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Archives of Toxicology (v.77, #8)
Human inhalation exposure to ethylene glycol by Jörn Carstens; György A. Csanády; Thomas H. Faller; Johannes G. Filser (pp. 425-432).
Two male volunteers (A and B) inhaled 1.43 and 1.34 mmol, respectively, of vaporous 13C-labeled ethylene glycol (13C2-EG) over 4 h. In plasma, 13C2-EG and its metabolite 13C2-glycolic acid (13C2-GA) were determined together with the natural burden from background GA using a gas chromatograph equipped with a mass selective detector. Maximum plasma concentrations of 13C2-EG were 11.0 and 15.8 µmol/l, and of 13C2-GA were 0.9 and 1.8 µmol/l, for volunteers A and B, respectively. Corresponding plasma half-lives were 2.1 and 2.6 h for 13C2-EG, and 2.9 and 2.6 h for 13C2-GA. Background GA concentrations were 25.8 and 28.3 µmol/l plasma. Unlabeled background EG, GA and oxalic acid (OA) were detected in urine in which the corresponding 13C-labeled compounds were also quantified. Within 28 h after the start of the exposures, 6.4% and 9.3% 13C2-EG, 0.70% and 0.92% 13C2-GA, as well as 0.08% and 0.28% 13C2-OA of the inhaled amounts of 13C2-EG, were excreted in urine by volunteers A and B, respectively. The amounts of 13C2-GA represented 3.7% and 14.2% of background urinary GA excreted over 24 h (274 and 88 µmol). The amounts of 13C2-OA were 0.5% and 2.1% of background urinary OA excreted over 24 h (215 and 177 µmol). From the findings obtained in plasma and urine and from a toxicokinetic analysis of these data, it is highly unlikely that workplace EG exposure according to the German exposure limit (MAK-value 10 ppm EG, 8 h) could lead to adverse effects from the metabolically formed GA and OA.
Keywords: Ethylene glycol; Glycolic acid; Oxalic acid; Human; Risk; Metabolism; Toxicokinetics
XRCC1, CYP2E1 and ALDH2 genetic polymorphisms and sister chromatid exchange frequency alterations amongst vinyl chloride monomer-exposed polyvinyl chloride workers by Ruey-Hong Wong; Jung-Der Wang; Ling-Ling Hsieh; Tsun-Jen Cheng (pp. 433-440).
Vinyl chloride monomer (VCM) is a known human carcinogen, which may be metabolized by cytochrome P450 2E1 (CYP2E1), aldehyde dehydrogenase 2 (ALDH2), and glutathione S-transferase T1 (GSTT1). A DNA-repair gene, X-ray repair cross-complementing group 1 (XRCC1, exon 10), may also be implicated in the process of VCM-related carcinogenesis. Thus, VCM-exposed workers with inherited susceptible metabolic and DNA-repair genotypes may experience an increased risk of genotoxiciy. This study was designed to investigate whether metabolic and DNA-repair genotypes affected sister chromatid exchange (SCE) frequency in occupationally VCM-exposed workers from polyvinyl chloride (PVC) manufacturing plants. Study subjects comprised 61 male workers having experienced VCM exposure, and 29 male controls. Questionnaires were administered to obtain detailed histories of cigarette-smoking habits, alcohol consumption behavior, and occupation. The frequency of SCE in peripheral lymphocytes was determined using a standardized method, and genotypes of CYP2E1, ALDH2, GSTT1 and XRCC1 were identified by the polymerase chain reaction (PCR) procedure. Our results demonstrated that smoking, age and VCM exposure and XRCC1 (P=0.03), CYP2E1 (P=0.04), and ALDH2 (P=0.08) were significantly associated with an increased SCE frequency. Further analysis of gene combinations, including CYP2E1, ALDH2 and XRCC1, revealed an increased trend for these genotypes to influence SCE frequencies for the low VCM-exposure group (P<0.01), but not so for the high VCM-exposure group (P=0.29) or for controls (P=0.49). These results suggest that workers with susceptible metabolic and DNA-repair genotypes, may experience an increased risk of DNA damage elicited by VCM exposure.
Keywords: Vinyl chloride monomer; CYP2E1 ; ALDH2 ; XRCC1 ; Sister chromatid exchange
Effects of Amanita phalloides toxins on insulin release: in vivo and in vitro studies by Eugenio De Carlo; Anna Milanesi; Chiara Martini; Pietro Maffei; Gianluca Tamagno; Pier Paolo Parnigotto; Cesare Scandellari; Nicola Sicolo (pp. 441-445).
