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Biomedical subjects

J Tuomisto

Publications and source records attributed to J Tuomisto.

At least 19 recordsLinked to original sources
PubMed1995

Alterations in plasma tryptophan binding to albumin in 2,3,7,8-tetrachlorodibenzo-p-dioxin-treated Long-Evans rats.

We have previously shown that the wasting syndrome in response to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) administration is associated with a specific increase in free tryptophan (unbound to albumin) in rats. The present series of experiments was undertaken to characterize how the binding of tryptophan to albumin is altered by TCDD and to find the underlying cause of the changes. TCDD administered to Long-Evans rats proved to diminish the maximal binding capacity (Bmax) of albumin for tryptophan by ca. 60% without any marked change in the binding affinity. Of candidate mediating factors, neither TCDD nor bilirubin affected the binding equilibrium of tryptophan with albumin in vitro. However, a mixture of free fatty acids greatly increased the proportion of free tryptophan at physiologically relevant concentrations. Similarly, the free fatty acid mixture added to plasma in vitro decreased only Bmax of albumin in a manner similar to the effect of TCDD administered in vivo. Extraction of lipid-soluble substances from the plasma with ether was effective in reversing the increase in free tryptophan in the plasma of TCDD-treated rats while dialysis of water-soluble substances was not. Ether extraction also resulted in a decrease in free fatty acids. We conclude that disturbances in lipid metabolism may be involved in the pathogenesis of TCDD-induced alterations in tryptophan binding to albumin in vivo.

Animals↗
PubMed1995

Polychlorodibenzo-p-dioxin and polychlorodibenzofuran concentrations in human fat samples in a village after pollution of drinking water with chlorophenols.

Polychorodibenzo-p-dioxin and polychlorodibenzofuran (PCDD/F) and polychlorobiphenyl (PCB) concentrations were analyzed in fat samples of seven people from a village where the population had been exposed to chlorophenols for over twenty years, and in seven matched controls. There was only a minor difference in both PCDD/F and PCB concentrations which seemed to reflect the general difference in background pollution between the locations. We found nothing which could be construed as evidence of elevated levels of PCDD/Fs due to the chlorophenol exposure. Hence any detrimental health effects must be considered as being due to chlorophenols rather than PCDD/F impurities.

Adipose Tissue↗
PubMed1995

Biochemical effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds on the central nervous system.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and related compounds are an important class of environmental contaminants which induce several types of biochemical alterations. Their effects have been most thoroughly characterized in the liver, especially regarding the Ah receptor-mediated induction of xenobiotic metabolizing enzymes. The behavioral signs exhibited by animals exposed to TCDD (progressive anorexia and body weight loss) suggest a role for the central nervous system (CNS) in TCDD toxicity. At lethal doses, TCDD affects the metabolism of serotonin, a neurotransmitter able to modulate food intake in the brain. This effect is associated with an elevated concentration of free tryptophan in the plasma. There does not appear to be any major changes in catecholaminergic neurotransmitter systems in TCDD-treated rats. Cytochrome P-450 related enzyme activities are induced by TCDD in the brain. As is the case in the liver, this induction does not correlate with susceptibility to TCDD lethality in rats. The involvement of the CNS in TCDD toxicity is still obscure. Elucidation of this role as well as the mechanism of TCDD-induced wasting may well advance our understanding of the regulation of food intake and body weight.

Animals↗
PubMed1994

Characterization of 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced brain serotonin metabolism in the rat.

It has previously been shown that a lethal dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) increases the brain concentrations of serotonin precursor, tryptophan, and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in TCDD-susceptible Long-Evans but not in TCDD-resistant Han/Wistar rats. In the present study, TCDD (50 micrograms/kg; LD100 for Long-Evans and nonlethal for Han/Wistar rats) enhanced de novo biosynthesis of serotonin in the brain of Long-Evans but not Han/Wistar or food-restricted Long-Evans rats 10 days after exposure. Furthermore, TCDD increased the plasma level of free tryptophan in Long-Evans rats alone, which may be causally related to the observed effects of TCDD on brain tryptophan levels. Administration of hemin modified the time course of TCDD-induced anorexia although 10 day cumulative food consumption was not altered. Hemin tended to attenuate TCDD-elicited increases in brain serotonin turnover, whereas a beta-adrenergic blocker, propranolol, did not. In the majority of Long-Evans rats, TCDD inhibited the main tryptophan degrading enzyme in the liver, tryptophan pyrrolase, but the rest exhibited augmented activities; these effects were not altered by hemin. TCDD increased the plasma levels of nonesterified fatty acids in Long-Evans (five-fold) but not in Han/Wistar rats. A slight elevation (two-fold) was also seen in food-restricted Long-Evans rats. It is concluded that TCDD selectively promotes brain serotonin turnover in Long-Evans rats and this acceleration is related to increased plasma levels of free tryptophan. The inhibition of tryptophan catabolism in the liver and elevation of plasma nonesterified fatty acids may contribute to these changes.

