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Biomedical subjects

L D Koller

Publications and source records attributed to L D Koller.

At least 37 records · Page 2Linked to original sources
PubMed1986

Trichloroacetic acid effects on rat liver peroxisomes and enzyme-altered foci.

The initiating and promoting effects of trichloroacetic acid (TCA) were investigated using a rat hepatic enzyme-altered foci bioassay. The experimental protocol used has been shown to induce gamma-glutamyltranspeptidase (GGT)-positive foci in hepatic tissue following an initiating dose with a genotoxic carcinogen. Twenty-four hours following 2/3 partial hepatectomy, rats received either a single oral dose (1500 mg/kg) or 5000 ppm TCA in drinking water for 10, 20, or 30 days. Two weeks after the end of TCA exposure, the rats were promoted for 3 or 6 months with 500 ppm phenobarbital in drinking water. TCA failed to induce GGT-positive foci using this initiation protocol. In addition, groups of 2/3 partially hepatectomized rats were initiated with a single oral dose of diethylnitrosamine (10 mg/kg) and then administered 50, 500, or 5000 ppm TCA drinking water. In this promotion protocol, TCA exposure resulted in a significant increase in the number of GGT-positive foci. The ability of TCA to stimulate peroxisomal-dependent palmitoyl-coenzyme A oxidation was also investigated. Only the 5000 ppm TCA treatment within the promotion protocol resulted in a significant, although minor, stimulation of peroxisomal enzyme activity. The findings support the hypothesis that TCA may possess weak promoting activity in the rat liver.

Animals↗
PubMed1986

Immune responses in rats supplemented with selenium.

It is generally accepted that Selenium (Se) is necessary for optimum performance of the immune system. Selenium deficiency results in immune suppression but little is known concerning the effect of excess Se on immune function. Recent evidence suggests that oral Se supplementation may impede oncogenesis, but the mechanism of this action is currently unknown. Conversely, under certain conditions, Se is suspected of promoting neoplasia. The studies described herein delineate the effects of excess Se (0.5, 2.0 or 5.0 p.p.m.) on specific immune functions of Se-adequate rats, namely, antibody synthesis, delayed-type hypersensitivity (DTH), natural killer (NK) cell activity, prostaglandin E2 (PGE2) synthesis, and interleukin 1 (IL-1) activity. Selenium administered to female Sprague-Dawley rats for 10 weeks at 0.5 and 2.0 p.p.m. resulted in significant (P less than or equal to 0.01) enhancement of splenic NK activity while the NK response in the 5.0 p.p.m. Se-treated rats was equivalent to the non-Se-treated controls. Conversely, the DTH response was significantly (P less than or equal to 0.01) suppressed at all three dosages while antibody synthesis and prostaglandin E2 activity were significantly (P less than or equal to 0.05) reduced compared to the controls at the highest dosage of Se. IL-1 activity was unaffected by Se exposure. These data could partially explain the contradictory oncogenic characteristics of Se. For instance, tumours that are NK sensitive could be prevented and/or responsive to Se therapy, while NK insensitive neoplasms could be enhanced by Se supplementation due to the impaired function of both humoral and cell-mediated immunity.

Animals↗
PubMed1986

The two faces of selenium-deficiency and toxicity--are similar in animals and man.

The purpose of this review article is to demonstrate the close parallelism of daily requirements, biological activity and minimum and maximum tolerable levels of selenium for animals and man. In addition, the carcinogenic/anticarcinogenic properties of selenium are discussed and a postulate of how these dichotomous effects may occur in accordance with selenium-induced immunomodulation is presented. A review of pertinent literature pertaining to the biological action of selenium in animals and man, including deficiency, toxicity, carcinogenicity and effects on immunity, is included to support these concepts. The predominant biochemical action of selenium in both animals and man is to serve as an antioxidant via the selenium-dependent enzyme, glutathione peroxidase, and thus protect cellular membranes and organelles from peroxidative damage. The signs and symptoms of selenium deficiency closely simulate each other for animals and man. Severe deficiency is characterized by cardiomyopathy while moderate deficiency results in less severe, myodegenerative syndromes such as muscular weakness and pain as well as a variety of other selenium-associated diseases. Clinical manifestations of many of these disorders require contributory factors, such as stress, to precipitate symptoms which are documented for animals and implicated for humans. Current evidence suggests that a daily selenium consumption for man of approximately 30 micrograms is necessary to prevent the selenium-deficient syndrome, Keshan disease, while approximately 90 micrograms/day/adult should be the minimum daily requirement for optimum biological performance. Recognizing that humans in several countries do not meet the proposed minimum daily requirement of 90 micrograms, several compelling reasons are presented in deriving this minimal daily nutritional intake. Selenosis can occur in laboratory animals, livestock, and humans following long-term exposure to selenium concentrations as low as 5 mg selenium/kg of diet (5 ppm). The selenium-induced lesions for all species are similar, which once again illustrates a positive corollary for selenium effects in both animals and man. From compilation of available data, the maximum tolerable level for selenium in man could be considered in the range of 1000 to 1500 micrograms/day. This is in contrast to the currently recommended maximum human tolerable level of 500 micrograms/day. The amount of selenium that can be tolerated, however, is dependent upon individual biological variation, nutritional status and general state of health.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1985

