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Biomedical subjects

J Tuomisto

Publications and source records attributed to J Tuomisto.

At least 91 records · Page 5Linked to original sources
PubMed1991

Characterization of the enhanced responsiveness to postingestive satiety signals in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-treated Han/Wistar rats.

Previous studies have shown that under free-feeding conditions, TCDD-treated Han/Wistar (H/W) rats consume less sucrose solution but ingest more saccharin solution than their controls thus implying hyperresponsiveness to postingestive satiety signals. In this study, nutrient preloads were employed to further elucidate this phenomenon. Male H/W rats were given a single high but usually non-lethal intraperitoneal dose (1000 micrograms/kg) of TCDD. Feed intake was stimulated by 24 hr feed deprivation at various time points after TCDD exposure. When TCDD-dosed rats were allowed to drink either a 20% sucrose or a 0.25% saccharin solution and then given access to feed, those that had had sucrose ate only about 50% of the amount consumed by the saccharin group. Although the preloads were similar in control rats, no such difference in subsequent feeding occurred. The sucrose solution also produced a longer-lasting suppression of feed intake in TCDD-treated compared with control rats when infused directly into the stomach. By contrast, TCDD-treated H/W rats failed to exhibit an augmented satiety response to parenterally applied glucose independent of testing time. Oral corn oil reduced feed intake in both control and TCDD-exposed rats, but the inhibition was slightly larger in TCDD-treated animals. TCDD did not markedly affect the responsiveness of H/W rats to the suppression of feeding by CCK-8 or bombesin. It is concluded that gastrointestinal factors appear critical to the exaggerated response of TCDD-treated H/W rats to nutrient energy.

Administration, Oral↗
PubMed1990

Effects of TCDD on vitamin A status and liver microsomal enzyme activities in a TCDD-susceptible and a TCDD-resistant rat strain.

To investigate the relationship between vitamin A status and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) lethality, the influence of TCDD on tissue and serum vitamin A levels was determined in the most TCDD-susceptible (Long-Evans) and the most TCDD-resistant (Han/Wistar) rat strains. The TCDD LD50 values of these two strains differ by a factor of more than 300. Groups of three rats per strain were used in a dose-response study (given single ip doses of 0, 4, 40, 400, 800 or 1600 micrograms TCDD/kg body weight and killed on day 11) and in a time-course experiment (given single ip doses of 0, 4 and, in the case of Han/Wistar rats only, 1600 micrograms TCDD/kg body weight, and killed on days 4, 11, 23, 50 and 76). The strains showed similar response over the 76-day study with respect to vitamin A levels in the liver, kidneys, testicles and serum after exposure to a sublethal dose of TCDD (4 micrograms/kg body weight). In contrast, TCDD doses lethal to the Long-Evans strain only (40-1600 micrograms/kg, day 11) markedly increased kidney and serum vitamin A levels in Han/Wistar rats, while they were practically without effect in Long-Evans rats. Hepatic cytochrome P-450 concentration, and the activities of 7-ethoxyresorufin O-deethylase, ethylmorphine N-demethylase, and uridine diphosphate glucuronosyltransferase (towards p-nitrophenol) were affected by the TCDD doses in much the same manner in both strains. These findings show that the correlations between TCDD lethality and changes in vitamin A status found among species of laboratory animals do not hold for Long-Evans and Han/Wistar strains of rat.

Animals↗
PubMed1990

Remarkable residual alterations in responses to feeding regulatory challenges in Han/Wistar rats after recovery from the acute toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).

