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Biomedical subjects

S D Sleight

Publications and source records attributed to S D Sleight.

At least 37 records · Page 2Linked to original sources
PubMed1983

Mechanism of chloroform nephrotoxicity. I. Time course of chloroform toxicity in male and female mice.

Chloroform (CHCl3) nephrotoxicity in male mice could be detected as early as 2 hr after CHCl3 administration (250 microliter/kg, sc) as decreased ability of renal cortical slices to accumulate p-aminohippurate (PAH) and tetraethylammonium (TEA). The decrease was preceded and paralleled by a reduction of renal cortical nonprotein sulfhydryl (NPSH) concentration, an index of tissue reduced glutathione concentration. Histologic alterations were not observed until NPSH concentrations and PAH and TEA accumulation had reached the nadir, 5 hr after CHCl3 administration. Female mice exhibited no evidence of nephrotoxicity to CHCl3 even when the dose was increased to 1000 microliter/kg or when pretreated with diethyl maleate to reduce renal cortical NPSH concentrations prior to CHCl3 injection. The extent of hepatotoxicity was similar in male and female mice and decreases of hepatic NPSH concentrations also were detected by 1.5 hr after CHCl3 administration. The rapid response of the kidney to CHCl3 toxicity in male mice and the similarity of liver toxicity in both sexes suggests that nephrotoxicity occurs independently of hepatotoxicity. Furthermore, the ability to detect these early changes in vivo following CHCl3 administration may permit the development of an in vitro model to evaluate the mechanism of CHCl3 nephrotoxicity.

Animals↗
PubMed1983

Effects of aminoglycosides on glomerular permeability, tubular reabsorption, and intracellular catabolism of the cationic low-molecular-weight protein lysozyme.

Gentamicin and other aminoglycoside antibiotics in high doses may produce proteinuria and other signs of nephrotoxicity. Proteinuria may result from general renal damage or may reflect alterations in specific steps in the renal handling of proteins. To distinguish between these two possibilities, experiments were designed to quantify the effects of nephrotoxic doses of several aminoglycosides on the renal handling of proteins in the isolated perfused rat kidney with the cationic low-molecular-weight protein lysozyme as a representative protein. Each aminoglycoside was administered ip to male Wistar rats (30 mg/kg/day) for 7 days. Lysozyme and 125I-lysozyme were added to the perfusate to achieve a lysozyme perfusate concentration of about 100 mg/liter. Clearances of inulin and lysozyme, release of tyrosine and trichloroacetic acid-soluble radioactive metabolites into the perfusate, and the glomerular sieving coefficient of lysozyme were determined. Scanning and transmission electron microscopy indicated that gentamicin and tobramycin decreased the number and diameter of the endothelial fenestrae of the glomerular capillaries. Concurrently, gentamicin and tobramycin decreased the glomerular sieving coefficient of lysozyme from 0.8 to 0.6 and 0.5, respectively. Netilmicin did not affect the percentage reabsorption of lysozyme whereas gentamicin and tobramycin decreased lysozyme reabsorption from 71.7 to 35.4 and 34.4% of the filtered load, respectively. Lysozyme degradation, estimated by the release of tyrosine into the perfusate during a 150-min perfusion period, was decreased from a control value of 12 mumol/liter to 4.43 and 4.65 mumol/liter in kidneys from rats treated with gentamicin and tobramycin, respectively. This study demonstrates that polycationic aminoglycosides may affect several processes involved in renal handling of lysozyme including glomerular permeability, tubular reabsorption, and intracellular proteolytic degradation.

Absorption↗
PubMed1983

Lipid peroxidation: a possible mechanism of cephaloridine-induced nephrotoxicity.

Cephaloridine produces renal cortical injury, but the precise mechanism responsible for this nephrotoxicity remains unclear. Recently cephaloridine has been shown to deplete reduced glutathione (GSH) concentration selectively in renal cortex. Cephaloridine nephrotoxicity can be potentiated by diethyl maleate (a GSH depletor), but no glutathione conjugate can be detected. Thus, it was of interest to investigate further the mechanism of depletion of renal cortical GSH by cephaloridine. In the present study, cephaloridine markedly decreased GSH in rat and rabbit renal cortex while concomitantly increasing oxidized glutathione (GSSG). Furthermore, cephaloridine increased lipid peroxidation specifically in renal cortical cells. Conjugated diene formation (an index of lipid peroxidation) was increased in renal cortex but not in the liver shortly following administration of cephaloridine. Removal of selenium and/or vitamin E from the diet, which should enhance lipid peroxidation, potentiated cephaloridine nephrotoxicity and enhanced cephaloridine-induced morphological damage in the kidney. These findings are consistent with a major role of lipid peroxidation in the etiology of cephaloridine nephrotoxicity.

