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Biomedical subjects

U G Ahlborg

Publications and source records attributed to U G Ahlborg.

At least 37 records · Page 2Linked to original sources
PubMed1991

Swedish dioxin survey: evaluation of the H-4-II E bioassay for screening environmental samples for dioxin-like enzyme induction.

The H-4-II E enzyme induction bioassay was used for testing both pure reference substances and extracts of wildlife samples. Polychlorinated naphthalenes were found to be as active as enzyme inducers as certain coplanar polychlorinated biphenyls (PCBs). Also a mixture of polybrominated diphenyl ethers (Bromkal 70-5DE) was shown to induce enzyme activity. In extracts of herring, containing polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs), bioassay and chemically derived TCDD-equivalents (TEQs) were nearly identical. When extracts containing other types of dioxin-like compounds as well were tested, the bioassay TEQs for most of them agreed well with chemical TEQs calculated for PCDDs, PCDFs and non-ortho PCBs. However, for ringed seal and whitefish, TEQs obtained from the bioassay were higher than those from the chemical analysis. Our results indicate that this bioassay is an excellent complement to chemical residue analysis and a useful tool in understanding the complex interactions of halogenated hydrocarbons. For risk assessment, such results should, however, be used most carefully as they are measured in vitro.

Animals↗
PubMed1991

Relative liver tumour promoting activity and toxicity of some polychlorinated dibenzo-p-dioxin- and dibenzofuran-congeners in female Sprague-Dawley rats.

The polychlorinated dibenzo-p-dioxins/dibenzofurans 1,2,3,7,8-pentachlorodibenzo-p-dioxin (PeCDD), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 2,3,4,7,8-pentachlorodibenzofuran (PeCDF) were studied for liver tumour promoting activity in a medium-term altered foci assay in nitrosamine-initiated female Sprague-Dawley rats. The congeners under study were administered by weekly subcutaneous injections at three dose levels for 20 weeks. Evaluation of gamma-glutamyltranspeptidase (GGT+), altered hepatic foci development, showed that all congeners studied acted as potent promoters of hepatocarcinogenesis. TCDD and PeCDD were virtually equipotent as enhancers of foci development while PeCDF displayed approximately ten per cent of the activity of the dioxins. Analysis of the dioxin- and furan-congeners by gas chromatography/mass spectroscopy (GC/MS) technique showed that the retention of PeCDD and PeCDF in liver tissue was approximately 7 and 20 times, respectively, as high as the retention of TCDD. Based on the concentration of the respective congener in liver tissue, PeCDD and PeCDF were 0.14 and 0.007 times as active as TCDD as promoters of foci development. The dose related enhancement of GGT+ foci development induced by the PCDD/PCDF congeners was accompanied by an increased incidence of histological changes in the liver.

Animals↗
PubMed1991

Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the vitamin A status of Hartley guinea pigs, Sprague-Dawley rats, C57Bl/6 mice, DBA/2 mice, and Golden Syrian hamsters.

Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on hepatic, renal, lung, and serum vitamin A levels were investigated in species/strains, which show highly variable susceptibility to TCDD toxicity. Young male Hartley guinea pigs, Sprague-Dawley rats, C57Bl/6 mice, DBA/2 mice, and Golden Syrian hamsters received single intraperitoneal doses, in the range 0.5-400 micrograms TCDD/kg body weight, aimed to produce a similar toxic and limited lethal effect in all species. Animals were sacrificed 1, 7, 14, 28, 56, and 112 days after TCDD injection. The time-related increase in hepatic vitamin A storage was inhibited by TCDD in all species studied, but the doses required to produce the inhibition were considerably varied due to species. The duration of the inhibition was dependent both on dose and species. All species, except for the guinea pig, managed to increase the liver reserves of vitamin A at the end of the study, as compared to the amount present at the time of TCDD treatment. A marked increase in renal vitamin A content, related to TCDD exposure, was observed in the rats, as opposed to a slight decrease in the guinea pigs and no effect in mice or hamsters. All species tested, except for the C57Bl/6 mouse, showed a marked TCDD-related decrease in pulmonary vitamin A. The rat was the only species which showed a consistent effect (a small increase) in serum vitamin A levels, as a result of exposure to TCDD. The effects of TCDD on the hepatic and pulmonary vitamin A contents correlated reasonably well with the observed toxic response in this study. However, the correlation could not be observed for the effects of TCDD on renal, and serum vitamin A levels.

