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Archives of Toxicology (v.69, #2)
Relationship between acute toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and disturbance of intermediary metabolism in the Long-Evans rat by Fang Fan; Karl K. Rozman (pp. 73-78).
The aim of this study was to examine the acute toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in a rat strain other than the Sprague-Dawley (S-D) rat, for which most of our data have been generated thus far. Doses for the biochemical study were selected based on an acute range-finding study, which indicated that Long-Evans (L-E) rats are somewhat less susceptible to TCDD toxicity than are S-D rats. Male L-E rats were dosed orally with 10, 20, 45, 67, 100 and 150 μg/kg TCDD. Body weight and feed intake were dose-dependently decreased prior to killing of the animals. Eight days after dosing, animals were killed and tryptophan, total T4 (TT4) and total T3 (TT3) levels were determined in serum, whereas the activities of ethoxyresorufin-O-deethylase (EROD), phosphoenolpyruvate carboxykinase (PEPCK), γ-glutamyl transpeptidase (γ-GT) and tryptophan 2,3-dioxygenase (TdO) were measured in liver. EROD activity was fully induced at all doses studied, indicating that as in S-D rats, Ah-receptor-mediated effects do not seem to play any major role in the acute toxicity of TCDD in this rat strain either. Hepatic PEPCK activity was dose-dependently decreased in a similar dose range as in S-D rats, indicating inhibition of gluconeogenesis. Feed intake was dose-dependently decreased as a result of a dose-dependent elevation in serum tryptophan levels, which in turn were related to reduced liver TdO activity. Hepatic γ-GT activity was also dose-dependently reduced. However, unlike in S-D rats, these dose-responses occurred in a higher dose range than the reduction of PEPCK activity which appears to be the explanation for the decreased susceptibility of L-E rats to TCDD. Serum TT4 levels were significantly decreased at all doses, whereas the serum concentration of TT3 appeared unaffected. The results of this study suggest that subtle differences in the regulation of intermediary metabolism between these two strains of rats are responsible for strain differences in the susceptibility to TCDD.
Keywords: 2,3,7,8-Tetrachlorodibenzo-p-dioxin Acute toxicity; Dose-response; Gluconeogenesis Feed intake; Phosphoenolpyruvate carboxykinase Serum tryptophan; Tryptophan 2,3-dioxygenase
Peri- and postnatal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin: effects on physiological development, reflexes, locomotor activity and learning behaviour in Wistar rats by Renate Thiel; Elisabeth Koch; Beate Ulbrich; Ibrahim Chahoud (pp. 79-86).
Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the development of rat offspring were studied after administration of a loading dose of 300 or 1000 ng TCDD/kg body wt on day 19 of pregnancy, followed by weekly maintenance doses of 120 or 400 ng TCDD/kg body wt. The dose regimens led to a fluctuation of average TCDD concentrations in the liver of the offspring of 4.9–14.9 ng/g (TCDD1000/400 group) or 1.4–6.3 ng/g (TCDD300/120 group) during the course of the experiment. In both TCDD-exposed groups the body weight of the offspring was significantly lower on postnatal day 7 (PND 7); in the high dose group from PND 7 to PND 31. Some landmarks of postnatal development were retarded in the exposed groups; in particular, the vaginal opening was delayed for several days in both TCDD-exposed groups. The TCDD-exposed animals revealed a reduced ability to remain on a rotating rod. During reflex testing, the rate of successfully responding animals was higher in the exposed groups. No statistically significant differences in the locomotor activity between controls and TCDD-exposed off-spring were detectable under our experimental conditions. In a discrimination learning test no effects on the learning ability were found. However, TCDD-exposed offspring showed an increase in unanswered trials during critical phases of the task. They also exhibited increased locomotor activity in a novel environment; prior to an amphetamine challenge dose of 1 mg/kg body weight. Amphetamine-induced activity was decreased in a dose-dependent manner.