Animals↗
PubMed1993

Cytogenetic effects of 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) in rat peripheral lymphocytes in vitro and in vivo.

3-Chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) is a potent direct-acting Salmonella mutagen found in wood pulp chlorination effluents and chlorinated drinking water. In cultured rat peripheral lymphocytes, MX induced significant dose-related increases in sister-chromatid exchanges (SCEs) and chromosome aberrations at doses of 20-60 micrograms/ml and of 60-80 micrograms/ml, respectively. MX produced primarily chromatid-type as opposed to chromosome-type aberrations. The peripheral lymphocytes of male and female rats exposed to MX by gavage 5 days a week for 14-18 weeks showed significant dose-related increases in SCEs at both levels of exposure (30 and 45-75 mg/kg) in both sexes. The present results demonstrate for the first time that MX is genotoxic in vivo.

Animals↗
PubMed1992

Puffing behavior during the smoking of a single cigarette in a naturalistic environment.

The 36 participants in this study were habitual low-yield cigarette smokers, medium-yield cigarette smokers, and switchers from medium- to low-yield cigarettes. All participants smoked both low- (0.4 mg) and medium-nicotine (0.9 mg) cigarettes during the study. Puffing indices were recorded during the first two cigarettes, after an overnight abstinence of smoking, by a portable flowmeter processor unit in a naturalistic environment. The puff volumes per cigarette and per day were significantly lower while switching to higher-yield cigarettes, mainly due to a decrease in the number of puffs and longer interpuff intervals, but also due to a decline in puff duration and flow rate. However, the downregulation by puff volume was incomplete, at most two thirds, as calculated by machine smoking yields. Within the course of smoking a single cigarette, the flow rate was quite stable, puff duration and puff volume decreased toward the end of the cigarette, and interpuff interval was longest during the middle of the cigarette. Total puff volumes per cigarette were similar in the first two cigarettes of the day after an overnight abstinence of smoking, with no significant differences in other puff parameters. Diurnal cotinine excretion revealed that nicotine titration in switching situations was very accurate among switchers and medium-yield cigarette smokers, but not among the low-yield cigarette smokers, and so called oversmoking was found with the higher-nicotine brand. Preferred cigarette type had little effect on the puffing patterns of smokers in single cigarettes.

Adult↗
PubMed1992

Effects of smoking abstinence and chain-smoking on puffing topography and diurnal nicotine exposure.

Effects of chain-smoking, a 15-h smoking abstinence, and the nicotine yield of cigarettes on puff indices were studied in eight healthy smokers by using a controlled crossover study design. Puff parameters were measured puff by puff with a portable measuring device when 10 or 20 cigarettes, with nicotine yields of 0.3 and 1.0 mg, were smoked per day. The interval between sessions was 1 h, and the 20 cigarettes per day were chain-smoked 2 at a time. Serum cotinine indicated that smokers compensate completely for the lower nicotine delivery from the 0.3-mg cigarette. Smokers almost doubled total puff volume per cigarette and per day mainly by taking more puffs from the low-nicotine cigarettes and slightly prolonging puff duration. However, nicotine deprivation and chain-smoking had a relatively minor effect on puffing indices with both brands, a fact that agrees poorly with the nicotine titration hypothesis. However, in the course of every single cigarette of the day smokers significantly reduced puff duration and puff volume toward the end of the cigarette, which probably involves satiation of the nicotine crave but may also be due to changes in taste of the smoke.

Adult↗
PubMed1992

Pharmacokinetics in rat of 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX), a drinking water mutagen, after a single dose.

The pharmacokinetics of 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) was evaluated after a single oral or intravenous administration in the rats using 14C-labelled compound. Twenty to 35% of the dose was absorbed into circulation from the gastrointestinal tract as assessed from the excretion in urine. The mean elimination half-life of the radioactivity in blood (T1/2 k10) was 3.8 hr. Traces of radioactivity remained in the blood for several days. The tissues lining the gastrointestinal and urinary tract, kidneys, stomach, small intestines and urinary bladder contained the highest radioactivity. The activity declined slowest in the kidneys. Urine was the main excretion route. Seventy-seven % of the total amount excreted appeared in urine in 12 hr and 90% in 24 hr. No radioactivity was exhaled in air suggesting that elimination through respiration did not occur. After an intravenous administration of 14C-MX, the T1/2 k10, was much longer, 22.9 hr, and the total elimination half-life (T1/2 beta), 42.1 hr. The results indicate that MX is absorbed from the gastrointestinal tract to a considerable degree and it is excreted in urine very rapidly. A fraction of MX or its metabolites is retained in blood for a longer period of time. The pharmacokinetics of MX does not suggest extensive cumulation of MX in tissues after continuous exposure.