The clinical picture of Amanita phalloides poisoning includes hypoglycaemia, usually related to hepatic damage. In fact, Amanita toxins induce hepatic glycogen depletion in humans and animals. However, in animals morphological changes of pancreatic β cells are reported, suggesting that an alteration of insulin secretion might be involved in the pathogenesis of hypoglycaemia. Therefore, we determined fasting glucose, insulin and C-peptide levels in ten patients intoxicated by Amanita phalloides and in ten control subjects. Fasting blood samples were drawn on 3 consecutive days, beginning 48–72 h after mushroom ingestion, and glucose, insulin and C-peptide concentrations were determined by routine methods. Serum glucose concentrations did not differ between poisoned subjects and controls, whereas insulin and C-peptide concentrations were significantly higher in poisoned subjects (P<0.01), with a significant positive correlation (R=0.97, P<0.001). We also evaluated the effects of α-amanitin, the main amatoxin, on in vitro insulin release. Rat islets were incubated with 5 and 50 mg/l α-amanitin, in the presence or absence of 5.6 mM glucose. In another protocol, islets were preincubated for 2 h with 5 and 50 mg/l α-amanitin in medium containing 5.6 mM glucose. After lavage, islets were incubated with increasing glucose (2.8–22.0 mM) to evaluate insulin release. In vitro, both concentrations of toxin induced insulin release (5 mg/l P<0.02, 50 mg/l P<0.01 vs controls), in the presence of 5.6 mM glucose. Islets preincubated with 5 mg/l α-amanitin showed a pattern of glucose-stimulated insulin release similar to controls, whereas islets preincubated with 50 mg/l α-amanitin showed an increased basal release with a reduced response to glucose stimulation. These observations show that Amanita toxins might play a role in the clinical context of Amanita poisoning. We demonstrate, for the first time, that α-amanitin induces insulin release and may exert a cytotoxic effect on β cells.
Keywords: Amanitin; Mushroom intoxication; Insulin; C-peptide; Islets
Short period exposure to di-(2-ethylhexyl) phthalate regulates testosterone metabolism in testis of prepubertal rats by Hyung-Sub Kim; Konomu Saito; Mayumi Ishizuka; Akio Kazusaka; Shoichi Fujita (pp. 446-451).
Exposure of pubertal rats to di-(2-ethylhexyl) phthalate (DEHP) for 14 days was reported to result in reduced testosterone (T) biosynthesis by altering androstenedione 17β-hydroxysteroid dehydrogenase (17β-HSD) activity. However, our study indicated that shorter period exposure of DEHP (100 or 1000 mg/kg for 5 days) to 4-week-old male rats did not affect the activity of 17β-HSD, the rate-limiting enzyme of T biosynthesis in the testis. Testosterone 5α-reductase (T5α-R) activity in the testis was significantly enhanced, while aromatase mRNA was significantly reduced by increasing doses of DEHP. The expressions of cytochrome P450 (CYP) isoforms, CYP2C11 and CYP3A, in the testis increased along with their enzymatic activities, T16α- and T6β-hydroxylation, respectively. Thus, the current study clearly indicates that the short period exposure to DEHP alters T metabolism through altering activities of T5α-R, aromatase and CYP2C11/3A2 in the testis of prepubertal rats, and that they are more sensitive marker enzymes to the DEHP exposure than those of biosynthetic enzymes of T from androstenedione.
Keywords: Di-(2-ethylhexyl) phthalate (DEHP); Testis; Testosterone 5α-reductase; Aromatase; Cytochrome P450
Sensorimotor deficits and increased brain nicotinic acetylcholine receptors following exposure to chlorpyrifos and/or nicotine in rats by Mohamed B. Abou-Donia; Ali Abdel-Rahman; Larry B. Goldstein; Anjelika M. Dechkovskaia; Deepti U. Shah; Sarah L. Bullman; Wasiuddin A. Khan (pp. 452-458).