Keywords: 2,3,7,8-Tetrachlorodibenzo-p-dioxin Postnatal development; Behaviour
The hr locus and the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in newborn mice by Michael J. Connor; S. Madli Puhvel; Midori Sakamoto; Jeevan Nanthur (pp. 87-90).
In mice, the recessive mutation hairless (hr) controls the cutaneous response to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) but its influence on TCDD's systemic toxicity is unclear. To clarify this, we compared the effects of lactational TCDD exposure on standardized litters of newborn HRS/J mice homozygous for either hr or +that were fostered by haired dams exposed to 0, 6, 8 or 12 μg TCDD/kg body weight on postnatal day 0. At 12 μg/kg, TCDD was lethal to both haired and hairless pups. At the lower doses (6 and 8 μg/kg) the survival of hr/hr pups was significantly lower than +/+ pups. Affected pups succumbed following a 1 to 2-day period of cachexia and wasting. As has been reported for other mouse strains, TCDD exposure impacted on their neonatal development and lessened the time to eye opening for both haired and hairless pups. However, the hairless animals were affected at lower doses than were the haired. The results of this study document that the hr/hr genotype does influence the systemic toxicity of TCDD in mice.
Keywords: Neonatal mice; Hairless mice; Toxicity hr locus; 2,3,7,8-Tetrachlorodibenzo-p-dioxin; TCDD Lactational exposure
Immunohistochemical localisation of six glutathione S-transferases within the nasal cavity of the rat by Kulwinder K. Banger; John R. Foster; Edward A. Lock; Celia J. Reed (pp. 91-98).
Many xenobiotics induce lesions within the nasal cavity of experimental animals which are site specific. This site selectivity may be due to regional deposition within the nasal cavity and/or the localisation of biotransformation enzymes. We have developed methodology which allows immunohistochemical localisation of xenobiotic biotransformation enzymes in transverse sections of the rat nasal cavity identical to those normally taken for pathological examination. We report the application of this methodology to six isoenzymes of the glutathione S-transferases (GSTs). All six isoenzymes were predominantly located within olfactory epithelium covering the ethmoturbinates (levels III and IV) and extending forwards into the dorsal meatus (level II). Squamous and transitional epithelia showed little or no staining while respiratory epithelium was weakly stained. Within the respiratory epithelium only the ciliated columnar cells and, to a lesser extent, some of the seromucous glands contained GSTs. Within olfactory epithelium the sustentacular cells, basal cells and subepithelial glands all stained positive for GSTs. The different cell types of olfactory epithelium preferentially express different GST isoenzymes: 1-1 and 2-2 were predominantly located in the subepithelial glands; 3-3, 4-4 and 8-8 in sustentacular and basal cells; 7-7 in basal cells.
Keywords: Nasal cavity; Immunohistochemistry Glutathione S-transferases
Studies on the comparative toxicity of S-(1,2-dichlorovinyl)-L-cysteine, S-(1,2-dichlorovinyl)-L-homocysteine and 1,1,2-trichloro-3,3,3-trifluoro-1-propene in the Fischer 344 rat by Maria L. Anthony; Christopher R. Beddell; John C. Lindon; Jeremy K. Nicholson (pp. 99-110).
The renal tubular toxicity of various halogenated xenobiotics has been attributed to their enzymatic bioactivation to reactive intermediates by S-conjugation. A combination of high resolution proton nuclear magnetic resonance (1H NMR) spectroscopy of urine, renal histopathology and more routinely used clinical chemistry methods has been used to explore the acute toxic and biochemical effects of S-(1,2-dichlorovinyl)-L-cysteine (DCVC), S-(1,2-dichlorovinyl)-L-homocysteine (DCVHC) and 1,1,2-trichloro-3,3,3-trifluoro-1-propene (TCTFP) up to 48 h following their administration to male Fischer 344 (F344) rats. In the absence of gross renal pathology, 1H NMR urinalysis revealed increased excretion of the tricarboxylic acid cycle intermediates citrate and succinate following DCVC administration. In contrast, both DCVHC and TCTFP produced functional defects in the S2 and S3 segments of the proximal tubule that were confirmed histologically. In these cases, 1H NMR urinalysis revealed increased excretion of glucose, L-lactate, acetate and 3-D-hydroxybutyrate (HB) as well as selective amino aciduria (alanine, valine, glutamate and glutamine). The significance of the proximal nephropathies induced by DCVHC and TCTFP is discussed in relation to biochemical observations on other xenobiotics that are toxic by similar mechanisms.