Animals↗
PubMed1983

Hepatic tumor-promoting ability of 3,3',4,4',5,5'-hexabromobiphenyl: the interrelationship between toxicity, induction of hepatic microsomal drug metabolizing enzymes, and tumor-promoting ability.

Female Sprague-Dawley rats were fed diets containing 0, 0.01, 0.1, or 1.0 mg/kg 3,3',4,4',5,5'-hexabromobiphenyl (345-HBB) for 140 days after a 70% partial hepatectomy and diethylnitrosamine administration (10 mg/kg body weight) to determine if 345-HBB had tumor-promoting ability in a two-stage hepatocarcinogenesis assay. Tumor-promoting ability was assessed by measuring enzyme-altered foci exhibiting gamma-glutamyl transpeptidase activity. Enhancement of enzyme-altered foci occurred only at a dietary concentration of 345-HBB (1.0 mg/kg) that was toxic. The toxic effects were decreased body weight gain, involution of the thymus, increased liver weight, histologic and ultrastructural alterations of the liver, and elevated serum concentrations of aspartate aminotransferase. 345-HBB is a strict 3-methylcholanthrene (MC) type of hepatic microsomal drug metabolizing enzyme inducer and caused a dose-related increase of cytochrome P-450. 345-HBB, at a dietary concentration of 0.1 mg/kg, caused a physiologic response in rats as determined by induction of hepatic microsomal drug metabolizing enzymes, but there was minimal evidence of toxicity and no evidence of tumor-promoting ability. Results indicate that there can be induction of MC type of hepatic microsomal drug-metabolizing enzymes without toxicity or tumor-promoting ability and that the tumor-promoting ability of 345-HBB was most likely the result of hepatic degeneration and necrosis. This finding is in contrast to previous studies in which a closely related congener, 2,2',4,4',5,5'-hexabromobiphenyl, enhanced the development of enzyme-altered foci at dietary concentrations that were not hepatotoxic.

Animals↗
PubMed1983

Vitamin A status, polybrominated biphenyl (PBB) toxicosis, and common bile duct hyperplasia in rats.

The interaction between dietary concentrations of vitamin A and PBB was evaluated in two experiments. In the first experiment, male weanling rats were used in a 2 X 3 factorial experiment. Concentrations of PBB were 0, 10, or 100 mg/kg of diet and diets were either vitamin A-deficient or were supplemented with 3000 IU vitamin A palmitate/kg of diet. In the second experiment the design was similar except that two vitamin A-supplemented diets were used, one containing 3,000 IU/vitamin A palmitate/kg of diet and the other 30,000 IU. Diets contained either 0 or 100 mg of PBB/kg. Clinical signs of vitamin A deficiency and mortality occurred early in rats fed vitamin A-deficient diets containing 100 mg of PBB/kg. Vitamin A supplementation provided partial protection against decreased weight gain associated with PBB. Decreases in thymic weight associated with PBB toxicosis were prevented by supplementation with vitamin A. Massive enlargement of the common bile duct occurred in rats fed a vitamin A-deficient diet containing 100 mg of PBB/kg. Histologically, this lesion consisted of extensive hyperplasia. A significant decrease in retinol concentrations in the sera was recorded in rats fed vitamin A-deficient diets containing 100 mg of PBB/kg. Interaction between vitamin A deficiency and PBB toxicosis affected vitamin A metabolism as manifested by the appearance of appreciable amounts of retinyl acetate in the liver vitamin A profile. These results suggest an interaction between PBB toxicity and vitamin A and emphasize the importance of nutritional factors such as vitamin A in assessment of PBB toxicosis.

Administration, Oral↗
PubMed1983

Induction of rabbit renal mixed-function oxidases by phenobarbital: cell specific ultrastructural changes in the proximal tubule.

Administration of phenobarbital (60 mg/kg) daily for 4 days to male rabbits resulted in induction of renal cytochrome P-450 (3.5-fold) and a corresponding increase in ethoxycoumarin-O-deethylase and benzphetamine-N-demethylase activity (17- and 4-fold, respectively). Kidney weight to body weight ratio and renal ethoxyresorufin-O-deethylase were not affected by phenobarbital pretreatment. Numerous focal areas of proliferation of smooth endoplasmic reticulum (SER) were evident in proximal tubule cells from phenobarbital treated rabbits while proximal tubular cells from control rabbits had only small and sparcely located aggregates of SER. Phenobarbital-induced SER proliferation was specifically localized to the S3 segment of the proximal tubule. Proliferation was not observed in S2 cells of the proximal tubule, cells of Henle's loop, distal tubules, or collecting tubules in rabbits pretreated with phenobarbital. These data demonstrate the biochemical heterogeneity of cell types within the proximal tubules of rabbits. Furthermore, induction of mixed-function oxidases specifically in S3 cells of the proximal tubule may be of toxicological significance in the metabolic activation of certain nephrotoxicants.