Animals↗
PubMed1991

Interaction between dietary vitamin A and single oral doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the TCDD-induced toxicity and on the vitamin A status in the rat.

The effect of dietary vitamin A on the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and the effect of TCDD on the tissue vitamin A levels in 8-week-old male Sprague-Dawley rats of variable vitamin A status, were investigated. Rats were fed purified casein based diets containing 2,000, 5,000, 8,000, or 21,000 IU of vitamin A/kg from weaning and throughout the experiment. The study was terminated 44 days after the administration of a single oral dose of 0, 15, 30, 60, or 120 micrograms TCDD/kg body wt. With this dietary regimen it was possible to obtain healthy animals of the same age with a vitamin A status that varied within a physiological range. LD50-values for TCDD could not be calculated in any dietary group due to the unexpectedly low mortality rate. The obtained data, however, suggest that low dietary intake of vitamin A impairs the ability to tolerate the lethal effect of TCDD and/or decreases the survival time. Some TCDD-related effects, i.e. body weight loss, liver enlargement and decreased testes weight, were more pronounced in the groups receiving low levels of dietary vitamin A, whereas the decrease in thymus weight was as severe in all dietary groups. Exposure to TCDD had a pronounced effect on tissue vitamin A contents. The effect differed between tissues and was dependent upon the dose of TCDD and on the vitamin A status of the animal. Generally, exposure to TCDD results in the reduction of vitamin A in most organs; very likely because the capacity for vitamin A storage is diminished. The kidney is an exception because it accumulates vitamin A in response either to TCDD itself or to the altered vitamin A status which TCDD induces. Data presented in this study are not sufficient to conclude if the observed changes of tissue vitamin A contents are sufficient to explain the spectrum of morphological changes, which is typical of TCDD exposure.

Animals↗
PubMed1991

Modulation of 2,3,7,8-tetrachlorodibenzo-p-dioxin and phenobarbital-induced promotion of hepatocarcinogenesis in rats by the type of diet and vitamin A deficiency.

This study was undertaken to investigate the influence of dietary vitamin A deficiency and type of diet on tetrachlorodibenzo-p-dioxin (TCDD)- and phenobarbital-induced liver tumor promotion in rats. Female Sprague-Dawley rats were partially hepatectomized and subsequently initiated with nitrosodiethylamine. One week later the rats were allocated to five different dietary regimens for the duration of the study: three purified (casein-based) diets containing 200, 1200, and 10000 IU vitamin A per kilogram, respectively, and two conventional (cereal-based) rat diets containing 2000 and 14000 IU vitamin A per kilogram, respectively. After an additional 4 weeks, groups of rats on each dietary regimen were started on one of four different promoter treatments: 0.07 micrograms TCDD/kg/week (sc); 0.7 micrograms TCDD/kg/week (sc); 500 ppm phenobarbital in the drinking water or vehicle only (arachis oil, sc). The study was terminated after 16 weeks of promoter treatment. Sections of liver were stained for gamma-glutamyltranspeptidase (GGT) activity and GGT-positive altered hepatic foci (AHF) were evaluated by stereological methods. All factors studied (TCDD, phenobarbital, dietary vitamin A content, and the type of diet) were shown to influence AHF development significantly. As expected, TCDD and phenobarbital enhanced foci development. Vitamin A deficiency enhanced foci development in its own right and increased the TCDD-induced response markedly. Dietary vitamin A content did not modulate phenobarbital promotion of AHF in the same manner. The enhancement of TCDD-induced effects on foci development by vitamin A deprivation was accompanied by an increased incidence of histological changes marking degeneration in the liver (e.g., oval cell hyperplasia) and accentuation of other TCDD-related toxic responses. In addition, the groups of rats maintained on the cereal-based diets and subjected to the various promoter/vitamin A regimens exhibited significantly higher AHF incidence as compared to correspondingly treated rats fed the purified, casein-based diets. In conclusion, vitamin A deficiency alone may promote hepatocarcinogenesis and enhance the promoting effect of TCDD treatment. However, TCDD-induced depletion of hepatic vitamin A stores was not implicated as a major cause of promotion by TCDD. Nevertheless, vitamin A deficiency brought about by TCDD alone may well act as a promotive stimulus concertedly with an as yet unidentified cellular mechanism in TCDD-induced liver tumor promotion. The differential effects of the two types of diets recorded in the study remain undocumented.

