Biomedical subjects

M Robinson

Publications and source records attributed to M Robinson.

At least 379 records · Page 21Linked to original sources

PubMed1986

Enhancement of the hepatotoxicity of chloroform in B6C3F1 mice by corn oil: implications for chloroform carcinogenesis.

A recent study of the ability of chloroform in drinking water to produce cancer reported that male Osborne-Mendel rats developed renal tumors, but that female B6C3F1 mice failed to develop hepatocellular carcinomas. The results obtained in the male Osborne-Mendel rats were comparable to those observed in an earlier study sponsored by the National Cancer Institute (NCI). On the other hand, the lack of an increased incidence of hepatocellular carcinomas in female B6C3F1 mice was in sharp contrast to previously reported results. The doses of chloroform used were comparable to that which produced an 85% incidence in the NCI study. We have investigated the extent to which the vehicle might be responsible for the different results in these two studies by examining the differential effects of chloroform when it was administered by gavage using corn oil versus a 2% Emulphor suspension as the vehicle. Male and female B6C3F1 mice were administered chloroform at 60, 130, and 270 mg/kg per day for 90 days. At sacrifice, body and organ weights were measured, and blood was recovered to perform the following serum chemistry measurements (in order of priority): glutamate oxalacetate transaminase (SGOT), lactate dehydrogenase (LDH), blood urea nitrogen (BUN), and triglyceride (TG) levels. The liver was sectioned for histopathological examination. Chloroform increased SGOT levels significantly only when administered in corn oil at a dose of 270 mg/kg in both male and female mice. It had no effect on LDH activity. There was a small increase in BUN when chloroform was administered in corn oil, but not when administered in 2% Emulphor. When administered in corn oil, chloroform significantly decreased serum TG levels but was without effect on this parameter when administered in 2% Emulphor. Chloroform decreased body weight and increased liver weight with both vehicles, but the effects were significantly greater when it was administered in corn oil. Mice administered chloroform in corn oil displayed a significant degree of diffuse parenchymal degeneration (5 of 10 males and 1 of 10 females) and mild to moderate early cirrhosis (5 of 10 males and 9 of 10 females); significant pathological lesions were not observed in the animals administered corn oil without chloroform nor in mice receiving chloroform in 2% Emulphor. These data indicate that administration of chloroform by corn oil gavage results in more marked hepatotoxic effects than observed when it is provided in an aqueous suspension.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1986

Prenatal weight gains related to the birth of healthy-sized infants to low-income women.

Prepregnancy weight status and weight gain during pregnancy are major independent variables associated with infant birth weight. This study quantitated the influence of weight gain on birth weight and identified rates and total amounts of weight gain related to the birth of healthy-sized infants to healthy low-income women who entered pregnancy underweight, at normal weight, overweight, or obese. Data used in the study were obtained from randomly sampled prenatal health records from Maternal and Infant Care (MIC) projects in Cleveland and Minneapolis. Subsamples of healthy mothers who delivered healthy-sized infants were identified from each sample, and rates and total amounts of weight gain by prepregnancy weight status group were calculated. There were 384 healthy mother and healthy-sized infant pairs in the Cleveland subsample and 75 such pairs in the Minneapolis sample. Multiple regression analysis revealed that the influence of prenatal weight gain and birth weight varied depending on prepregnancy weight status. Prenatal weight gains related to the birth of healthy-sized infants (newborns with birth weights of 3,000 to 4,500 gm) to healthy mothers in the Cleveland MIC sample averaged 33 lb for underweight, 32 lb for normal weight, 29 lb for overweight, and 19 lb for obese women. Except for obese women, rates and total amount of weight gain associated with the birth of healthy-sized infants were equivalent for the two samples.

Birth Weight↗

PubMed1985

Metabolism of platelet-activating factor by rat alveolar macrophages: lyso-PAF as an obligatory intermediate in the formation of alkylarachidonoyl glycerophosphocholine species.