Keywords: 3-D-hydroxybutyrate; Glucose; L-lactate 1H NMR urinalysis; S-Conjugate-mediated nephrotoxicity; S-1,2-Dichlorovinyl)-L-cysteine; S-(1,2-Dichlorovinyl)-L-homocysteine; 1,1,2-Trichloro-3,3,3-trifluoro-1-propene
Studies on the muscle toxicant 2,3,5,6,-tetramethyl p-phenylenediamine: effects on various biomarkers including urinary creative and taurine by Ruth P. Draper; Catherine J. Waterfield; Malcolm J. York; John A. Timbrell (pp. 111-117).
The effect of the specific muscle toxicant, 2,3,5,6-tetramethyl p-phenylenediamine (TMPD), on urinary creatine and taurine, markers of testicular and liver dysfunction, respectively, has been investigated in male Sprague-Dawley rats. Damage to the gastrocnemius and soleus muscles was accompanied by a rise in serum creatine kinase (predominantly the muscle-specific isoenzyme, CKMM), alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Increases in serum α-hydroxybutyrate dehydrogenase (HBDH) and total lactate dehydrogenase (LDH) (mainly isoenzymes, LDH1 and LDH2), occurred but only minor damage to the heart and no rise in CK-MB, (heart muscle isoenzyme) was seen. Damage to stage XIV tubules in the testis was evident histologically after the highest dose. This was accompanied by an increase in LDH-C4 testis-specific isoenzyme and a decrease in serum testosterone. Apart from reduced serum albumin, no other serum parameters indicated liver damage and there was only slight liver steatosis in some animals at the highest dose. Urinary taurine was not significantly raised after any dose of TMPD, but there was a significant increase in urinary creatine after the highest does. It can be concluded that in the presence of discrete muscle damage, the use of urinary taurine and urinary creatine as markers of liver and testicular dysfunction, respectively, is not confounded. However, a variety of different markers should be used in conjunction to fully delineate the tissue damage due to toxic chemicals.
Keywords: Muscle; 2,3,5,6-Tetramethyl p-phenylenediamine; Urinary marker; Creatine; Taurine; Testis; Liver
Non-reactivating effects of HI-6 on hippocampal neurotransmission by Bert P. C. Melchers; Anton L. van der Laaken; Ruud W. Busker; Pieter L. B. Bruijnzeel; Herman P. M. Van Helden (pp. 118-126).
Effects of the oxime HI-6, unrelated to reactivation of acetylcholinesterase (AChE), on field potentials in the dentate gyrus of the rat hippocampus following AChE inhibition, were investigated both in vitro and in vivo. In hippocampal slices, AChE inhibition decreased the perforant path evoked population spike amplitude (PSA). This effect could be prevented by pre-incubation of the slices with atropine (0.1–1 μM) or with the M1 muscarinic receptor antagonist pirenzepine (1 μM). A similar preventive effect was found after pre-incubation with the GABAA antagonist picrotoxin (20 μM), suggesting that the effects of AChE inhibition in vitro may be due to an enhancement of GABAergic inhibitory activity via activation of M1-muscarinic receptors. The effects of AChE inhibition in vivo were variable; both increases and decreases of the PSA were found. Following AChE inhibition, HI-6 increased the PSA dose-dependently, both in the in vivo and in the in vitro hippocampus. At higher oxime doses the perforant path stimulation elicited multiple population spikes. The effects of the oxime were presumably not mediated by an antagonism of cholinergic receptors, since they could not be mimicked with cholinergic antagonists like atropine, mecamylamine or gallamine. Further testing of the nature of the HI-6 effect in hippocampal slices in vitro, using a paired antidromic-orthodromic stimulation protocol, showed that HI-6 may interfere with GABAergic inhibition.