The effect of lead and polychlorinated biphenyl exposure on rat natural killer cell cytotoxicity.

Splenic natural killer (NK) cell cytotoxicity was assessed in rats chronically exposed to lead (Pb) as lead acetate in the drinking water or polychlorinated biphenyl (PCB) as Aroclor 1254 in the feed. Rats treated with cyclophosphamide were included as positive immunosuppressed controls. Weanling, male Sprague-Dawley rats exposed to 50 and 500 ppm PCB in the feed for ten weeks exhibited significantly suppressed (P less than 0.01) splenic NK activity. Cyclophosphamide injected i.p. six days prior to termination at a dose of 75 mg/kg also significantly inhibited splenic NK activity. NK cell activity was reduced, though not significantly, in spleen cells isolated from animals exposed to 10 and 1000 ppm Pb as Pb acetate in the drinking water for ten weeks. In vitro exposure of rat spleen cells to PCB at concentrations of 0.4 and 20.0 micrograms/ml similarly resulted in a significant depression of splenic NK cell activity. In addition, in vitro exposure to lead at the same concentrations resulted in suppressed NK cell cytotoxicity of rat splenocytes. These results indicate that two environmental contaminants have the ability to adversely affect NK cell cytotoxicity. The effects seen here with Pb and PCB on NK cells may in part explain the tumor inducing effect these chemicals are suspected of possessing via compromising the immune surveillance system.

Animals↗
PubMed1985

Effect of lead, polychlorinated biphenyls, and cyclophosphamide on rat natural killer cells, interleukin 2, and antibody synthesis.

Interleukin 2 (IL2) activity, natural killer cell (NKC) cytotoxicity, and serum antibody (Ab) levels were assessed in rats exposed to 10 or 1000 ppm lead (Pb) as lead acetate in the drinking water or 50 or 500 ppm polychlorinated biphenyls (PCB) as Aroclor 1254 in the feed for 10 weeks or injected one time with 75 mg/kg cyclophosphamide (CY). Assays for IL2 activity and NKC cytotoxicity were also performed following in vitro exposure of rat splenocytes to Pb (0.4 or 40 micrograms/ml) or PCB (0.4 or 20.0 micrograms/ml) for 24 hr in vitro. NKC cytotoxicity and IL2 activity were significantly suppressed following in vitro exposure to either Pb or PCB. Chronic exposure to PCB, but not Pb, significantly reduced NKC cytolytic activity and significantly elevated Con A-stimulated IL2 activity. Ab synthesis was significantly suppressed in groups of rats chronically exposed to Pb or PCB. CY-injected rats had significantly reduced IL2 activity, NKC cytotoxicity, and Ab levels. High background levels of IL2, presumably induced by KLH injections shortly before termination, were significantly suppressed in PCB-, Pb-, and CY-treated rats. This suppression of IL2 activity was completely reversed by in vitro stimulation with Con A in Pb- or PCB-, but not CY-, treated groups. These results indicate that PCB, Pb, and CY alter IL2 synthesis and adversely affect NKC cytotoxicity and Ab synthesis following in vivo or in vitro exposure. The effects of PCB on NKC cytotoxicity may partially explain the tumor-promoting effect of this chemical via compromising immunosurveillance.

Animals↗
PubMed1985

Neoplasia induced in male rats fed lead acetate, ethyl urea, and sodium nitrite.

