copper (226 +/- 48 mg atoms/kg dry wt: +/- SD) were found in vesicles adjacent to the nucleus, which did not accumulate particulate tracers, or calcium from the lumen of the intestine. These vesicles probably result from the coalescence of Golgi-derived primary lysosomes followed by fusion with endocytic vacuoles. They may provide a mechanism of copper excretion from the neonatal rat.

Acid Phosphatase↗
PubMed1986

Physiological zinc-binding proteins of medium molecular weight in the rat gut.

1. Gel filtration on Sephadex G 75 was used to separate the medium-molecular-weight zinc-binding proteins from the soluble fractions from the duodenal and jejuno-ileal segments of the rat gut at 30 min after the intragastric administration of a tracer dose of 65Zn. These proteins were resolved by ion-exchange chromatography on DEAE cellulose. 2. In both the duodenum and jejuno-ileal segment an appreciable fraction of the total soluble Zn was bound in a protein fraction that resembled metallothionein (MT) in its behaviour on gel filtration. These fractions, however, were not homogeneous, but contained several medium-molecular-weight Zn-binding proteins. In the duodenum, but not in the jejuno-ileal segment, two of these proteins appeared to be the isometallothioneins, ZnMT-I and ZnMT-II. 3. These results suggest a possible role for MT in the binding of newly-absorbed Zn in the duodenal mucosal cells. They also show that gel filtration alone is insufficient for the identification of MT in the intestine.

Animals↗
PubMed1986

Mechanism of polar body formation in the mouse oocyte: an interaction between the chromosomes, the cytoskeleton and the plasma membrane.

The influence of mouse oocyte chromosomes on their immediate environment has been investigated following their dispersal by dissolution of the metaphase spindle with nocodazole. Small clusters of chromosomes become redistributed around the egg cortex in a microfilament-dependent process. Each cluster has the capacity, on removal from nocodazole, to organize a spindle that rotates to yield a polar body. In this process of spindle formation, the chromosome clusters are able both to promote tubulin polymerization in their vicinity and to recruit microtubule-organizing centres (MTOCs) which organize the polymerized tubulin into spindles. In addition each oocyte chromosome cluster, as well as the non-dispersed sperm-derived haploid group of chromosomes, induces a focal accumulation of subcortical actin (corresponding to a filamentous area devoid of organelles) and a loss of surface Concanavalin A binding activity (corresponding to a loss of surface microvilli) in the overlying cortex. This induction ceases with the formation of pronuclei whether or not the pronuclei migrate centrally. Pronuclear formation is sensitive to the action of nocodazole for up to 2-4 h postinsemination, and pronuclear migration is totally sensitive to the drug. If pronuclei are blocked in a peripheral location by nocodazole they are associated with an elevation in Con A binding activity of the overlying membrane which corresponds to an area of the surface rich in blebby microvilli.

Animals↗
PubMed1986

Parthenogenesis and cytoskeletal organization in ageing mouse eggs.

The cytoskeletal organization of the mouse egg changes during ageing in vivo and in vitro. The earliest change observed is the disappearance of the microfilament-rich area overlying the meiotic spindle. This is followed by the migration of the spindle towards the centre of the egg. Finally the spindle breaks down and the chromosomes are no longer organized on a metaphase plate. This spindle disruption may result from changes in the microtubule nucleating material found at the spindle poles and from an increase in the critical concentration for tubulin polymerization. It is possible to correlate the changes in the cytoskeletal organization of the egg occurring during ageing with the different types of parthenogenetic embryos obtained after ethanol activation. These observations strengthen the hypothesis that the actin-rich cortical area that overlies the meiotic spindle forms a domain to which the meiotic cleavage furrow is restricted and provides some insights into the mechanisms by which different types of parthenogenetic embryos are generated.

Actins↗
PubMed1985

The chronic toxicity of equine cadmium metallothionein in the rat.

