Forgot your password?
New user?
New Window Opens on the Secret Life of Microbes: Scientists Develop First Microbial Profiles of Ecosystems
CAS announces the release of SciFinder Scholar for Mac OS X
Press Releases
Press Releases
| Check out our New Publishers' Select for Free Articles |
Archives of Toxicology (v.79, #2)
Elevated internal exposure of children in simulated acute inhalation of volatile organic compounds: effects of concentration and duration by Klaus Abraham; Hans Mielke; Wilhelm Huisinga; Ursula Gundert-Remy (pp. 63-73).
When deriving health-based exposure limits in recent years, increasing attention has been drawn to susceptible subpopulations, in particular to children. We investigated the differences in kinetics between children and adults during inhalation of styrene as a typical category-3 volatile organic compound (VOC), i.e., a gas with a low reactivity and low water solubility allowing a high rate of alveolar absorption. Internal exposure was simulated using a physiologically based kinetic model over a broad range of airborne concentrations (1–1000 ppm) and for an exposure time of up to 8 h according to the scenario in the acute exposure guideline level (AEGL) program. Age-specific anatomical and physiological parameters and compound-specific data was derived from the literature. The calculated concentrations in arterial blood are higher in children than in adults, and are highest in the newborn. For an 8-h exposure to low concentrations, the calculated arterial concentration in the newborn is higher by a factor of 2.3 than in the adult. This is due mainly to the relatively high ventilation rate and the immature metabolism. With increasing airborne concentration, the ratio of arterial concentrations (newborn/adult) increases to a maximum of 3.8 at 130 ppm in ambient air, and declines with further increments of concentration to a value of 1.7. This is because the metabolism of the newborn becomes non-linear at lower concentrations than in adults. At high concentrations, metabolism is saturated in both age groups. For shorter exposures, the dose dependency of the concentration ratios (newborn/adult) is less pronounced. This is the first article to show that the intraspecies assessment factor may vary with concentration and duration of exposure.
Keywords: Children; Inhalation; Kinetics; Model; Risk assessment; Styrene
Effects of dioxane on cytochrome P450 enzymes in liver, kidney, lung and nasal mucosa of rat by A. Nannelli; A. De Rubertis; V. Longo; P. G. Gervasi (pp. 74-82).
The effect of acute and chronic dioxane administration on hepatic, renal, pulmonary and nasal mucosa P450 enzymes and liver toxicity were investigated in male rats. The acute treatment consisted of two doses (2 g/kg) of dioxane given for 2 days by gavage, whereas the chronic treatment consisted of 1.5% of dioxane in drinking water for 10 days. Both the acute and chronic dioxane treatments induced cytochrome P450 2B1/2- and P450 2E1-dependent microsomal monooxygenase activities (pentoxyresorufin O-depentylase and p-nitrophenol hydroxylase) in the liver, whereas in the kidney and nasal mucosa, only the 2E1 marker activities were enhanced. In addition in the liver, an induction of 2α-testosterone hydroxylase (associated with the constitutive and hormone-dependent P450 2C11) was also revealed, whereas the hepatic P450 4A-dependent ω-lauric acid hydroxylase was not enhanced by any dioxane treatment. These inductions were mostly confirmed by western blot analysis of liver, kidney and nasal mucosa microsomes. In the lung, no alteration of P450 activities was observed. To assess the mechanism of 2E1 induction, the hepatic, renal and nasal mucosa 2E1 mRNA levels were also examined. Following two kinds of dioxane administration, in the liver the 2E1 induction was not accompanied by a significant alteration of 2E1 mRNA levels, while both in the kidney and nasal mucosa the 2E1 mRNA increased about 2- to 3-fold, indicating an organ-specific regulation of this P450 isoform. Furthermore, dioxane was unable to alter the plasma alanine aminotransferase activity and hepatic glutathione (GSH) content, examined as an index of toxicity, when it was administered into rats with P450 2B1/2 and 2E1 preinduced by phenobarbital or fasting pretreatment. These results support the lack of or a poor formation of reactive and toxic intermediates during the biotrasformation of this solvent, even when its metabolism was enhanced by P450 inducers. The chronic administration of dioxane was also unable to induce the palmitoyl CoA oxidase, a marker of peroxisome proliferation, excluding this as a way to explain its toxicity. Thus, although the mechanism of dioxane carcinogenicity remains unclear, the present results suggest that the induction of 2E1 following a prolonged administration of dioxane might provide oxygen radical species, and thereby contribute to its organ-specific toxicity.
Keywords: Dioxane; Cytochrome P450 induction; Kidney; Nasal mucosa
Production of nitric oxide elevates nitrosothiol formation resulting in decreased glutathione in macrophages exposed to asbestos or asbestos substitutes by Tamako Nishiike; Yasumitsu Nishimura; Yasuhiko Wada; Hiroshi Iguchi (pp. 83-89).
The purpose of this study was to investigate the effects of pneumoconiogenic particles, such as asbestos, on nitrosothiol formation in macrophages. In addition, the effects of man-made mineral fibers (MMMFs) were also evaluated, because they have come into heavy use as substitutes for asbestos. RAW264.7 cells and J774 cells of murine macrophage cell lines were cultured with chrysotile B (CH) asbestos, crocidolite (CR) asbestos, or MMMFs comprised of glass wool (GW), rock wool (RW), or ceramic (RF1). All of these fibers significantly increased nitric oxide (NO) production in the culture with macrophages. Chrysotile B, CR, and GW significantly decreased the level of reduced glutathione (GSH) in RAW264.7 cells. S-nitrosothiol (RS-NO) formation was increased by both types of cells on exposure to every fiber. A large portion of this increased RS-NO may be in the form of S-nitrosoglutathione (GS-NO), because GSH is the most abundant thiol substance in the cell. Both CH and GW significantly increased superoxide anion in the media cultured of RAW264.7 cells. These results indicate that macrophages exposed to asbestos or MMMFs are subject to oxidative stress, not only through the generation of reactive oxygen and nitrogen species, but also through decreases in the level of the cellular antioxidant, GSH, by GS-NO formation. The increase of RS-NO in macrophages exposed to asbestos or MMMFs may deserve more attention as the indicator of continuous oxidative stress by NO on cells and tissues, which causes inflammation and involves the development of asbestos-induced diseases.