Sprague-Dawley rats were exposed to 0, 26, or 2600 ppm lead as lead acetate in drinking water for 76 weeks. At 28 weeks of lead exposure, a portion of each group was exposed simultaneously to 6.36 g/kg ethyl urea (EU) and 2.0 g/kg sodium nitrite (NaNO2) for a duration of 20 weeks, and then continued an additional 28 weeks on standard diet free of EU and NaNO2. The animals were observed for incidence, latency, and distribution of tumors. Rats exposed to 2600 ppm lead alone had 81% renal tumors, while rats given 2600 ppm lead in combination with EU/NaNO2 had a 50% incidence. Renal tumors did not occur in the EU/NaNO2 only or EU/NaNO2-26 ppm lead groups. The major tumor type found in EU/NaNO2-exposed rats was lymphosarcoma. Lead did not appear to be syncarcinogenic to the activity of ethylnitrosourea, the carcinogen formed by oral exposure to EU and NaNO2. The lead-induced renal neoplasms were histologically similar to those which occur spontaneously in man and, therefore, may serve as an animal model to study human disease.

Animals↗
PubMed1984

A sensitive delayed-type hypersensitivity model in the rat for assessing in vivo cell-mediated immunity.

Many drugs and other chemicals can alter cell-mediated immunity (CMI), a response that often correlates with delayed-type hypersensitivity (DTH). Several DTH assays were evaluated to determine a method best suited for assessing chemically induced modulation of CMI in rats. The effects of various antigens, adjuvants, doses, routes, and immunosuppressants were investigated. The DTH method which produced optimum results in rats uses a footpad swelling reaction elicited by specific preparations of bovine serum albumin (BSA) and Freund's complete adjuvant (FCA). The rats were sensitized with 100 micrograms BSA in FCA injected subcutaneously at the base of the tail, and were challenged 7 days later with 75 microliter of 2% heat-aggregated BSA suspension injected into the left rear footpad. Footpad swelling was measured with pressure calipers 24 h later and compared to the contralateral footpad which was sham-injected with 75 microliters of physiological saline. Antigen-injected footpads were nearly double the thickness (7-8 mm) of the control footpads (3-4 mm), and variation between animals was small (CV = 5%). Dexamethasone and cyclophosphamide significantly suppressed the DTH reaction. Histopathological examination of the DTH reaction sites revealed a mononuclear cell infiltrate which is characteristic of type IV hypersensitivity. In addition to being highly quantitative and sensitive, this method provides a simple and reproducible assessment of CMI responses in the rat.

Aging↗
PubMed1984

Multiple immunoassay in a single animal: a practical approach to immunotoxicologic testing.

A battery of immunoassays were developed for the rat which measured the major arms of the immune system, namely, humoral immunity, cell-mediated immunity (CMI), and macrophage function. Humoral immunity was assessed by the enzyme-linked immunosorbent assay (using keyhole limpet hemocyanin as antigen). CMI was measured by delayed-type hypersensitivity to heat-aggregated bovine serum albumin using a footpad swelling technique. Macrophage function was assessed by measuring the ability of macrophages to phagocytize sheep red blood cells in vitro. The feasibility of performing all three immunoassays in the same animal was investigated by treating groups of rats with all combinations of antigenic exposure used to induce each type of response. Multiple antigenic treatment regimens did not significantly alter responses to individual antigens used in this study. Animals exposed to the concurrent antigen treatment regimens remained sensitive to immunosuppressants. These data suggest that multiple immunoassays can be successfully performed utilizing a single animal which has been concurrently treated with different antigens. The inclusion of additional assays into this protocol and the efficacy to immunotoxicologic testing is discussed.

Animals↗
PubMed1984

Alteration of natural killer cell-mediated cytotoxicity in rats treated with selenium, diethylnitrosamine and ethylnitrosourea.