Animals↗
PubMed1990

Changes in cytosolic CA2+ are not involved in DDT-induced loss of gap junctional communication in WB-F344 cells.

Recent studies have demonstrated that the insecticide DDT is a tumor promoting agent. Similar to many other tumor promoting agents, DDT has been shown to inhibit gap junctional intercellular communication (GJIC) between cells in culture, and it has been suggested that DDT-induced loss of communication between adjacent cells may depend on changes in cytosolic free Ca2+ concentration [( Ca2+]i). In the present study, the role of [Ca2+]i in DDT-induced loss of GJIC was investigated in WB-F344 in rat liver cells using the scrape-loading/dye transfer assay (SLDT) and the Ca2+ fluorescent indicator, fura-2. Our results show that DDT at noncytotoxic concentrations caused a reversible loss of GJIC. Inhibition of GJIC was not associated with detectable increases in [Ca2+]i, and was not prevented by loading cells with the intracellular Ca2+ chelator, BAPTA. In addition, the hydroquinone, tBuBHQ, which caused a 2-3 fold sustained increase in [Ca2+]i, did not inhibit GJIC. Conversely, when untreated cells were loaded with increasing BAPTA concentrations, GJIC were lost. These results indicate that increases in [Ca2+]i are not responsible for DDT-induced loss of communication and that, in general, an increase in [Ca2+]i within physiological levels is not sufficient to abolish GJIC. However, Ca2(+)-dependent processes that are active at normal resting [Ca2+]i appear to be required for the maintenance of GJIC.

Animals↗
PubMed1990

Promotion of altered hepatic foci development in rat liver, cytochrome P450 enzyme induction and inhibition of cell-cell communication by DDT and some structurally related organohalogen pesticides.

The organochlorine pesticide 1,1'-(2,2,2-trichloroethylidene) bis(4-chlorobenzene) (DDT) and four structural analogues (bromopropylate, chlorobenzilate, dicofol and fenarimol) were investigated for their ability to inhibit gap junctional intercellular communication both in the Chinese hamster V79 metabolic co-operation assay and in the scrape-loading/dye-transfer assay in WB-F344 rat liver epithelial cells. The pesticides were also studied for their ability to enhance the development of gamma-glutamyltranspeptidase-positive altered hepatic foci and induce cytochrome P450 monooxygenase isoenzymes in nitrosamine-initiated male Sprague-Dawley rats. The in vitro studies showed all organohalogens except fenarimol to be potent inhibitors of cell-cell communication in both test systems used. Concomitant results were recorded in the in vivo study. Thus, all potent inhibitors of intercellular communication were found to enhance significantly foci development and fenarimol was again without any significant effect. All pesticides studied were shown to be potent inducers of the phenobarbital-inducible cytochrome P450b isoenzyme and to cause hepatomegaly. Thus, no strict correlation between cytochrome P450b induction/liver growth and tumour promotion-related effects in vivo and in vitro was apparent for these organohalogen pesticides in the present study.