Despite well-known adverse effects associated with cigarette smoking, approximately 20% of the US population continues to smoke and many more are exposed to environmental tobacco smoke. Many of the same individuals are also exposed to environmental neurotoxic chemicals such as the organophosphorus insecticide chlorpyrifos. In the present study, the effects of exposure to low doses of nicotine and chlorpyrifos alone and in combination, were studied on the central cholinergic system and sensorimotor performance in rats. Male Sprague-Dawley rats (250–300 g) were treated with nicotine (1 mg/kg s.c., in normal saline), chlorpyrifos (0.1 mg/kg dermally, in 0.1 ml 70% ethanol), or a combination of both, daily for 30 days. Control rats were treated with saline and dermally with ethanol. Sensorimotor behavior was evaluated 24 h following the last dose using a battery of tests. There was a significant deficit in incline plane performance, beam-walk score and beam-walk time following exposure to each chemical, alone or in combination. The deficit in incline plane performance was greater when the two chemicals were given in combination than with either compound alone. Biochemical analysis showed a decrease in cerebellar and an increase in midbrain acetylcholinesterase (AChE) activity following combined exposure. Exposure to nicotine alone resulted in a significant increase in AChE activity in brainstem and midbrain, whereas there was no significant change after exposure to chlorpyrifos, alone. A significant increase in ligand binding to nicotinic acetylcholine receptors (nAChR) was observed in brainstem and cortex following exposure to nicotine or chlorpyrifos. This was further augmented with combined exposure, which caused a modest but significant increase in m2 muscarinic acetylcholine receptors (m2-mAChR) ligand binding in the cortex. These data suggest that exposure to either nicotine or chlorpyrifos or a combination of the two may impair neurobehavioral performance and affect the central nervous system cholinergic pathways.
Keywords: Organophosphorus Insecticides; Chlorpyrifos; Nicotine; Central nervous system; Acetylcholinesterase; Muscarinic acetylcholine receptor; Nicotinic acetylcholine receptor; Neurotoxicity; Combined exposure; Sensorimotor; Smoking
Effect of cytochrome P-450 inhibition on tetrahydrofuran-induced hepatocellular proliferation in female mice by B. van Ravenzwaay; A. O. Gamer; E. Leibold; W. Kaufmann (pp. 459-464).
The studies presented were designed to investigate the effects of cytochrome P450 inhibition on tetrahydrofuran-induced hepatocellular proliferation in female B6C3F1 mice. Groups of female B6C3F1 mice were exposed to dynamic atmospheres containing tetrahydrofuran (THF) concentrations of 0, 5,400 or 15,000 mg/m3 for 6 h per day, for 5 consecutive days. One-half of the animals in each THF exposure group were pretreated with the cytochrome P450 inhibitor 1-aminobenzotriazole (ABT) at 100 mg/kg (i.p.) 1 h before the start of each THF exposure period. Treatment with THF at 15,000 mg/m3 caused marked microsomal enzyme induction in the liver. The cytochrome P450 content was nearly doubled (+98%), pentoxyresorufin-O-depentylase (PROD) and ethoxyresorufin-O-deethylase (EROD) activities were increased by 600% and 160%, respectively. ABT pretreatment effectively blocked microsomal enzyme induction at 15,000 mg/m3. THF exposure had no effect on the subcellular morphology of hepatocytes, whereas ABT-pretreatment caused centrilobular fatty change. THF at 15,000 mg/m3 caused increased cell proliferation in zone 3 (central vein region) of the liver (according to Rappaport), as indicated by a significantly higher PCNA (Proliferating Cell Nuclear Antigen) labelling index, but there were no effects at 5,400 ppm. ABT pretreatment prior to THF exposure at 15,000 mg/m3 caused an exacerbated proliferative response of mouse liver, significantly higher PCNA labelling indices being observed in zones 2 (midzonal region) and 3. The exacerbated proliferative response of mouse liver under conditions of inhibited THF metabolism suggests that the mitogenic effects are related to prevailing THF tissue concentrations and not to the generation of THF oxidative metabolite(s).
Keywords: Tetrahydrofuran; Mouse liver; Tumour; Cell proliferation; Cytochrome P450
2-Butoxyethanol enhances the adherence of red blood cells by Alexander Koshkaryev; Gregory Barshtein; Abraham Nyska; Nathan Ezov; Tal Levin-Harrus; Shay Shabat; Meir Nyska; Meir Redlich; Felix Tsipis; Saul Yedgar (pp. 465-469).
We recently presented a unique, chemically-induced rat model of hemolytic anemia and disseminated thrombosis. In this 2-butoxyethanol (BE)-induced model the organs developing infarction are comparable to those seen in human diseases, characterized by hemolysis and thrombosis (e.g., thalassemia, sickle-cell disease, paroxysmal nocturnal hemoglobinuria, disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, and hemolytic uremic syndrome). Red blood cells (RBCs) have special flow properties, namely, self-aggregability, deformability, and potential adherence to endothelial cells (ECs) of the blood vessel wall, which are essential for adequate blood flow and tissue perfusion; their alteration facilitates circulatory disorders. To examine the possible contribution of alterations in RBC flow properties to the observed thrombosis in the present investigation we determined the BE-induced changes in adherence, aggregability, and deformability of RBCs from male and female Fischer F344 rats exposed to two, three, or four daily doses of BE at 250 mg BE/kg body weight. Control animals were treated with the vehicle alone. Blood was taken on days 2, 3, 4, and 29. The administration of BE did not affect the RBCs aggregability but markedly enhanced their adherence to extracellular matrix; such enhancement was correlated with adherence to cultured ECs. RBC/EC interaction has been shown to be a potent catalyst of vascular occlusion in hemolytic hemoglobinopathies; thus the enhanced RBC adherence to EC is a likely mechanism by which thrombosis and organ infarct are induced in BE-treated rats.