Adult male Han/Wistar rats were treated with 1000 micrograms 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)/kg body weight and allowed to restabilize their body weight at a lower level. Therefore, their feeding or drinking responses were determined to the following ip challenges: NaCl (1 M, 10 ml/kg body weight); 2-deoxy-D-glucose (2DG; 400 mg/kg); sodium mercaptoacetate (MA; 800 mumol/kg); 2DG + MA (200 mg/kg + 400 mumol/kg); insulin (10 U/kg). In addition, the suppressive effects of naloxone (10 mg/kg), glucose (1.36 mg/kg) and fructose (1.36 mg/kg) on feed intake stimulated by 24-hr food deprivation were examined. After the restabilization, the body weights of TCDD-treated rats followed the course of body changes in control rats. The responses to NaCl were also similar in TCDD-treated and control rats. However, marked differences were observed in all other responses studied. Pretreatment with TCDD abolished 2DG-induced feeding, attenuated the effects of insulin and naloxone, caused an aberrant decrease in feed intake following MA, and resulted in hypersensitivity to the satiating effects of glucose and fructose. These data show that exposure to a high dose of TCDD leads to notable distortions in responses to metabolic challenges in Han/Wistar rats, which are present even when they have seemingly recovered from the acute toxicity. The results also indicate that the central nervous system plays a crucial role in TCDD toxicity, and suggest hypersensitivity to peripheral satiety signals coupled with hyporesponsiveness to metabolic cues of energy deficit to be important mechanisms in the pathogenesis of the wasting syndrome.

Animals↗
PubMed1990

2,3,7,8-Tetrachlorodibenzo-p-dioxin enhances responsiveness to post-ingestive satiety signals.

The present study was designed to characterize the hypophagia that is a salient feature of the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced wasting syndrome. When TCDD-treated Long-Evans (L-E; dose 50 micrograms/kg) and Han-Wistar (H-W; 3000 micrograms/kg) rats were offered a simultaneous choice of three diets differing in their macronutrient composition, no selective aversion was seen to any of the varieties, although total energy intake decreased drastically and especially so in L-E rats. Further studies in H-W rats showed that TCDD treatment leads to a permanent retardation of weight gain accompanied by a decreased intake of chow and of a 10% sucrose solution, and to a reduced or unchanged consumption of water. In contrast, there was a progressive increase in saccharin drinking (when offered as the only choice) in TCDD-dosed rats with time. TCDD-treated animals also tended to consume a greater proportion of their daily feed intake during the daytime. These results imply that TCDD induces aversion to eating energy-providing food, irrespective of its type, and that TCDD exerts this at least in part by sensitizing the rats to post-ingestive satiety factors.

Animals↗
PubMed1990

Tissue distribution, metabolism, and excretion of 14C-TCDD in a TCDD-susceptible and a TCDD-resistant rat strain.

A comparative study was carried out in the most TCDD-resistant [Han/Wistar (H/W), LD50 greater than 3000 micrograms/kg] and the most TCDD-susceptible [Long-Evans (L-E), LD50 about 10 micrograms/kg] rat strain to assess the significance of kinetic factors in TCDD toxicity. Young adult males of both strains were administered 5 micrograms/kg (1.9 microCi/kg) 14C-TCDD intraperitoneally. Four rats per strain were killed at 4 hr, 1, 4, 8, 16, and 32 days after exposure. A total of 22 tissues along with blood and serum were sampled for liquid scintillation counting. From half of the animals, daily urine and faeces were also analyzed. In addition, 3 rats per strain were given 50 micrograms/kg (19 microCi/kg) 14C-TCDD and prepared for whole-body autoradiography after 1, 4 or 8 days. The livers of two rats per strain killed at 4 hr, 4 or 16 days, and the excreta from two rats of both strains collected on days 1-4, 5-8, 13-16, and 29-32 after exposure were analyzed for metabolites of TCDD by high pressure liquid chromatography. The label was mainly excreted in faeces as metabolites of TCDD, and the half-life of elimination was 20.8 (L-E) or 21.9 (H/W) days. A very similar overall distribution pattern was observed in both strains irrespective of dose, and the liver was the major site of accumulation. Practically all liver 14C-activity was found as the parent compound. Moderate strain-related differences were observed in the thyroid, thymus, prostate, adrenals, and brown and white fat, where lower values were recorded in H/W rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue↗
PubMed1990

Studies on the role of lipid peroxidation in the acute toxicity of TCDD in rats.