Animals↗
PubMed1989

Marked alterations in retinoid homeostasis of Sprague-Dawley rats induced by a single i.p. dose of 10 micrograms/kg of 2,3,7,8-tetrachlorodibenzo-p-dioxin.

Interference of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in retinoid homeostasis was investigated in Sprague-Dawley rats with a low (dietary induced) retinoid status, that were fed a [3H]retinol-containing diet (37 MBq, 10,000 IU/kg diet) for 21 days to facilitate determination of retinoid concentrations in various tissues. The rats were exposed to a single i.p. dose of 10 micrograms TCDD/kg body weight in corn oil, or to corn oil at day 7 of [3H]retinol supplementation. TCDD induced significant reductions in retinol and retinyl ester concentrations and [3H] retinol-derived radioactivity in the liver, the lung, the intestine and the adrenals to 3-5%, 40-45%, 37%, and 56% of control values, respectively, at 14 days after exposure. In contrast, the retinoid concentrations and the amount of [3H]retinol-derived radioactivity in the kidney and serum of TCDD-treated rats was increased to 440% and 140% of corn oil-treated controls, respectively, at the termination time of the experiment. Analysis of the amount of serum retinol binding protein (RBP) by gel-permeation chromatography revealed an 150% increase in the free fraction of retinol-RBP, i.e., uncoupled to transthyretin (TTR), in serum of TCDD-treated rats. In addition, urinary excretion of [3H]retinol-derived radioactivity was significantly enhanced (to 140% of controls) by TCDD. These data indicate that TCDD induces an increased mobilization of retinoids from hepatic and extrahepatic storage sites into serum accompanied by an enhanced elimination via the kidney into the urine of rats.

Adrenal Glands↗
PubMed1988

Chlorobenzilate-induced effects on enzyme-altered foci in rat liver and intercellular communication in rat liver WB-F344 epithelial cells.

The mouse liver carcinogen chlorobenzilate (CB), a DDT-related pesticide, was investigated for enhancement of enzyme altered foci incidence in partially hepatectomized, diethyl-nitrosamine-initiated rats. In this in vivo experiment, CB administered per os (25 or 100 mg/kg per day for 10 weeks) enhanced foci incidence at the high dose level. In order to study potential mechanisms involved, CB was investigated for inhibition of gap-junctional intercellular communication in rat liver epithelial WB-F344 cells and Chinese hamster V79 cells in vitro. CB abolished dye transfer in WB-F344 cells and inhibited metabolic cooperation in V79 cells. Two CB metabolites were unable to induce such tumor promotion related effects. The results of this investigation provide support for the involvement of an epigenetic, tumor promoting mechanism in CB-induced liver tumors in laboratory animals.

Animals↗
PubMed1988

Inhibition of metabolic cooperation in vitro and enhancement of enzyme altered foci incidence in rat liver by the pyrethroid insecticide fenvalerate.

The synthetic pyrethroids cypermethrin, delta-methrin, fenvalerate, permethrin, and the fenvalerate metabolite p-chlorophenylisovaleric acid were investigated for inhibition of gap-junctional intercellular communication in vitro in the Chinese hamster lung fibroblast (V79) metabolic cooperation assay. Fenvalerate was furthermore studied for enhancement of gamma-glutamyl transpeptidase-positive enzyme altered foci incidence in partially hepatectomized, nitrosodiethylamine-initiated male Sprague Dawley rats. The in vitro studies showed that fenvalerate and p-chlorophenylisovaleric acid were inhibitors of intercellular communication at non-cytotoxic concentrations while cypermethrin, deltamethrin, and permethrin were inactive. In the in vivo study in rat liver, fenvalerate administered p.o. (75 mg/kg/day) 5 days a week for 10 weeks induced significantly more foci per cm3 and a larger percentage of liver tissue occupied by foci tissue compared to a vehicle control group. Analysis of size distributions of foci in fenvalerate- and vehicle-treated rats showed elevated foci incidences in fenvalerate-treated rats at all foci sizes. Fenvalerate induced no hepatotoxic effects as judged by plasma transaminase activities and histopathology. The results of this study suggest fenvalerate to be a potential tumour promoter.