Keywords: HI-6; Crotylsarin; S27; Non-reactivating effects; Hippocampal field potentials
A laser Raman spectroscopic study on the interaction of alkylmercury with thiol and sulfur-containing compounds by Ryoji Yamamoto; Kimiaki Sumino; Katsuhiko Nakamae (pp. 127-131).
The interaction of the methylmercury cation with sulfur compounds in aqueous solution at physiological pH was studied by laser Raman spectroscopy. Metal binding is shown to occur preferentially at the sulfhydryl group of sulfur compounds. Raman frequencies of S−Hg stretching of the one-to-one methylmercury-sulfhydryl or sulfur-containing complexes were observed at approximately 330 cm−1. There was no frequency shift when ligands were exchanged. However, the relative intensity (I S−Hg/I C−Hg) was different. The relative intensities of MeHg-thioglycerol, MeHg-cysteine and MeHg-2-mercaptobenzothiazole were 0.18, 0.43 and 0.62, respectively. Methylmercury shifted from combination states of lager relative intensity to ones of smaller relative intensity. These results may cast light on the distribution and excretion mechanisms of methylmercury in the human body.
Keywords: Methylmercury; Laser Raman; Ligand exchange; Sulfur-containing compound; Relative intensity
Suppression of interleukin-1β and tumour necrosis factor-α biosynthesis by cadmium in in vitro activated human peripheral blood mononuclear cells by Stamatios E. Theocharis; Vassilios L. Souliotis; Panayiotis G. Panayiotidis (pp. 132-136).
Cadmium is a highly toxic element responsible for acute and chronic toxicity in man. There is evidence that cadmium induces pathophysiological effects by modulating components of the immune system. Cytokines are being increasingly recognized as essential mediators of normal and pathologic immune responses. Cadmium at concentrations varying from 1.0×10−4 to 3.3×10−6 M inhibited the phytohemagglutinin induced production of interleukin-1β and tumour necrosis factor-α, in in vitro activated human peripheral blood mononuclear cells. The messenger RNA levels of interleukin-1β and tumour necrosis factor-α were examined during a 24-h culture period, at different time points. The decreased messenger RNA levels at the time points of the maximum expression of interleukin-1β and tumour necrosis factor-α indicate that cadmium suppresses their production at the transcriptional level.
Keywords: Cadmium; IL-1β; TNF-α; Biosynthesis; Lymphocytes
A copper deficient diet prevents hepatic copper accumulation and dysfunction in Long-Evans Cinnamon (LEC) rats with an abnormal copper metabolism and hereditary hepatitis by Naoki Sugawara; Chieko Sugawara (pp. 137-140).
Long-Evans Cinnamon (LEC) rats that develop spontaneous hepatitis due to an inherently abnormal Cu metabolism have recently been established. This investigation concerns the effects of a Cu-deficient diet on the Cu metabolism linked to hepatic injury in LEC rats. The hepatic Cu concentration at 30 days after birth was 94±4 Cu μg/g liver in LEC rats, whereas that of Fischer rats at the same age was 7±1 Cu μg/g. From 30 days after birth, all rats were fed a semisynthetic diet with two different levels of Cu, 0.5 or 30 μg/g food, for 35 days. In LEC rats fed a Cu-deficient diet (0.5 μg/g), the hepatic Cu concentration was 39±7 μg/g. The Cu-normal diet (30 μg/g) LEC group had a concentration of 357±15 μg/g in the hepatic Cu. The group had significantly higher aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT) and γ-glutamyl transferase (GGT) levels than did the LEC rats given the Cu-deficient diet. These results suggest that the occurrence of acute hepatitis in LEC rats can be prevented by feeding the animals a Cu-deficient diet.
Keywords: LEC rats; Copper deficient diet; Copper toxicosis; Hepatitis