Lipid peroxidation has been shown to be enhanced following exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), but its role in TCDD toxicity is unclear. The present study was undertaken to further elucidate the relations between lipid peroxidation and TCDD lethality. A time course and dose-response experiment in Long-Evans (L-E; LD50 ca. 10 micrograms/kg) and Han/Wistar (H/W; LD50 greater than 3000 micrograms/kg) rats showed that hepatic lipid peroxidation, measured as the amount of thiobarbituric acid-reactive substances (TBA-RS), was induced by TCDD dose-dependently in L-E, but not in H/W rats. Hepatic glutathione peroxidase activity was suppressed in much the same manner in both strains. Lipid peroxidation correlated with body weight loss in L-E rats alone. When 500 micrograms/kg of TCDD was given to L-E rats, lipid peroxidation increased about 3-fold on Day 11 in the liver, while no change was seen in cardiac or renal TBA-RS. The pair-fed controls did not survive the 11-day test period and exhibited gastrointestinal hemorrhages. At 6 days, liver atrophy and elevated (over 2-fold) TBA-RS values were recorded in pair-fed controls but not in their TCDD-treated counterparts. TCDD decreased hepatic glutathione peroxidase activity by almost 50% at 6 days, while pair-feeding was without effect. Liver morphology was different between TCDD-treated and pair-fed rats. Moreover, the livers of TCDD-treated L-E rats contained much higher concentrations of probably peripheral fat-derived fatty acids than did the livers of pair-fed or ad libitum control rats. Restricted feeding over 6 days induced hepatic lipid peroxidation more in H/W than in L-E rats. Endotoxin increased liver TBA levels similarly in both strains having an additive effect with high doses of TCDD in H/W rats. Added as a 0.5% concentration in chow, butylated hydroxyanisole (BHA), but not ethoxyquin, tended to increase survival rate and time in L-E rats exposed to 20 micrograms/kg of TCDD; at 50 micrograms/kg the only survivor was again in the BHA group. However, neither antioxidant had any effect on initial body weight loss. It is concluded that lipid peroxidation mainly arises as a secondary phenomenon in TCDD toxicity, is not the cause of the typical histopathological liver lesion, but may contribute to lethality.

Animals↗
PubMed1990

Changes in rat brain monoamines, monoamine metabolites and histamine after a single administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).

Male Long-Evans rats were given 50 micrograms/kg 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) intraperitoneally and after 1, 4, 28 or 76 hr, noradrenaline, dopamine, dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), tryptophan and histamine were measured in the brain (dissected into ten parts) as well as in the pituitary gland. Several slight but significant changes were observed, e.g. in the hypothalamus where HVA and 5-HIAA were decreased after 4 hr, noradrenaline was decreased after 76 hr and histamine increased after 28 hr. Several late changes were also found, conspicuously tryptophan was increased in most brain areas after 76 hr and in some cases earlier; these changes may be due to starvation after hypophagia rather than TCDD directly. The results demonstrate that TCDD causes changes in brain neurotransmitter systems, but the changes are minor and it is not likely that aminergic systems are the key mediators in TCDD-induced hypophagia.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1990

Procaine (Gerovital): no effect on the rehabilitation result in patients with back or hip disease.

Gerovital was compared with placebo and another procaine preparation in a double blind study of 88 rehabilitation patients suffering from back or hip disease. In an open part of the study procaine from intramuscularly injected Gerovital disappeared from the plasma within 15-30 minutes. In patients treated with Gerovital or another procaine no clinical, physiological or psychological benefits were found in addition to the improvements following rehabilitation compared with placebo treatment. Clinical examination showed that the benefits of rehabilitation were similar in patients receiving Gerovital, another procaine and placebo.

Aged↗
PubMed1990

Genotoxicity of drinking waters.

Drinking waters in many countries have been shown to contain non-volatile polar mutagenic compounds as well as trihalomethanes. Their nature is uncertain, but one compound, a chlorinated furanone (3-chloro-4-(dichloro-methyl)-5-hydroxy-2(5H)-furanone;MX) seems to be responsible for one third to over one half of the mutagenicity. Its concentration seems to correlate rather well also with the total bacterial mutagenicity. Animal toxicity studies are being used to evaluate the possible carcinogenicity risk of this compound as a first stage in complete risk assessment of the whole complex mixture. Epidemiological risk assessment is also possible, since mutagenicity values can be predicted on the basis of organic material in the raw water and the amount of chlorine used. This information has been collected in Finland retrospectively from waterworks, and will be correlated with the Finnish Cancer Registry data.