1-Alkyl-2-acetyl-sn-glycero-3-phosphocholine (alkylacetyl-GPC; platelet-activating factor; PAF) is actively taken up and metabolized by rat alveolar macrophages maintained in culture. The major metabolic products are lyso-PAF (alkyllyso-GPC) and alkylacyl-GPC. Lyso-PAF accumulates primarily in the media, whereas alkylacyl-GPC is predominantly associated with cellular lipids. The addition of unlabeled lyso-PAF to incubations initiated with [3H]PAF results in an increase in the amount of lyso-[3H]PAF product formed and a decrease in the final product, [3H]alkylacyl-GPC; however, the total amount of [3H]PAF metabolized remains unchanged. Unlabeled lyso-PAF thus enters the metabolic pool of the cell and competes with the deacetylated product of [3H]PAF, i.e., lyso-PAF, for acylation. High-performance liquid chromatography demonstrated that the reacylated product derived from lyso-PAF consisted primarily of the arachidonoyl-containing species that exists as the 16:0-20:4 molecular species. These results document that PAF is inactivated in rat alveolar macrophages via a deacetylation-reacylation reaction with lyso-PAF as an obligatory intermediate. The sequestering of arachidonic acid into the PAF precursor pool and the substantial amount of lyso-PAF secreted by macrophages into the extracellular fluid appear to be significant events in the inactivation process.

Animals↗

PubMed1985

Acylation of lysophospholipids by rabbit alveolar macrophages. Specificities of CoA-dependent and CoA-independent reactions.

Intact alveolar macrophages were found to acylate alkyl- and acyllysophospholipids with a high selectivity for arachidonate. A specific mechanism appears responsible for the incorporation of arachidonate into lysophospholipids in intact cells since the kinetic pattern for the formation of the 20:4 species was different from all other species. This specificity was investigated in more detail by examining the enzymatic acylation of 1-alkyl-2-lyso-sn-glycero-3-phosphocholine by macrophage membranes; in the absence of CoA, ATP, and Mg2+, this lysophospholipid was acylated with a high preference for arachidonate that was independent of added free fatty acids. The addition of CoA alone increased the rate of acylation of 1-alkyl-2-lyso-sn-glycero-3-phosphocholine, mainly due to an increase in the formation of species other than those containing arachidonate. When CoA, ATP, and Mg2+ were present, the macrophage membranes catalyzed the acylation of 1-alkyl-2-lyso-sn-glycero-3-phosphocholine without preference for arachidonate. A different apparent Km and Vmax was observed for reactions involving each cofactor condition. We conclude that the acylation of alkyl- and acyllysophospholipids by rabbit alveolar macrophages occurs by three separate mechanisms: a CoA-independent transacylation, a CoA-dependent transacylation (reverse reaction catalyzed by acyl-CoA acyltransferase), and an acyl-CoA-dependent acylation. The CoA-independent transacylation reaction is unique in that it is specific for arachidonate and accounts for the selective acylation of alkyl- and acyllysophospholipids by arachidonate in membrane preparations of alveolar macrophages. This reaction appears to be extremely important in the remodeling of phospholipid molecular species and the mobilization of arachidonate into ether-linked lipids. The transfer of arachidonate to 1-alkyl-2-lyso-sn-glycero-3-phosphocholine also is of importance in the final inactivation step for platelet activating factor (1-alkyl-2-acetyl-sn-glycero-3-phosphocholine), whereby 1-alkyl-2-arachidonoyl-sn-glycerol-3-phosphocholine (a stored precursor of both platelet activating factor and arachidonic acid metabolites) is formed.

Acylation↗

PubMed1985

Metabolism of unique diarachidonoyl and linoleoylarachidonoyl species of ethanolamine and choline phosphoglycerides in rat testes.

Selected molecular species of rat testicular 1,2-diradyl-sn-glycero-3-phosphocholines and 1,2-diradyl-sn-glycero-3-phosphoethanolamines were quantitated as their diradylglycerobenzoate derivatives, using a recently developed high-performance liquid chromatographic method. Increased amounts of docosapentaenoic acid were found in glycerophospholipids containing ether moieties compared with the diacyl phospholipids (e.g., docosapentaenoate-containing species comprised more than 80% of the alkylacyl subclass of the ethanolamine phosholipids as opposed to 29.3% of the diacyl subclass). Within 2 h after intratesticular injections of [5,6,8,9,11,12,14,15-3H]arachidonic acid, the 20:4-20:4 and 18:2-20:4 molecular species of the diacyl subclass of both the choline and ethanolamine glycerophosphatides had the highest specific radioactivities. These unique molecular species (20:4-20:4 and 18:2-20:4) also exhibited the largest percentage decrease in specific radioactivity 24 h after the intratesticular injections of [3H]arachidonic acid, which indicates these two species possess a high metabolic turnover. Two of the arachidonate-containing molecular species (18:1-20:4 and 18:0-20:4) in the ethanolamine plasmalogens showed only a small decrease in specific radioactivity, whereas a third species (16:0-20:4) actually had a 44% increase in specific radioactivity 24 h after the intratesticular injections of [3H]arachidonate. These data indicate that the 20:4-20:4, 18:2-20:4 and 18:1-20:4 species of phosphatidylcholine and/or phosphatidylethanolamine are most rapidly labeled after administration of [3H]arachidonic acid and that they appear to serve as the source of the [3H]arachidonate that is ultimately transferred to ethanolamine plasmalogens.