Animals↗
PubMed1982

Polybrominated biphenyls as promoters in experimental hepatocarcinogenesis in rats.

Female Sprague Dawley rats were fed polybrominated biphenyls (PBB) for six months after a 70% partial hepatectomy and diethylnitrosamine administration (10 mg/kg body weight) to determine if PBB could serve as a tumor promoter in a two stage hepatocarcinogenesis test system. Firemaster BP-6, a commercial mixture of PBB, and its major congener, 2,2',4,4',5,5'-hexabromobiphenyl (HBB) were used in this study. Tumor promoting ability was assessed by measuring enzyme altered foci exhibiting gamma glutamyl transpeptidase activity. Dietary concentrations of 10 and 100 p.p.m. of the mixture of PBB and of HBB were found to be promoters of hepatocarcinogenesis. The mixture of PBB had a greater tumor promoting ability than HBB.

Acyltransferases↗
PubMed1981

Subchronic administration of technical pentachlorophenol to lactating dairy cattle: performance, general health, and pathologic changes.

Technical grade pentachlorophenol (penta) was fed subchronically to lactating dairy cattle to establish whether exposure approximating farm environments containing substantial penta-treated wood represents a hazard to animal health. Four Holstein cattle in early lactation were fed .2 mg penta/kg body weight per day for 75 to 84 days followed by 2 mg penta/kg body weight per day for 56 to 60 days. Each treated cow was paired with a control cow of equivalent stage of lactation. Milk production, feed intake, and body weight were not affected by either dose except that treated cattle were more efficient converters of feed to milk during the early stage of the 2 mg/kg period. Neither milk fat production nor somatic cell count in milk were affected by exposure to penta. Postmortem examination revealed enlargement of liver, lungs, kidneys, and adrenals and thickening of the urinary bladder wall. Chronic interstitial nephritis and subacute urocystitis were the major pathologic changes in penta-treated cattle. In vitro testing of kidney slices confirmed significant loss of renal function. The relationship of lesions to administration penta is not clear.

Animals↗
PubMed1981

Toxicosis in sows and their pigs caused by feeding rations containing polybrominated biphenyls to sows during pregnancy and lactation.

The toxicity and the distribution of polybrominated biphenyls (PBB) were investigated by feeding rations containing different concentrations of PBB to sows during pregnancy and lactation. Sows and newborn pigs were clinically unaffected. Mortality was increased among pigs nursing sows fed rations containing PBB. Although transplacental passage of PBB resulted in an appreciable amount of PBB in tissues of newborn pigs, far more PBB were transferred to the pigs through the milk. On a body-weight basis, nursing pigs consumed PBB in concentrations similar to the concentrations given to the sows. The highest tissue concentrations of PBB (fat basis) were found in the liver, followed by the adipose tissue, kidney, and brain. Dietary concentrations of 10 mg of PBB/kg of feed increased serum concentrations of alkaline phosphatase, alanine aminotransferase, and thyroid hormones of pigs, whereas dietary concentrations of 100 or 200 mg of PBB/kg of feed caused those values to decrease. Gross pathologic changes consisted of increased weight of the thyroid gland of newborn pigs and increased weight of the liver of 4-week-old pigs. Histologically, thyroid glands of newborn pigs were slightly hyperplastic, and the colloid was scant and vacuolated. In the liver, lesions consisted of fatty change and centrolobular necrosis; changes were more severe in the sows than in the pigs nursing those sows. Measuring serum concentrations of ornithine carbamoyltransferase was the most effective clinical test in assessing the degree of liver damage in the pigs.

Adipose Tissue↗
PubMed1980

Inhibition of N-2-fluorenylacetamide-induced mammary tumorigenesis in rats by dietary polybrominated biphenyls.

Female SD rats were maintained for approximately 1 year on diets containing 300 ppm N-2-fluorenylacetamide (2-FAA), 50 ppm polybrominated biphenyls (PBB), or a combination of these chemicals (PBB + 2-FAA). Ingestion of 2-FAA significantly reduced the average survival time of the rats; this effect was virtually blocked by the simultaneous ingestion of PBB. Simultaneous ingestion of PBB also significantly reduced the overall incidence of 2-FAA-induced tumors during the examination period. The lower incidence of tumorigenesis was accompanied by an increase in the latency time for tumor induction; tumors were found in 100% of the animals given 2-FAA after 29 weeks of carcinogen ingestion, whereas only 50% of the PBB + 2-FAA-fed animals had tumors at the end of the experiment (53 wk of carcinogen ingestion). PBB significantly reduced the incidence of 2-FAA-induced tumors at nonhepatic locations (mammary gland and ear duct) but did not affect the incidence of hepatic tumors to a statistically significant extent. PBB ingestion did not significantly increase the incidence of tumors when compared with controls; 1 tumor was found in 1 of 12 rats fed 50 ppm PBB for 57 weeks, and no tumors were detected in 8 controls.