Keywords: S-nitrosothiol; Glutathione; Nitric oxide; Asbestos; Man-made mineral fibers
Changes in expression of bcl-2 and bax in Syrian hamster embryo (SHE) cells exposed to ZnCl2 by M. A. Maire; C. Rast; C. Pagnout; P. Vasseur (pp. 90-101).
Zinc is involved in many physiological processes and plays a critical role in functional and structural cells. Zinc at concentrations ranging from 100 to 150 μmol L−1 has been shown to induce morphological transformation of Syrian hamster embryo (SHE) cells. At these concentrations, zinc inhibited apoptosis in SHE cells. The objective of this study was to elucidate the mechanisms of action of zinc on the apoptotic pathway. Effects of 100 and 150 μmol L−1 ZnCl2 on the expression of two members of the Bcl-2 family of proteins and on the transcription factor c-Myc in SHE cells was investigated using RT-PCR. No effect on the proto-oncogene c-myc was observed. Up-regulation of bcl-2 expression was found and bax expression was reduced. These changes have been corroborated by immunoblotting. Effects of Zn2+ on bcl-2/bax ratio were confirmed in apoptotic camptothecin-treated SHE cells. Cloned and sequenced cDNAs obtained from RT-PCR amplifications allowed us to check the RT-PCR products encoded the expected proteins. This study demonstrated that zinc acts in the early phases of the apoptotic process by modification of the bcl-2/bax ratio in normal and apoptotic SHE cells.
Keywords: Apoptosis; Zinc; SHE cell transformation assay; RT-PCR; Western blot; Proteins sequences homology; Camptothecin
Protective effect of baicalin on tert-butyl hydroperoxide-induced rat hepatotoxicity by Jin-Ming Hwang; Chau-Jong Wang; Fen-Pi Chou; Tsui-Hwa Tseng; Yih-Shou Hsieh; Jeng-Dong Hsu; Chia-Yih Chu (pp. 102-109).
Baicalin (BA) is a flavonoid compound purified from Scutellaria baicalensis Georgi that is used as a traditional Chinese herbal medicine. Baicalin was studied for the mechanism of its inhibitory effects on the tert-butyl hydroperoxide (t-BHP)-induced cytotoxicity and lipid peroxidation in rat liver system. Baicalin expressed an antioxidant property by its capacity for quenching the free radicals of 1,1-diphenyl-2-picrylhydrazyl (DPPH). Further investigations using the t-BHP-induced cytotoxicity in rat primary hepatocytes demonstrated that baicalin, at the concentrations of 2–220 μM, significantly decreased the leakages of lactate dehydrogenase (LDH) and alanine aminotransferase (ALT), and the formation of malondialdehyde (MDA) induced by 30 min treatment of t-BHP(1.5 mM). Baicalin also attenuated the t-BHP-induced depletion of glutathione (GSH) and high level of DNA repaired synthesis. An in vivo study in rats showed that pretreatment with baicalin (i.p.) at concentrations of 0.5 and 5 mg/kg for 5 days before a single i.p. dose of t-BHP (0.1 mmol/kg) significantly lowered the serum levels of hepatic enzyme markers (ALT and AST) and reduced oxidative stress in the liver. Histopathological evaluation of the rat livers revealed that baicalin reduced the incidence of liver lesions induced by t-BHP including hepatocyte swelling, leukocyte infiltration, and necrosis. Based on the results described above, we speculate that baicalin may play a chemopreventive role via reducing oxidative stress in living systems.
Keywords: Baicalin; tert-Butylhydroperoxide; Cytotoxicity; Genotoxicity; Hepatocyte
Mutagenicity of the mycotoxin patulin in cultured Chinese hamster V79 cells, and its modulation by intracellular glutathione by David M. Schumacher; Manfred Metzler; Leane Lehmann (pp. 110-121).
Because the ability of the mycotoxin patulin (PAT) to cause gene mutations in mammalian cells is still ambiguous, we have studied the mutagenicity of PAT at the hypoxanthine–guanine phosphoribosyltransferase (HPRT) gene locus in cultured Chinese hamster V79 cells with normal, depleted, and elevated glutathione (GSH) levels. PAT was more toxic to GSH-depleted cells than to normal cells and caused an increase of the intracellular GSH level in normal and GSH-depleted cells. It also caused synchronization of the cell cycle due to a temporary accumulation of cells in the G2/M phase; this G2/M arrest was more persistent in GSH-depleted than in normal cells. PAT gave rise to a clear and concentration-dependent induction of HPRT mutations at non-cytotoxic concentrations in V79 cells with normal GSH level; the lowest PAT concentration causing a significant number of mutant cells was 0.3 micromolar, and the mutagenic potency of PAT equaled that of the established mutagen 4-nitroquinoline-N-oxide. The mutagenicity of PAT was again more pronounced, by a factor of about three, in GSH-depleted V79 cells. Elevated GSH levels abolished all observed effects of PAT. These data support the notion that PAT is a mutagenic mycotoxin, in particular in cells with low GSH concentration. The ability of PAT to cause gene mutations in mammalian cells might have a bearing on its carcinogenicity.
Keywords: Patulin; Mutations; V79 cells; Glutathione; HPRT gene