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Archives of Toxicology (v.68, #1)
Aluminum interaction with phosphoinositide-associated signal transduction by Alfred Haug; Biao Shi; Victor Vitorello (pp. 1-7).
Concerning molecular and cellular mechanisms of aluminum toxicity, recent studies support the hypothesis that interactions of aluminum ions with elements of signal transduction pathways are apparently primary events in cells. In the case of the phosphoinositide-associated signalling pathway of neuroblastoma cells, guanine nucleotide-binding proteins (G proteins) and a phosphatidylinositol-4,5-diphosphate (PIP2)-specific phospholipase C are probable interaction sites for inhibitory actions of aluminum ions. Following interiorization of aluminum by the cell, metal interactions decrease the accumulation of inositol phosphates, especially that of inositol-1,4,5-triphosphate (IP3), concomitant with derangements of intracellular Ca2+ homeostasis. In the presence of high concentrations of Ca2+, formation of IP3 is also diminished in aluminum-pretreated cells, presumably involving a process not requiring Mg2+-dependent G proteins. At higher aluminum doses, metal-induced changes in the lipid milieu of the membrane-bound phospholipase may play a role. These types of primary interactions of aluminum ions with elements of cellular communication channels are probably crucial in the manifestation of the multifacetted aluminum toxicity syndrome. If present as a phosphate-like fluoroaluminate, a stimulatory role of aluminum ions is displayed in G protein-coupled transmembrane signalling.
Keywords: Aluminum toxicity; Calcium regulation; G proteins; Neuroblastoma; Phosphoinositides; Phospholipase C; Signal transduction
Biomonitoring of aromatic amines IV: use of hemoglobin adducts to demonstrate the bioavailability of cleavage products from diarylide azo pigments in vivo by Iris Zwirner-Baier; Hans-Günter Neumann (pp. 8-14).
The release and availability of the carcinogenic component of the soluble azo dye Direct Red 46 and the insoluble axo pigment Pigment Yellow 17 were analyzed in Wistar rats using hemoglobin adducts as a dosimeter. The levels of hemoglobin adducts were found to be very low. Intestinal cleavage and release of 3,3'-dichlorobenzidine (3,3'-DCB) from Direct Red 46 and Pigment Yellow 17 was calculated to be 3% and 0.6% of the dose, respectively, in a 4-week feeding study. It is proposed to measure blood samples from exposed humans in order to test the applicability of the method and eventually to use it for controlling human exposure to the carcinogenic colorant components.
Keywords: Biomonitoring; Azo pigments; Hemoglobin adducts; 3,3′-Dichlorobenzidine
Metabolic alterations in hepatocytes promoted by the herbicides paraquat, dinoseb and 2,4-D by C. M. Palmeira; A. J. Moreno; V. M. C. Madeira (pp. 24-31).
The cytotoxic effects of the herbicides paraquat (1,1′-dimethyl-4,4′-bipyridylium dichloride), dinoseb (2-sec-butyl-4,6-dinitrophenol) and 2,4-D (2,4-dichlorophenoxyacetic acid) on freshly isolated rat hepatocytes were investigated. Paraquat and 2,4-D (1–10 mM) caused a dose and time dependent cell death accompanied by depletion of intracellular glutathione (GSH) and mirroring increase of oxidized glutathione (GSSG). Dinoseb, the most effective cytotoxic compound under study (used in concentrations 1000 fold lower than paraquat and 2,4-D), exhibited moderate effects upon the level of GSH and GSSG. These limited effects are at variance with significant effects upon the adenine and pyridine nucleotide contents. ATP and NADH levels are rapidly depleted by herbicide metabolism. This depletion is observed in the millimolar range for paraquat and 2,4-D and in the micromolar range for dinoseb. 2,4-D completely depletes cellular ATP, with subsequent cell death, as detected by LDH leakage. Paraquat rapidly depletes NADH, according to the redox cycling of the herbicide metabolism. The most effective compound is dinoseb since it exerts similar effects as described for paraquat and 2,4-D at concentrations 1000 fold lower. Simultaneously with NADH and ATP depletion, the levels of ADP, AMP and NAd+ increase in hepatocytes incubated in the presence of the herbicides. In contrast to NADH, the time course and extent of ATP depletion and fall in energy charge correlate reasonably with the time of onset and rate of cell death. It is concluded that the herbicides, paraquat and 2,4-D are hepatotoxic and initiate the process of cell death by decreasing cellular GSH. As a consequence of this primary disturbance, alteration of adenine and pyridine nucleotides contents is a critical event in the induction of irreversible cell injury.
Keywords: Herbicide; NADH; Glutathione; Hepatocyte
Ethoxyresorufin O-deethylase (EROD) and aryl hydrocarbon hydroxylase (AHH)-inducing potency and lethality of chlorinated naphthalenes in chicken (Gallus domesticus) and eider duck (Somateria mollissima) embryos by Magnus Engwall; Björn Brunström; Eva Jakobsson (pp. 37-42).