Keywords: Rat; 2-Butoxyethanol; Hemolysis; Thrombosis; Red blood cell
Changes in low molecular weight DNA fragmentation in white blood cells after diisocyanate exposure of workers by B. Marczynski; R. Merget; B. Teschner; M. Korn; S. Rabstein; T. Brüning (pp. 470-476).
The pathogenesis of diisocyanate-induced asthma is still largely unknown. Recently, it has been shown that thiol-redox homeostasis of human airway epithelial cells may be altered after in vitro exposure to diisocyanates. In the present study, low molecular weight (LMW) DNA fragmentation patterns in white blood cells (WBCs) were assessed on 16 industrial workers with work-related asthma, before and after chamber challenges with one of three commonly used diisocyanates in concentrations up to 30 ppb. LMW-DNA fragmentation changes were evaluated after 15 h incubation of WBCs embedded in agarose plugs in lysis buffer with or without hydrogen peroxide (H2O2). Increased LMW-DNA fragmentation occurred in WBCs taken at 30 min or 19 h after the end of the chamber challenge in both subjects with positive and in 8 of 14 subjects with negative challenges. In contrast, no change in LMW-DNA fragmentation was seen in WBCs taken at the same time intervals from 11 non-exposed controls. There was no association between changes in DNA fragmentation patterns and possible confounding factors such as age, smoking status, atopy, medication, duration of occupational exposure and period since exposure cessation. These results indicate that diisocyanate exposure can induce DNA fragmentation. Similarities in the increased amounts of WBC LMW-DNA fragments following diisocyanate exposure with the DNA fragmentation after plugs lysis in buffer with H2O2 support the hypothesis that diisocyanates change the intracellular redox steady-state. Whether this effect plays any role in isocyanate-induced asthma has to be investigated in larger epidemiological studies.
Keywords: Diisocyanates; White blood cells; DNA fragmentation; Reactive oxygen species
Effect of chrysin, a flavonoid compound, on the mutagenic activity of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and benzo(a)pyrene (B(a)P) in bacterial and human hepatoma (HepG2) cells by Maria Uhl; Sonja Ecker; Fekadu Kassie; Evelyne Lhoste; Asima Chakraborty; Georges Mohn; Siegfried Knasmüller (pp. 477-484).
The aim of the present study was to investigate the antimutagenic effects of chrysin (CR), a flavonoid compound contained in many fruits, vegetables and honey. Earlier investigations with bacterial indicators showed that CR is one of the most potent antimutagens among the flavonoids. In the present study, we tested the compound in the Salmonella strains TA98 and TA100 in combination with benzo(a)pyrene (B(a)P) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and found pronounced protective activity over a concentration range between 10 and 100 μg/ml. The compound itself was devoid of mutagenic activity at all concentrations tested. In the micronucleus (MN) assay with human-derived HepG2 cells, a different pattern of activity was seen. CR itself caused significant induction of MN at dose levels ≥15 μg/ml; in combination experiments with B(a)P and PhIP, U-shaped dose-response curves were obtained and protection was found only in a narrow dose range (5 – 10 μg/ml). Our findings indicate that the molecular mechanisms that account for the antimutagenic effects of CR in bacterial cells are different from those responsible for the effects in HepG2 cells. Earlier reports indicate that the antimutagenic effects of CR towards B(a)P and heterocyclic amines in bacterial indicators is due to inhibition of the activity of CYP1A. In contrast to this, we found a significant induction of CYP1A1 activity in HepG2 cells by CR. It can also be excluded that induction of GST, which is involved in the detoxification of polycyclic aromatic hydrocarbons accounts for the protective effects of CR against B(a)P since this enzyme was not significantly induced in the HepG2 cells. In the case of PhIP, induction of UDGPT and/or inhibition of sulfotransferase seen in human derived HepG2 cells after exposure to CR might play a role in the antimutagenic effects. In conclusion, our findings show that data from antimutagenicity studies with bacterial indicators cannot be extrapolated to HepG2 cells, and that CR causes genotoxic effects at higher dose levels in the latter cells. The implications of these observations for human chemoprevention strategies are discussed.
Keywords: Chrysin; Antimutagenicity; Benzo(a)pyrene; 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine; HepG2 cells