Animals↗

PubMed1985

Differences between plasma and synovial fluid fibronectin.

Fibronectin is a high molecular weight glycoprotein of plasma and tissue fluids, and one of its functions is to opsonise particulate material. Chromatographic and electrophoretic analyses showed that the main components of fibronectin are biochemically similar in rheumatoid patients' plasma and synovial fluid. But synovial fluid fibronectin also contains a slow-moving component seen on two-dimensional immunoelectrophoresis, suggesting the presence of fibronectin complexes. Affinity chromatography provided evidence that these involved IgG, and in vitro studies showed that fibronectin influenced the reaction between IgG and anti-IgG. Synovial fluid fibronectin is functionally active in binding to gelatin in an haemagglutination assay, and it gave a relatively higher degree of haemagglutination than did plasma fibronectin, supporting the concept of multivalent fibronectin complexes in synovial fluid. These results suggest synovial fluid fibronectin may be involved in the opsonic removal of IgG-containing complexes from synovial fluid.

Arthritis, Rheumatoid↗

PubMed1985

Hymenolepis citelli (Cestoda) and Nematospiroides dubius (Nematoda): interspecific interaction in mice.

In mice concurrently infected with Hymenolepis citelli and Nematospiroides dubius, survival of the tapeworm was prolonged, and there was an impairment of the efferent arm of the response to the cestode. The immunological rejection of a six cysticercoid primary H. citelli infection was delayed by the N. dubius infection. The growth of the cestode was poorer in concurrently infected mice, and this effect was rapid, being evident within 4 days of the N. dubius infection. Maximum biomass in the controls was reached on Day 20, whereas in the concurrently infected mice it was reached on Day 25. The induction of acquired immunity to homologous H. citelli infection was suppressed, although the expression of a secondary response against homologous challenge was not abrogated in doubly infected mice. The results are discussed with reference to the immunodepressive effects the nematode is known to have on heterologous antigenic stimulation.

Animals↗

PubMed1985

Dietary related periodontitis and oro-nasal fistulation in rats.

An outbreak of periodontitis and oro-nasal fistulation in rats in a routine long-term bioassay is described. There was strong circumstantial and pathological evidence that the lesions were caused by long pointed food fibres present in an expanded diet which was fed as a powder.

Animals↗

PubMed1985

Evaluation of mutagenic and carcinogenic properties of brominated and chlorinated acetonitriles: by-products of chlorination.

The present study was undertaken to determine if chlorinated and brominated acetonitriles formed during the chlorination of drinking water possess mutagenic and/or carcinogenic properties. Chloroacetonitrile (CAN), dichloroacetonitrile (DCAN), trichloroacetonitrile (TCAN), bromochloroacetonitrile (BCAN), and dibromoacetonitrile (DBAN) were tested for their ability (1) to produce point mutations in the Salmonella/microsome assay, (2) to induce sister chromatid exchanges (SCE) in Chinese hamster ovary (CHO) cells in vitro, (3) to produce micronuclei in polychromatic erythrocytes in CD-1 mice, and (4) to act as tumor initiators in the skin of Sencar mice. DCAN and BCAN were found to be direct-acting mutagens in Salmonella. All five haloacetonitriles induced SCE in CHO cells in vitro. This activity paralleled the extent of chlorine substitution and was further enhanced in the dihaloacetonitrile series when bromine was substituted for chlorine. None of the haloacetonitriles showed evidence of activity in the mouse micronucleus assay. DBAN, BCAN, and CAN initiated tumors in the mouse skin with topical applications followed by a 20-week promotion schedule of 12-O tetradecanoylphorbol-13-acetate applications (p less than 0.02). These data indicate that the haloacetonitriles do display mutagenic and carcinogenic properties in some test systems and the hazard associated with their occurrence in drinking water and production within the gastrointestinal tract require further evaluation.

Acetonitriles↗

PubMed1985

Carcinogenicity of chloroform in drinking water to male Osborne-Mendel rats and female B6C3F1 mice.