The 7-ethoxyresorufin O-deethylase (EROD)-and aryl hydrocarbon hydroxylase (AHH)-inducing potencies and lethalities of a technical preparation of polychlorinated naphthalenes (PCNs) (Halowax 1014, approximate congener ratio: 20% tetrachloronaphthalenes, 40% pentachloronaphthalenes, 40% hexachloronaphthalenes), a mixture of 50% 1,2,3,5,6,7-hexachloronaphthalene and 50% 1,2,3,4,6,7-hexachloronaphthalene (HxCN-mix), and 1,2,3,4,5,6,7-heptachloronaphthalene (HpCN) were studied in chicken (Gallus domesticus) and eider duck (Somateria mollissima) embryos. Mortality and hepatic EROD activity were determined on day 10 of incubation in chicken embryos exposed to various doses of the PCNs via the air-sacs of the eggs on day 7. The HxCN-mix and Halowax 1014 proved to have both embryolethal and EROD-inducing properties, while the HpCN had low EROD-inducing potency and embryolethality. ED50 values for EROD induction by the HxCN-mix and Halowax 1014 were estimated to be 0.06 mg/kg egg and 0.2 mg/kg egg, respectively. Fifty percent of the chicken embryos died (6/12) when given 3.0 mg/kg of the HxCN-mix while a similar dose of Halowax 1014 caused mortality in 4 out of 12 chicken embryos. The dose-response curve for EROD induction by Halowax 1014 exhibited a decline after the maximal level was reached. When Halowax 1014 (1.0 mg/kg egg) was coinjected with 3,3′,4,4′5-pentachlorobiphenyl (PCB IUPAC #126) (0.1 μg/kg egg) no additive effects on EROD activity were found, but when the same dose of Halowax 1014 was coinjected with a dose of PCB #126, known to cause maximal induction (1.0 μg/kg egg), the resulting EROD activity was lower than that caused solely by 1.0 μg PCB #126/kg egg. These findings indicate that Halowax 1014 has both EROD-inducing and EROD-inhibiting properties. Mortality and EROD and AHH activities were determined on day 18 (chicken) or day 24 (eider) of incubation in embryos exposed to 1.0 mg/kg egg via the yolksac on day 4 (chicken) or day 5 (eider). The HxCN-mix and Halowax 1014 induced AHH and EROD in both chicken and eider, but the induction rates were higher in the eider embryos. The HxCN-mix and Halowax 1014 caused degenerative hepatic lesions and pericardial oedema in the chicken embryos but not in the eider embryos. The most toxic PCNs tested (the HxCN-mix and Halowax 1014) were approximately of the same EROD-inducing potency as previously found for the most toxic mono-ortho-chlorinated biphenyls (Brunström 1990), and 1000 times less toxic and potent as EROD inducers compared with PCB #126 (Brunström and Andersson 1988). HpCN was considerably less toxic and exhibited a low EROD-inducing potency. The chicken embryos were more sensitive to the hepatotoxic effects produced by Halowax 1014 and the HxCN-mix than the eider duck embryos, while the eider embryos were more responsive in terms of EROD and AHH induction. The two HxCNs studied usually make up approximately 1% of the total quantity of PCNs present in Halowax 1014 [when determined with gas chromatography (flame ionization detection)]. Therefore, the relatively high toxic potency of Halowax 1014 cannot be explained by its content of the two HxCNs.
Keywords: Chick embryos; Eider embryos; Environmental pollutants; Enzyme induction; Polychlorinated naphthalenes; Toxicity
Studies of the biochemical toxicology of uranyl nitrate in the rat by Maria L. Anthony; Kevin P. R. Gartland; Christopher R. Beddell; John C. Lindon; Jeremy K. Nicholson (pp. 43-53).
High resolution 1H NMR spectroscopy of urine and plasma, conventional clinical chemical methods and histopathology have been applied to investigate the effects of uranyl nitrate (UN) on renal function and biochemistry in the Fischer 344 (F344) rat. Administration of UN (5–20 mg/kg) to male F344 rats resulted in a dose-related proximal nephropathy assessed conventionally by histopathology and urinary excretion of N-acetyl-ß-d-glucosaminidase (NAG), and related to changes in the patterns of low MW metabolites observed in 400 MHz 1H NMR spectra of urine. The changes in urinary metabolite profiles included elevations in glucose accompanied by minor elevations in certain amino acids (alanine, valine and glutamate). 1H NMR urinalysis also revealed altered excretion of low MW metabolites which are not routinely measured, such as l-lactate, acetate, citrate, succinate and 2-oxoglutarate (2-OG). In addition, the striking appearance of high concentrations of 3-d-hydroxybutyrate (HB) in the urine was noted, in the absence of acetoacetate or acetone, and it is suggested that this may provide a new marker of proximal tubular damage for certain types of nephrotoxic mechanism. Broadening of the 1H NMR signals of citrate following 10 mg/kg UN was shown to be due to a dynamic exchange process involving chelation with urinary Ca2+ and Mg2+ ions. Conventional biochemical analysis of plasma from UN-treated rats revealed dose-related increases in creatinine, urea and HB concentrations. 1H NMR-detected evidence of raised alanine aminotransferase (ALT) levels in rats administered the highest dose of UN was indicated by the partial deuteration of alanine in lyophilised plasma reconstituted in 2H2O. The degree of 1H NMR-detected abnormalities agreed well with histopathological observations and conventional biochemical indices of nephrotoxicity and more fully characterised the renal changes produced by UN. The significance of HB-uria in UN-induced proximal nephropathy is discussed in relation to biochemical observations on other proximal nephrotoxins.
Keywords: 3-d-Hydroxybutyrate; 2-D COSY; Glucose; Lactate; Nephrotoxicity; 1H NMR urinalysis; Uranyl nitrate; Urinary enzymes