2-Acetylaminofluorene↗
PubMed1980

Immunoglobulin A response of the bovine fetus and neonate to Escherichia coli.

The chronologic appearance of immunoglobulin (Ig) A-containing plasma cells and their distribution and numbers in the intestinal tract, spleen, and mesenteric lymph nodes were determined in beef calves inoculated in utero with Escherichia coli O26-K60:NM bacterin or with saline solution. Secondary responses were assessed by oral revaccination or by challenge exposure to live E coli. Specific immunofluorescent procedures were used to count IgA-containing plasma cells. Appreciable numbers of IgA-containing plasma cells were seen in in utero-vaccinated calves at birth. Oral vaccination or challenge exposure with E coli increased the number of plasma cells. The caudal part of the jejunum and the ileum and related lymph nodes had more IgA-containing cells than any of the other tissues examined. In revaccinated and challenge exposed calves, the spleen was especially active in the formation of IgA-containing plasma cells. The results indicate that the entire small intestine, the draining lymph nodes, and the spleen were involved in IgA formation in these young calves. Age as a factor in IgA production was seen in the control calves which had no indication of IgA-containing cells before 9 days of age. None of the in utero-vaccinated calves at birth or at necropsy had evidence of IgA in serum.

Animals↗
PubMed1980

Pathologic features of iodide toxicosis in calves.

Forty Holstein-Friesian heifer calves were divided into four groups of ten each and dosed orally with ethylenediamine dihydriodide to provide 0, 50, 250, or 1,250 mg of iodide/animal each day. Five calves in each group were given thyrotropin-releasing hormone at 4-week intervals. Two calves given 1,250 mg of iodide (active ingredient)/day died by 70 days and had severe bronchopneumonia. At 6 months, the remaining 38 calves were killed. Pneumonia was evident in calves given iodide, with the severity apparently dose-related. Squamous metaplasia of tracheal epithelium occurred in all calves given 1,250 mg of iodide. Similar changes were seen in the interlobular duct of the parotid gland of two calves given 1,250 mg of iodide and in one calf given 250 mg. Scanning electron microscopy revealed changes in the tracheal mucosa, the severity of which were related to the dose of iodide fed. Changes in the thyroid glands of calves given 1,250 mg of iodide included large follicles, flat epithelium, and large amounts of colloid. In calves given 1,250 mg of iodide plus thyrotropin-releasing hormone, the histologic features of the thyroid glands were similar to controls. Serum vitamin A concentrations were less in calves given 1,250 mg of iodide relative to that of control calves. In general, calves were able to compensate fpr excessive dietary iodide after an initial period of an apparent increased susceptibility to respiratory tract infection.

Animals↗
PubMed1978

Polybrominated biphenyl toxicosis in rats fed an iodine-deficient, iodine-adequate, or iodine-excess diet.

Young male Sprague-Dawley rats were fed 0, 1, 10, or 100 ppm of polybrominated biphenyls (PBB) in iodine-deficient, iodine-adequate (0.2 ppm), or iodine-excess (1000 ppm) diets. Six rats in each of the 12 groups were killed at 30 days and the remaining six in each group at 60 days. Growth rates were similar in all rats fed diets containing 0, 1, or 10 ppm PBB but were slower from 30 to 60 days in rats given 100 ppm PBB. Results of routine hematologic examinations and urinalyses were essentially normal. Although liver weights were substantially increased by PBB, the smallest increases were in rats fed an iodine-deficient diet. Thyroid weights were increased by iodine deficiency and by 10 and 100 ppm PBB. Electropherograms of serum proteins, serum lipoproteins, and LDH isozymes at 60 days from rats given PBB indicated hepatic alterations, but changes were least dramatic in rats fed an iodine-deficient diet plus PBB and most severe in rats fed iodine-excess diets plus PBB. Hepatic lesions were basically similar to those previously described except that bile duct proliferation was seen at 60 days only in rats fed an iodine-deficient diet and 100 ppm PBB. Histologic changes in thyroid glands were associated with iodine deficiency and with PBB. The iodine-excess diet plus 100 ppm PBB induced squamous metaplasia of respiratory bronchiolar epithelium. These results indicate interrelationships between PBB and iodine which may affect the toxicosis caused by PBB.

Animal Feed↗