The carcinogenic activity of chloroform administered at 0, 200, 400, 900, and 1800 mg/liter in drinking water was studied in male Osborne-Mendel rats and female B6C3F1 mice. A second control group was included in the study and was restricted to the water consumption of the high-dose group. Animals were maintained on study for 104 weeks. Group sizes were adjusted at low doses such that a detectable tumor response would result at the lowest dose if there was a linear relationship with dose, and the higher doses produced responses similar to previous carcinogenesis bioassays of chloroform. The primary finding was that chloroform increased the yield of renal tubular adenomas and adenocarcinomas in male rats in a dose-related manner. For the high-dose group, which corresponded to a time-weighted average dose of 160 mg/kg per day for 104 weeks, there was a 14% incidence of renal tubular adenomas and adenocarcinomas, vs 1% in the control group. This compares to a 24% incidence observed when 180 mg/kg per day of chloroform was administered for 78 weeks in earlier studies. In contrast, chloroform in the drinking water of mice failed to increase the incidence of hepatocellular carcinomas in female B6C3F1 mice. The highest dose group received a time-weighted average dose of 263 mg/kg for 104 weeks, resulting in a 5% combined incidence of hepatocellular adenoma and carcinoma relative to a 6% incidence in the control groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1985

Irreversible depression in the ratio of tetraploid:diploid liver nuclei in rats treated with 3'-methyl-4-dimethylaminoazobenzene (3'M).

A reduction in the ratio of tetraploid to diploid liver nuclei has been investigated as an early indicator of hepatocarcinogenesis in the rat using the liver carcinogen 3'-methyl-4-dimethylaminoazobenzene (3'M). In a dose ranging study 3'M was administered by gavage to rats at 5, 12.5 and 25 mg/kg for up to 10 weeks and the following parameters studied: bodyweight gain, dye binding to hepatic protein, nuclear ploidy in liver and histopathology. Significant reduction in bodyweight occurred only with 25 mg/kg; dye binding to protein occurred in a dose-related manner; depression of the percentage of tetraploid nuclei compared with diploids was dose-related and effects were detected even at the lowest dose. These observations were consistent with those from previous studies by other investigators. In a separate experiment 3'M was administered at the maximum tolerated dose (MTD) of 25 mg/kg for 3 weeks, during which time there was a significant reduction in bodyweight gain and a reduction in the ratio of tetraploid:diploid liver nuclei. After cessation of dosing the rate of bodyweight gain returned to normal but there was no corresponding recovery of the ratio of tetraploid:diploid nuclei in the liver. A long-term continuous gavage study at 2.5 mg/kg revealed a time dependent reduction in the ratio of tetraploid:diploid liver hepatocyte nuclei and histopathological changes that included hepatocarcinoma were also observed. There was no correlation between the severity of pathological changes and the change in nuclear ploidy ratio in this experiment and it is concluded that the changes in ploidy ratio are related to the carcinogenic effect of 3'M and are independent of its gross toxicity.

Animals↗

PubMed1985

Genetic control of immunity to Nematospiroides dubius: a 9-day anthelmintic abbreviated immunizing regime which separates weak and strong responder strains of mice.

Experiments were designed to re-examine the variables which influence the ability of single primary infections to elicit acquired immunity to Nematospiroides dubius, in particular the importance of the presence or absence of adult worms, as these are known to exert immunomodulatory effects. Briefly, anthelmintic abbreviated infections were considerably more effective at eliciting acquired immunity than longer infections in which adult worms were allowed to reside in the intestine. A 9-day anthelmintic abbreviated infection was extremely effective at stimulation of acquired immunity in NIH mice and very few immunising infection larvae were required. Immunity to subsequent reinfection developed rapidly after the primary infection worms had been eliminated; by day 21 post-infection, the mice were almost totally immune. Abbreviated infections were used to examine the capacity of a number of mouse strains to develop immunity to reinfection. Strains of mice were chosen to allow the effects of MHC linked and non-MHC linked (background) genes to be identified. CBA and C3H strains (both H-2k) were found to be weak responders to N. dubius. B10G (H-2q) mice responded better than C57Bl/10 (H-2b), although these strains have identical background genes. DBA/2 mice were stronger responders compared to BALB/c mice, both strains sharing a common MHC haplotype (H-2d). (NIH X B10G) F1 mice (H-2q) were better responders than either of the parental strains. Several mouse strains all sharing the H-2q haplotype were particularly effective at developing immunity to N. dubius, as were also SJL mice which were the sole representatives of the H-2s haplotype, in the present study. The results established that the response phenotype is influenced by both background and MHC genes and demonstrated gene complementation in the capacity of mice to acquire immunity to N. dubius.

Animals↗

PubMed1985