Absorption↗
PubMed1992

Acute neurobehavioural effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in Han/Wistar rats.

The neurobehavioural effects of a single non-lethal dose (1000 micrograms/kg intraperitoneally) of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) were assessed in young male Han/Wistar rats, highly resistant to acute lethality of TCDD. TCDD decreased body weight significantly compared with ad libitum fed controls. TCDD did not change the behaviour or the motility of rats in the open field test 8 days after the treatment nor did it affect the spontaneous motor activity up to 27 days after the exposure. In the elevated plus-maze test for anxiety, TCDD-treated rats did not differ from either ad libitum fed controls or pair-fed controls. In the 24-hr passive avoidance test, the learning of TCDD-treated rats did not differ significantly from that of ad libitum fed controls or pair-fed controls from 8 hr to 16 days after the treatment. TCDD did not affect the motor coordination or the maintenance of balance on the rotating rod but it impaired them slightly in the elevated horizontal bridge test 16 hr after exposure. It did not affect nociception in the hot plate test 16 hr or 8 days after the injection. The results suggest that a single sublethal dose of TCDD does not alter markedly the general behaviour of Han/Wistar rats, in contrast to its striking effect on feeding behaviour which results in a marked decrease in body weight gain.

Animals↗
PubMed1991

Identification of aromatic moieties and mycosamine in antifungal heptaenes with high-performance liquid chromatography, high-performance liquid chromatography-mass spectrometry and gas chromatography-mass spectrometry.

A high-performance liquid chromatographic (HPLC) method for the determination of the aromaticity of heptaene polyene antibiotics has been developed. The released aromatic moiety of the heptaene polyenes aureofungin, candicidin, candimycin, hamycin and trichomycin was assayed after alkaline hydrolysis. The presence of p-aminoacetophenone (PAAP) and N-methyl-p-aminoacetophenone (N-methyl-PAAP) in the hydrolysates was determined by HPLC, HPLC-mass spectrometry (HPLC-MS) and gas chromatography-MS (GC-MS). Candicidin and hamycin contained only the PAAP residue; aureofungin contained both PAAP and N-methyl-PAAP. Trichomycin contained PAAP and also some unknown component of molecular weight 179. The aromatic nature of the individual components of the heptaene complex was demonstrated using radioactivity flow detection for the determination of the incorporation of [14C]-p-aminobenzoic acid to individual candicidin components. Ammonia chemical ionization MS was successfully used for the GC-MS identification of the acetylated mycosamine moiety of heptaenes.

4-Aminobenzoic Acid↗
PubMed1991

Do new hypotheses on the mechanism of action of dioxins help in risk evaluation?

The mechanism of action of chlorinated dibenzodioxins such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is not known, but the prevailing hypothesis is the binding to a specific protein, the Ah-receptor, and subsequent alteration of the expression of specific genes. This Ah-receptor hypothesis does not explain all aspects of toxicity, notably the extreme variation of toxicity between different animal species. We have found two rat strains that differ widely in their sensitivity to TCDD. The resistant Han/Wistar (H/W) rat tolerates doses up to 3000 micrograms kg-1, while 20 micrograms kg-1 is lethal to Long-Evans (L-E) rats. Several morphological, biochemical and endocrinological parameters as well as pharmacokinetics have been screened, but the strains behave by and large similarly. However, there is a clear behavioural difference: TCDD causes anorexia in both strains, but H/W rats start eating again in 1-2 weeks, whereas the reduction of feed intake is permanent in L-E rats until they die in about 3 weeks. Han/Wistar rats, which recover after a single large dose of TCDD, behave aberrantly for months; they seem to have a supersensitive satiety response while they do not respond normally to energy deficiency. Therefore the regulation of feed intake or of body weight seem to be altered permanently by TCDD. It is also of interest that TCDD is more toxic after a central than after a peripheral administration. These findings may be of importance for the risk evaluation of dioxins, because they might help to explain the wide species/strain variation which complicates the assessment of dioxin risk to humans.

Animals↗
PubMed1991

Polyene antibiotics increase the ionic permeability of synaptosomal plasma membranes.