Weanling, female Sprague--Dawley rats were divided into 14 separate groups. Three of these groups were administered 0.5, 2.0 or 5.0 ppm selenium (Se) in the drinking water for 10 weeks. Three groups received intraperitoneal injections of 1, 5 or 10 mg/kg diethylnitrosamine (DEN) twice weekly for 10 weeks. The remaining animals received 0.150% or 0.316% ethylurea (EU) in the feed and 1 or 10 ppm nitrite as sodium nitrite in the drinking water either alone or in combination. Separate groups of rats treated with cyclophosphamide (CY) were included as positive immuno-suppressed controls. Following the 10-week chemical exposure period, splenic natural killer (NK) cell-mediated cytotoxicity was assessed by a 4-h chromium release assay using YAC-1 tumor cells as targets. The NK cell cytotoxic response was enhanced in both the low and medium dose selenium-exposed groups. In contrast, rats exposed to 0.316% EU + 10 ppm NO2 had significantly depressed NK cell activity. CY treatment also resulted in a significant reduction of splenic NK cell cytotoxicity.

Animals↗
PubMed1984

Toxicologic, pathologic, and immunotoxic effects of 2,4-dichlorophenol in rats.

2,4-Dichlorophenol (DCP) is a drinking and waste-water contaminant formed by the spontaneous reaction of chlorine with phenols following chlorination of water for disinfection and deodorization. Rats were exposed to 0, 3, 30, or 300 ppm DCP in drinking water either in utero or for 12 wk postnatally following in utero exposure. Toxicity to DCP was assessed by organ and body weight changes, histopathology, and effects on reproduction and immunocompetence. Reproductive parameters measured included conception, litter size, pup birth weight, number stillborn, survival to weaning, and weaning weight. Immune parameters assessed were humoral immunity (antibody production) by an indirect enzyme-linked immunosorbent assay (ELISA), cell-mediated immunity by a delayed-type hypersensitivity response, and macrophage function by phagocytosis of radiolabeled blood cells. Rats that received the combined in utero and postnatal treatment with 300 ppm DCP had significantly increased liver and spleen weights, enhanced humoral immune responsiveness, and depressed cell-mediated immunity. Histopathologic changes were unremarkable in DCP-exposed rats, even in the presence of increased liver and spleen weights. The 6-wk-old progeny of DCP-treated dams had normal immune functions and showed no signs of DCP toxicity, other than increased spleen weights in the 300-ppm exposure group. The results indicate that (1) the immune system may be a sensitive target for chlorinated phenolic compounds, (2) DCP may exert different effects on separate major immune responses, and (3) unlike some other chlorinated phenols, DCP does not appear to alter reproductive performance in rats.

Animals↗
PubMed1984

Comparison of selenium levels and glutathione peroxidase activity in bovine whole blood.

Blood glutathione peroxidase activity and selenium levels were found to correlate well, indicating that glutathione peroxidase activity can be used to assess blood selenium levels in beef cattle. The glutathione peroxidase activity of blood is less stable than is the selenium concentration but when blood was stored at 4 degrees C, the glutathione peroxidase activity remained constant for seven days.

Animals↗
PubMed1984

Transplacental transfer and colostral concentrations of selenium in beef cattle.

Three groups of 20-month-old pregnant Hereford heifers received 3 regimens of selenium (Se) supplementation. Group 1 received pelleted alfalfa hay, soybean meal, which contained Se (0.313 mg/kg), and 90 mg of Se as sodium selenite/kg of salt-mineral mix ad libitum. Group 2 received the pelleted hay and soybean meal, and group 3 received only the pelleted alfalfa hay. At time of parturition, the mean whole blood Se concentrations were: group 1 = 0.250 mg of Se/kg of blood, group 2 = 0.162 mg/kg, and group 3 = 0.052 mg/kg, whereas the respective mean blood glutathione peroxidase (GSH-Px) values were 144, 80, and 30 mU/mg of hemoglobin. In comparison, the mean whole blood Se values for the calves were 0.242, 0.175, and 0.81 mg/kg, respectively, and their blood GSH-Px values were 154, 113, and 50 mU/mg of hemoglobin, respectively. Thus, the blood Se and GSH-Px values for each group reflected dietary intake of Se. The calf blood GSH-Px values were similar to their dams for group 1, but were 41% higher in group 2 and 67% greater in group 3. The data suggested that the fetus can sequester blood Se, accumulating values greater than the dam, and that larger amounts were concentrated in the fetus when smaller amounts were available from the dam. The colostrum contained modest to low amounts of Se proportionate to dietary intake of this element. However, milk 7 days after parturient contained inadequate amounts of Se to sustain blood Se values in calves and the milk from heifers with low normal blood Se was essentially void of Se (0.009 mg/kg). (ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

Effects of chlorinated phenols on immunity in rats.