The extensive renal tubular necrosis that results in male rats after the intravenous injection of a single, low dose of equine kidney cadmium (Cd), zinc(Zn)-metallothionein (MT) (0.2 mg MT-bound-Cd/kg body wt.) is followed within 72 h by active regeneration. With repeated administration of the same dose at 3- or 4-day intervals, lesion resolves although, at least initially, the kidney content of Cd increases progressively. At any time during treatment, about 40% of the accumulated Cd is bound as the endogenous (Cd, Cu)MT. The rate of increase in the renal Cd content is dependent on the ratio of Cd:Zn in the injected metalloprotein, and is appreciably less when the constant dose of protein-bound Cd is given as a (2.4 Cd:1 Zn)MT, than as a (3.0 Cd:1 Zn)MT. On repeated administration of the latter preparation, however, the concentration of Cd in the kidney does not attain a critical concentration, above which persistent tubular damage occurs, but reaches a maximum of about 150-160 micrograms Cd/g wet wt. (after 16 doses) and then declines. After 19 doses of the (2.4 Cd:1 Zn)MT under the same conditions, the renal Cd concentration is submaximal and is less (92 micrograms Cd/g wet wt.) than that after either 16 or 27 doses of the (3.0 Cd:1 Zn)MT. In animals that are dosed with either of the heterologous MT preparations, the first dose, although not innocuous, seems to protect the kidneys against further damage by subsequent doses. Repeated doses, however, lead to vascular changes, e.g. lymphoid infiltration, periarteriole oedema and dilation of the arcuate veins, and to dilation of the glomerular spaces.

Animals↗
PubMed1985

Histological demonstration of immunoreactive zinc metallothionein in liver and ileum of rat and man.

A sensitive immunohistochemical technique was used to demonstrate zinc metallothionein in rat and human liver and ileum. In the liver, immunoreactivity was observed within the hepatocyte nucleus and cytoplasm, in sinusoids, canaliculi and blood vessels. In the ileum, immunoreactivity was present in the enterocyte nucleus and cytoplasm, and in the lamina propria. The effects of fasting alone and fasting with zinc injection were studied. In the liver, maximum staining was observed after 6 h fasting in the sinusoids, canaliculi and hepatocyte cytoplasm, and this pattern was not present in zinc injected animals. In the ileum, the greatest staining in the enterocyte cytoplasm and basal region was in control animals and after 6 and 12 h fasting. A similar pattern was observed in zinc-injected animals. Decreased staining was seen after 18 h fasting in both liver and ileum. In human ileum, the patients with colitis had less metallothionein immunoreactivity and those on steroid therapy had more immunoreactivity than the controls. We suggest a physiological transport and short term storage function for zinc metallothionein in rat and man.

Animals↗
PubMed1985

The acute toxicity and teratogenicity of nickel in pregnant rats.

The increase susceptibility of the pregnant rat to intraperitoneally administered nickel (Ni) is apparent at 12 and 19 days of pregnancy and cannot be due, therefore, to the increase in total body weight. Teratogenic malformations occur when Ni is administered during organogenesis and are maximal at dose levels that are toxic for the dam. The yolk sac and chorioallantoic placentas accumulate Ni, but this does not prevent the transport of the metal to the embryo or foetus. The Ni concentrations in the conceptuses decrease more slowly with time than those in the maternal organs. In the foetuses, the decrease in concentration is due to the increase in weight, since the content of Ni increases between 4 h and 24 h. Foetal uptake of [14C]thymidine, [3H]leucine and 65Zn is unaffected at 3 h after the injection of the dam with 4 mg Ni/kg body wt. Incorporation of [3H]leucine into foetal protein, but not the incorporation of [14C]-thymidine into DNA, is decreased at this time. A major effect of treatment with this teratogenic dose is an increase in the maternal plasma glucose concentration which, in turn, alters the supply of the sugar to the foetus. The possible relevance of temporary foetal hyperglycaemia to teratogenesis is discussed.

Abnormalities, Drug-Induced↗
PubMed1985

The teratogenic potential of alkoxy acids in post-implantation rat embryo culture: structure-activity relationships.

Alkoxy acids are the active metabolites of teratogenic glycol ethers. To examine the relationship of chemical structure to embryotoxicity, the effects of 6 acids on the development of 9.5-day rat embryos over 48 h in culture were studied. Methoxyacetic acid (MAA) and ethoxyacetic acid (EAA) (5 mM) were growth-retarding and induced gross structural defects, with MAA being more effective. n-Propoxyacetic acid (n-PAA) and n-butoxyacetic acid (n-BAA) (5 mM) were markedly less embryotoxic and produced only minor anomalies. Thus, the activities of these substituted acetic acids decreased with the increase in the length of the alkoxy chain. 3-Methoxypropionic acid (3-MPA) and 4-methoxybutyric acid (4-MBA) (5 mM) were much less active than MAA and induced only minor defects. Therefore in this series: RO(CH2)nCOOH, an increase in the value of n caused a greater reduction in embryotoxicity than did an increase in chain length of the alkyl group R.

Abnormalities, Drug-Induced↗