The effects of antifungal heptaene antibiotics candicidin and amphotericin B were investigated in isolated cerebral cortical nerve terminals (synaptosomes). The synaptosomes were incubated with candicidin or amphotericin B in the presence or absence of external Ca2+. Candicidin (0.4-0.8 I.U./mL) increased intrasynaptosomal free Ca2+ significantly. This increase was not significantly suppressed by 30 microM verapamil or 2 microM nifedipine. In the absence of extrasynaptosomal Ca2+ intrasynaptosomal free Ca2+ was not changed by candicidin. Amphotericin B increased intrasynaptosomal free Ca2+ as well. Candicidin (0.05-0.6 I.U./mL) increased the respiration rate up to 3.5-fold above the basal rate. This response was not affected by the absence of extracellular Ca2+. Ouabain completely blocked the increase of respiration caused by candicidin, whereas tetrodotoxin was ineffective. The plasma membrane depolarized in a dose-dependent manner after candicidin (0.2-0.8 I.U./mL). The mitochondrial membrane potential was little affected and only at the highest concentrations. The results indicate that heptaene polyenes increase synaptosomal ionic permeability, which is reflected in increased Ca2(+)-influx and accelerated respiration. The increment in synaptosomal free calcium takes place probably as a nonspecific leak via typical polyene-cholesterol channels. The respiration is accelerated by increased Na(+)-permeability through the plasma membrane which stimulates the function of Na+, K(+)-ATPase and thus increases the energy demand.

Amphotericin B↗
PubMed1991

Smoking behavior in low-yield cigarette smokers and switchers in the natural environment.

Urinary cotinine and puffing parameters were studied in 36 smoking students. Three smoking groups, formed according to the tar content of their preferred cigarette, were compared. Eighteen students had always smoked low-yield, 10 medium-yield and 8 were switchers from medium- to low-yield cigarettes. The subjects smoked their preferred brand (the first week), low-yield cigarettes (the second week) and medium-yield cigarettes (the third week). Day urine samples were collected for cotinine analysis during the two last days of the test weeks. Puffing indices were reported on the last day of every test week with a portable microcomputer assisted analyzer with flowhead cigarette holder. Urinary cotinine concentrations were rather constant within the groups, but lower among the low-yield cigarette smokers as compared to the switchers (p less than 0.05). Also the female smokers had lower cotinine concentrations than the male smokers (p less than 0.05). The compensatory behavior seen in every smoking group while they were smoking low-yield cigarettes was based on up-regulation in single puff volume, puff duration and total smoking time when compared to values with medium-yield cigarettes. The correlation between cotinine concentration and diurnal puff volume (1/day) was poor. It is concluded that the benefit possibly gained with low-yield cigarettes is not long lasting.

Adult↗
PubMed1991

Binding of the strong bacterial mutagen, 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) to bovine serum albumin.

Binding of 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) to bovine serum albumin (BSA) was studied. MX bound mainly reversibly to BSA but, for a minor part, also irreversibly. It was possible to extract the main part of the reversibly bound MX with ethyl acetate and the extractable compound was chromatographically identical to MX. The affinity-binding characteristics of the interaction with albumin were K = 1.6 x 10(7) M-1, n = 3.4. Furthermore, mutagenicity studies indicated that reversibly bound MX remained mutagenic but that irreversibly bound MX was no longer mutagenic in the Ames test. These results suggest that the binding of MX to albumin is an important factor for both the toxicological effects and the toxicokinetics of MX.

Animals↗
PubMed1991

TCDD decreases rapidly and persistently serum melatonin concentration without morphologically affecting the pineal gland in TCDD-resistant Han/Wistar rats.

The highly toxic environmental contaminant, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was recently reported to decrease serum melatonin levels throughout the circadian cycle in the most TCDD-susceptible strain of rat, Long-Evans. To find out whether this effect is related to the mechanism of acute lethality of TCDD, serum melatonin levels were measured at the nocturnal peak phase in the most TCDD-resistant rat strain variant, Han/Wistar rats, 6 hr to 28 days after TCDD exposure. The same dose as used in the previous study, 50 micrograms/kg, decreased serum melatonin levels to approximately half the control values by the first day after the treatment. Melatonin concentrations remained at this reduced level over the whole observation period. In an auxiliary experiment, Han/Wistar rats were dosed with 1000 micrograms/kg TCDD and killed on day 3. Neither light nor electron microscopic examination of their pineal glands revealed any alteration attributable to TCDD treatment. These findings might indicate that the reduction of serum melatonin levels in the rat by TCDD is not related to its lethal effect and is not due to a direct damage of the pineal gland.

Animals↗
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↗