Animals↗
PubMed1990

The LD50, excretion and serum and bone levels of F after a high single F and F + Mg dose in rats with findings on cardiac Ca and Mg.

The LD50 for fluoride was elevated from less than 60 mg F/kg body weight to 172 mg F/kg when magnesium (as MgCl2), equivalent to 3 times that of F, was administered by gavage 30 min after the F dose. A dose of 30 mg F/kg elevated the mean steady state of F in serum nearly 1.5-fold and in femoral bone nearly 2-fold when administered with or without the subsequent Mg dose and observed 24 h after the electrolyte dosages. Also, in 24-hour urine the mean F excretion was highest in the F and FMg groups. The total F excretion (fecal + urinary) was elevated 8- and 10-fold when fluoride was administered with or without magnesium, as compared to control levels. Magnesium administration with fluoride did not significantly modify the above mean values of the group given fluoride alone. This suggests that interference with the absorption of fluoride was not the primary protective function of magnesium against the acute toxicity of fluoride. Additional experiments, conducted to further clarify the toxic mechanism of fluoride and the protective mechanism of magnesium, resulted in the following findings: An intraperitoneal dose of 20 mg F/kg elevated fluoride concentration in serum in 1 h about 20 times compared to the controls. Magnesium injected simultaneously with fluoride did not modify the effect of fluoride alone. No significant changes were found in the concentrations of K, Mg, Na or Ca of the lung, skeletal muscle, kidney or liver after these injections except for some trend of elevation of Ca in the heart. However, after a dose of 30 mg F/kg i.p., the heart Ca/Mg mole ratio was elevated within 1 h from 0.037 to 0.194, while all of these rats died within 1 h after the injections. When magnesium, equivalent to 3 times the amount of fluoride was injected, this mole ratio was only 0.095, and all rats in this group survived over 1 h. These results suggest that the lethality of fluoride may be dominantly mediated by the elevated Ca (Ca/Mg ratio) in the heart muscle and that this is correctable by Mg.

Animals↗
PubMed1989

The central nervous system may be involved in TCDD toxicity.

In the present study, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was administered to both the most TCDD-susceptible (Long-Evans) and the most TCDD-resistant rat strain (Han/Wistar) as a constant 1-week infusion either centrally (intracerebroventricularly; i.c.v.) or peripherally (s.c.). Lethality, feed and water consumption as well as weight gain were observed. For both strains of rat, feed intake was most severely affected in the groups given TCDD i.c.v., while the s.c. infusion of TCDD did not markedly depress eating. The same pattern of responsiveness was discernible in the reduction of water consumption and of weight gain. Two out of 7 i.c.v.-treated rats of the TCDD-susceptible strain died after TCDD exposure, whereas all s.c.-dosed animals survived. A statistically significant strain difference was manifest in the magnitude of response between the i.c.v.-TCDD groups in feed intake and body weight change. Moreover, no deaths occurred among the TCDD-resistant Han/Wistar rats. An additional experiment did not disclose any difference in TCDD toxicity between 2 peripheral routes (s.c. and i.p.). Further, lethality tended to have a shorter latent period with the readily absorbable dimethyl sulphoxide (DMSO) as the solvent than with the potentially slowly absorbed corn oil. These findings suggest an important role for the central nervous system in TCDD toxicity.

Animals↗
PubMed1989

Target tissue morphology and serum biochemistry following 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure in a TCDD-susceptible and a TCDD-resistant rat strain.