Female Sprague - Dawley rats were exposed to 0, 5, 50 or 500 ppm 2-chlorophenol (2-CP) or pentachlorophenol (PCP) from weaning to 3 weeks postparturition after breeding at 90 days of age. Progeny were weaned at 3 weeks of age and continued on chlorophenol treatment for 10 weeks at which time major immune functions were tested. Humoral immunity was measured by an indirect ELISA, cell-mediated immunity was monitored by delayed-type hypersensitivity (DTH) to oxazolone, and macrophage function was tested by phagocytosis of sheep red blood cells. Rats treated with cyclophosphamide were included as a positive immunosuppressed control. PCP-treated rats had significantly decreased antibody titers and DTH response and increased induced peritoneal macrophage numbers which displayed hyperphagocytic activity. Immune responses in rats treated with 2-CP were not significantly different from controls. The data indicate that (1) the immune system may be a sensitive target for PCP toxicity but not for 2-CP, (2) closely related chlorophenolic chemical isomers may exert different toxic effects on the immune system, and (3) PCP can exert depressive effects on some major immune parameters while enhancing others.

Animals↗
PubMed1983

Evaluation of ELISA for detecting in vivo chemical immunomodulation.

Immunotoxicology is a relatively new field of investigation and is becoming recognized and used by toxicologists involved in drug and chemical testing. The purpose of this study was to evaluate the enzyme-linked immunosorbent assay (ELISA) as a means of quantitating humoral immune responses in rats exposed to immunomodulating chemicals. The ELISA proved to be highly sensitive and quantitative, simple to perform, and reliable. The assay is also economically feasible and automated so that large numbers of samples can be analyzed at one time. The antigen used in the study was bovine serum albumin, and the immunosuppressive chemicals used to validate the system were lead, polychlorinated biphenyl, cyclophosphamide, and dexamethasone. Practical application of the procedure to immunotoxicology testing is discussed.

Animals↗
PubMed1983

Effect of toxaphene exposure on immune responses in mice.

Toxaphene was fed to female weanling Swiss-Webster mice at dosages of 10, 100, and 200 ppm for 8 wk. Immunologic assays revealed depressed IgG antibody formation in those animals receiving 100 and 200 ppm toxaphene, as compared to controls. Cell-mediated immune responses were not affected in the toxaphene-exposed mice. In another experiment, mature female mice fed the same amounts of toxaphene were mated 3 wk after feeding began and were maintained on the diets until 3 wk after parturition, at which time the pups were weaned onto the control ration. Assays performed on the offspring 8 wk after their birth revealed suppressed antibody formation in the 100-ppm-toxaphene group and enhanced antibody formation in the 200-ppm group. The cell-mediated immune response was suppressed in the offspring from the 100-ppm group, while no change from the controls occurred in the other groups. Phagocytic ability of macrophages was significantly reduced in all toxaphene-treated groups, but to a greater extent in the offspring of the mice that consumed 100 ppm toxaphene.

Animals↗
PubMed1983

Selenium deficiency of beef cattle in Idaho and Washington and a practical means of prevention.

The majority of beef cattle assayed for whole blood glutathione peroxidase (GSH-Px) activity in Idaho and Washington were deficient in selenium. Cattle in the more arid sections of these states tended to have higher selenium levels than those in areas with moderate and high rainfall. Animals pastured on irrigated forages had lower selenium concentrations than those grazed on dry land pasture. Cattle were supplemented by the addition of sodium selenite to a salt-mineral mixture. Ninety mg selenium per kg (ppm) salt-mineral mix fed to cattle significantly (P less than 0.001) elevated selenium (GSH-Px) levels well into normal ranges by 3 months when fed to extremely selenium deficient animals. Thirty ppm selenium was insufficient to raise GSH-Px levels into normal ranges. In addition, 20 ppm selenium was insufficient to sustain blood selenium concentrations of selenium adequate animals. Selenium given in the salt-mineral mix provided an effective, economical, and easily regulated source of dietary selenium. This supplement can be provided the entire year even under range conditions. Calves of cows placed on the 90 ppm selenium supplement had significantly (P less than 0.005) improved weaning weights (10 months) and an indication of a decreased incidence of infectious diseases.

Animals↗