Animals↗
PubMed1988

Calmodulin involvement in TPA and DDT induced inhibition of intercellular communication.

The organochlorine pesticide DDT is a liver tumour promoter and a potent inhibitor of intercellular communication. Present knowledge of the mechanism by which DDT inhibits intercellular communication is limited but it has been suggested that increased intracellular free calcium induced by DDT could be of importance. As the effects of calcium are closely associated with the multifunctional protein calmodulin (CaM) in most cells the potential binding of DDT to CaM and subsequent effects on CaM-stimulated Ca2+/Mg2+-ATPase activity were studied. DDT inhibited CaM-stimulated Ca2+/Mg2+-ATPase activity and bound to CaM in a manner similar to established CaM-inhibitors. Subsequently an in vitro assay for measuring inhibition of metabolic cooperation between 6-thioguanine (TG)-sensitive and TG-resistant Chinese hamster (V79) cells was used to investigate the possible involvement of CaM in the regulation of intercellular communication. Calmidazolium (CzM), a potent CaM inhibitor, was tested alone or in combination with the tumour promoters 12-O-tetradecanoyl phorbol-13-acetate (TPA) or DDT known inhibitors of intercellular communication. The results showed that CzM alone was without effect with regard to inhibition of metabolic cooperation but potentiated the response induced by TPA, an effect not noticed with DDT. These results suggest different mechanisms of action of TPA and DDT on metabolic cooperation and support the hypothesis that with calcium CaM may be of importance for drug-induced inhibition of intercellular communication and tumour promotion.

Animals↗
PubMed1988

Tumour promotion related effects by the cyclodiene insecticide endosulfan studied in vitro and in vivo.

The cyclodiene insecticide endosulfan is structurally related to the tumour promoting pesticides chlordane and heptachlor. Divergent conclusions have been reported regarding the carcinogenic activity of endosulfan. In this study we have investigated if endosulfan and four of its metabolites possess tumour promotion related effects. Two in vitro test systems detecting inhibition of intercellular communication were used; the Chinese hamster lung fibroblast (V79) metabolic cooperation assay and a scrape loading/dye transfer assay using rat liver WB epithelial cells. At non-cytotoxic concentrations, technical grade endosulfan, analytical grade endosulfan (alpha- and beta-isomers and an alpha beta-isomer mixture) and endosulfan-sulfate inhibited gap junctional communication in both assay systems. In addition, the metabolite endosulfan-ether was effective in the rat liver WB epithelial cells. Endosulfan was also studied for enhancement of gamma-glutamyl transpeptidase positive enzyme altered foci incidence in partially hepatectomized, nitrosodiethylamine-initiated male Sprague-Dawley rats. However, endosulfan administered orally (1 or 5 mg/kg/day) five days a week for ten weeks did not enhance enzyme altered foci incidence. These apparently contradictory results with regard to possible tumour promoting activity of endosulfan are discussed in relation to metabolism, systemic toxicity and tissue/species specificity in tumour promotion.

Animals↗
PubMed1987

Retinol (vitamin A) inhibits the mutagenicity of o-aminoazotoluene activated by liver microsomes from several species in the Ames test.

Retinol (vitamin A) has earlier been shown to inhibit the mutagenicity of o-aminoazotoluene (OAAT) in the Salmonella/microsome assay when OAAT is activated with S9 from Sprague-Dawley rats. The results presented in this paper confirm this and also show that S9 from mice, hamsters and gerbils activates OAAT to mutagenic metabolites detected by Salmonella typhimurium TA100. However, S9 from rabbits is inactive. The S9 fraction from rabbits also shows a low aryl hydrocarbon hydroxylase (AHH) activity. The AHH activity or protein content of the microsomal fraction cannot be used to predict the activating capacity of S9 from the other species. Retinol, added in vitro, inhibits the mutagenic effect of OAAT activated by mouse, gerbil or hamster S9. The strongest inhibition is observed with hamster S9 while the inhibition of mouse and gerbil S9 is lower but still higher than in the rat.