The mode of action of the highly toxic environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is unknown. It was recently discovered that two strains of rat, Long-Evans (L-E) and Han/Wistar (H/W), differ widely in susceptibility to TCDD. Employing this strain divergence as a probe, the present study set out to assess the role of various biochemical and morphological effects in TCDD lethality. In the main experiment, the rats were treated once ip with 0,5,50, or (H/W) 500 micrograms/kg TCDD and killed 1 to 16 days postexposure. Several target organs were evaluated by light microscopy and a number of serum lipid and carbohydrate parameters as well as a few major regulatory hormones were analyzed. The results demonstrated that most alterations caused by TCDD were essentially similar in both strains. TCDD reduced circulating thyroxine to a slightly greater extent and more permanently in the sensitive L-E strain. Moreover, a highly significant interaction on thyroid-stimulating hormone was found among strain, dose, and time. Serum concentrations of corticosterone and free fatty acids were increased only in the L-E rats given 50 micrograms/kg TCDD, i.e., at an apparent LD100 dose level for this strain. Yet, the most striking interstrain difference was seen in the liver which was distinctly affected after Day 4 in L-E rats given 50 micrograms/kg TCDD but only marginally affected in rats from any H/W group. The lesion, while showing no necrotic cell changes, was suggestive of plasma membrane damage, possibly reflecting the production of free radicals. The relation of the findings to possible mechanisms of TCDD action is discussed.

Animals↗
PubMed1988

Hepatic Ah-receptor levels and the effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on hepatic microsomal monooxygenase activities in a TCDD-susceptible and -resistant rat strain.

Previous studies have shown that in two inbred strains of mice, straightforward correlations exist among the number of hepatic Ah-receptors, enzyme inducibility by TCDD, and lethality of TCDD. Here, studies were conducted in two strains of rats (Han/Wistar and Long-Evans) which differ widely in susceptibility to the lethal effects of TCDD, to determine if these are general phenomenona in TCDD toxicity. The total number of specific binding sites (Ah-receptors) for [3H]TCDD proved to be approximately equal in the livers of both rat strains. Likewise, no notable difference was detected in the effect of TCDD on the activities of 7-ethoxyresorufin O-deethylase, 7-ethoxycoumarin O-deethylase, and ethylmorphine N-demethylase or on the amount of cytochrome P-450 in hepatic microsomal fractions. Immunoblot analysis was carried out with monoclonal antibodies (Mabs). Mab 1-7-1 directed against rat liver 3-methylcholanthrene (MC)-inducible P-450 recognized forms P-450c and P-450d in TCDD-treated rats in a dose-dependent fashion and to a similar extent in both strains. In contrast, Mab 2-66-3 (against phenobarbital-inducible P-450) did not recognize any proteins in either strain, confirming the conclusion that TCDD elicits a MC-type induction of hepatic cytochrome P-450 in both strains of rats. Thus, it seems that the correlations observed in mice do not hold in rats and therefore should not be generalized. The parameters measured in the present study are causally unrelated to the mechanism of lethal action of TCDD in these rat strains.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1988

Screening of pharmacological agents given peripherally with respect to TCDD-induced wasting syndrome in Long-Evans rats.

A salient sign of fatal 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) intoxication is dramatic body weight loss accompanied by hypophagia. Yet, the nature of this wasting syndrome is unknown. As all of the current leptogenic (weight reducing) drugs exert their action by affecting aminergic neurotransmission, this study set out to screen the reversibility of TCDD-induced anorexia with the following agents modulating aminergic neurotransmission: amphetamine, amperozide, chlordiazepoxide, clonidine, haloperidol, morphine, PCPA, phenoxybenzamine, reserpine and sotalol. In addition, dexamethasone, indomethacin, and insulin were included in the drug battery. The agents were administered subcutaneously to adult male Long-Evans rats over a period lasting from 3 to 14 days. Half of each drug group was concomitantly exposed to a lethal dose of TCDD (20 micrograms/kg). None of the regimens were able to mitigate the wasting syndrome. TCDD proved to markedly diminish the nocturnal feed intake while practically sparing daytime feed consumption. Insulin increased the daytime feeding of TCDD-exposed rats, and the termination of treatment resulted in almost total aphagia in this group. Amphetamine, dexamethasone, PCPA, and reserpine caused weight loss in drug control rats and aggravated the action of TCDD. However, clonidine had no effect on the weight of control rats but accelerated weight decline in TCDD-cotreated animals. TCDD seemed to have a somewhat minor influence on drinking than on feeding. Clonidine stimulated water intake in controls but not in TCDD-exposed rats. These results suggest that aminergic neurotransmission is not specifically or crucially affected by TCDD, but further studies are needed to confirm this conclusion.

Analysis of Variance↗