Animals↗
PubMed1987

Interaction between quercetin, TPA and DDT in the V79 metabolic cooperation assay.

An in vitro assay measuring inhibition of metabolic cooperation between 6-thioguanine sensitive and 6-thioguanine resistant Chinese hamster (V79) cells in co-culture was used to detect chemically induced inhibition of gap-junctional intercellular communication. Inhibition of this cellular process by xenobiotics has been suggested to be an important event in tumour promotion. This study was undertaken to determine the effect on metabolic cooperation by the bioflavonoid quercetin alone and in co-exposure experiments with two recognized tumour promoters, the phorbol ester TPA and the organochlorine pesticide DDT. Furthermore, co-exposure experiments with TPA and DDT were performed. Quercetin alone did not affect metabolic cooperation at noncytotoxic doses. Treatment of the cells with either TPA, DDT or TPA together with DDT caused significant inhibition of metabolic cooperation. This effect was dose-dependently decreased by addition of quercetin. These findings suggest that quercetin inhibits or compensates a common effect induced by both TPA and DDT. Treatment of the cells with a fixed dose of TPA and increasing doses of DDT, or a fixed dose of DDT and increasing doses of TPA, caused significantly higher recovery of mutant cells than a calculated additive response. The data indicate that TPA and DDT induce a synergistic response with respect to affecting intercellular communication. The results suggest that there are different pathways of action for TPA and DDT.

Animals↗
PubMed1987

Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the lactating rat on maternal and neonatal vitamin A status.

Female Sprague-Dawley rats were given a single oral dose of 10 micrograms TCDD/kg body wt after delivery. Pups were killed on postnatal day (PND) 0, 2, 4, 8, or 16. Dams and remaining weanlings were killed on PND 22 and 32, respectively. Thymus weight was lower in dams exposed to TCDD than in controls, whereas no differences in body weight or relative liver weight were found. The total amount and the concentration of vitamin A were lower in the liver but higher in the kidneys and in serum of TCDD-treated dams than in controls. TCDD-exposed weanlings showed lower weight gain, liver enlargement and thymus atrophy compared to controls. Growth reduction became more pronounced with time, liver enlargement was at its peak on PND 8 and thymus atrophy was most pronounced on PND 16, although all three effects persisted throughout the study. The total amount of vitamin A increased at a similar rate in control and TCDD-exposed weanlings throughout lactation. When the young started to eat pelleted diet there was a pronounced increase in hepatic vitamin A content. Between PND 16 and 32 controls increased their hepatic vitamin A content 21-fold, compared to 12-fold in TCDD-exposed offspring. The hepatic stores of TCDD-treated animals reached 45% of the stores of control pups on PND 32. From PND 8 renal vitamin A was significantly higher in the TCDD-exposed young than in the controls. At PND 32 TCDD-exposed weanlings had six times more renal vitamin A than controls.

Animals↗
PubMed1985

Effects of vitamin A on the metabolism and mutagenicity of 2AAF in vitro and on the covalent binding to rat liver DNA/RNA in vivo.

Vitamin A has been shown to affect the in vitro metabolism of 2AAF. At low concentrations of retinol or retinyl palmitate, a decreased production of ring-hydroxylated as well as deacetylated and N-hydroxylated metabolites was observed, measured by high performance liquid chromatography. The increased mutagenicity of 2AAF observed after addition of vitamin A in the Ames test cannot therefore be explained as a result of stimulated N-hydroxylation. However, the addition of retinol was found to enhance the mutagenicity of the metabolite N-OH-2AAF in the presence of an S-9 fraction of rat liver homogenate. No differences with regard to the covalent binding of 2AAF or its metabolites to rat liver DNA/RNA in vivo could be demonstrated in animals fed diets with normal or high vitamin A content.

2-Acetylaminofluorene↗