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Archives of Toxicology (v.74, #4-5)
No Title by Ricarda Thier; Jürgen Lewalter; Hermann M. Bolt (pp. 184-189).
The high acute toxicity of acrylonitrile may be a result of its intrinsic biological reactivity or of its metabolite cyanide. Intravenous N-acetylcysteine has been recommended for treatment of accidental intoxications in acrylonitrile workers, but such recommendations vary internationally. Acrylonitrile is metabolized in humans and experimental animals via two competing pathways; the glutathione-dependent pathway is considered to represent an avenue of detoxication whilst the oxidative pathway leads to a genotoxic epoxide, cyanoethylene oxide, and to elimination of cyanide. Cases of acute acrylonitrile overexposure or intoxication have occurred within persons having industrial contact with acrylonitrile; the route of exposure was by inhalation and/or by skin contact. The combined observations lead to the conclusion of a much higher impact of the oxidative metabolism of acrylonitrile in humans than in rodents. This is confirmed by differences in the clinical picture of acute life-threatening intoxications in both species, as well as by differential efficacies of antidotes. A combination of N-acetylcysteine with sodium thiosulfate seems an appropriate measure for antidote therapy of acute acrylonitrile intoxications. Clinical observations also highlight the practical importance of human individual susceptibility differences. Furthermore, differential adduct monitoring, assessing protein adducts with different rates of decay, enables the development of more elaborated biological monitoring strategies for the surveillance of workers with potential acrylonitrile contact.
Keywords: Acrylonitrile Protein adducts N-Cyanoethyl-valine N-Cyanoethyl-asparaginic acid Cyanide Intoxication Antidote therapy
No Title by Naoki Sugawara; Chieko Sugawara (pp. 190-195).
Long-Evans Cinnamon (LEC) rats inherently lacking in serum ceruloplasmin (CP) activity and biliary Cu excretion were established from a closed colony of Long-Evans rats. These deficiencies, linked to a dysfunction of P-type ATPase, stimulate deposition of Cu and then of Cu metallothionein (MT) in the liver. Male LEC and Fischer rats were injected subcutaneously with Ag (AgNO3), which is an antagonist to Cu. They were operated on 24 h after the injection while under anesthesia. Total uptake of Ag into the liver was not stimulated, but its uptake into the MT fraction increased significantly in the LEC rats. Ag injection notably decreased the activity of serum CP in the Fischer rats, but not in the LEC rats. The decrease was accompanied by a reduction of serum Cu. In Fischer rat serum treated with Ag, Ag was detected mainly in the albumin region and partly in the CP fraction. In LEC rat serum, however, the Ag concentration was about 1/20 of that in the Fischer rats, and Ag was not detected in the CP fraction. Ag injection decreased the biliary excretion of Cu in the Fischer rats (0.183–0.052 µg Cu/20 min sampling), but not in the LEC rats (0.014–0.014 µg Cu/20 min sampling). On the other hand, biliary excretion of Ag was much greater in the Fischer rats (1.25 µg Ag/20 min) than in the LEC rats (0.04 µg Ag/20 min). Our results suggest that uptake of Ag into the liver is not dependent on the hepatic Cu content and status, but that biliary excretion of Ag from the liver is affected by these. Hepatic MT is not a transporter of hepatobiliary excretion of Cu and Ag. It seems likely that, unlike Cu excretion, Ag is excreted by not only the CP route but also by another route into the serum. Ag may compete with Cu in the uptake into CP (conversion of apo-CP to holo-CP).
Keywords: Copper Silver Biliary excretion Ceruloplasmin Long-Evans Cinnamon (LEC) rat P-type ATPase
No Title by Saroj K. Chakrabarti; Chengjiang Bai (pp. 196-202).
Pregnant rats were fed either a control (20% protein) or low (3.5%) protein diet during gestation and lactation. The pups were separated from their mothers on postnatal day 21, and were given the same diet as their corresponding mothers. The groups of pups from each diet group were treated on either postnatal day 21 or postnatal day 60 with 7.5 mg methylmercury chloride (MeHgCl) per kg b.w. once daily by gavage for 10 consecutive days, and the development of ataxia (hindlimb crossing) was monitored. The offspring from mothers on the protein-deficient diet were found to be more sensitive to MeHg-induced ataxia than those on the protein-sufficient diet. The former accumulated more mercury in different brain regions than the latter. The rates of protein synthesis in different brain regions of the offspring fed the protein-deficient diet were significantly reduced compared with the rates in those fed the protein-sufficient diet. However, MeHg treatment did not significantly modify the rates of such protein synthesis further in protein-deficient rats. Thus, a significantly much higher inhibition of the intrinsic rates of protein synthesis in different brain regions due to severe protein deficiency, as observed in this study, may be partly responsible for the increased susceptibility of developing rats fed a protein-deficient diet to MeHg-induced ataxia, or hindlimb crossing, although other factor(s) might also be involved.
Keywords: Methylmercury Pre- and postnatal protein malnutrition Hindlimb crossing Protein synthesis
No Title by Elmar Richter; Stefan Rösler; Axel Becker (pp. 203-206).
High levels of haemoglobin (Hb) adducts from 4-aminobiphenyl (4-ABP), a proven human carcinogen, have been reported in untreated animals from different laboratories fed various commercial standard diets. Therefore, the impact of dietary modifications on 4-ABP Hb adducts was investigated. Female Sprague-Dawley rats were fed a regular standard diet or three different test diets for 4 weeks. 4-ABP Hb adducts were significantly lower in rats on vegetable-based test diets #2 (596±183 pg/g Hb, P=0.028) and #3 (537±48 pg/g Hb, P=0.009) compared with controls (974±154 pg/g Hb). Cereal-based test diet #1 (1080±388 pg/g Hb) had no influence on the basal Hb adduct levels determined before the start of the experiment (1054±163 pg/g Hb). In conclusion, the body burden of rats with 4-ABP could be significantly reduced by dietary modifications.
Keywords: Haemoglobin adducts Aromatic amines 4-Aminobiphenyl Rat Laboratory diet
No Title by Alex Fidder; Daan Noort; Albert G. Hulst; Leo P. A. de Jong; Hendrik P. Benschop (pp. 207-214).
The development of a procedure for retrospective detection and quantitation of exposure to the arsenical dichloro(2-chlorovinyl)arsine (lewisite; L1) has been initiated. Upon incubation of human blood with [14C]L1 (20 nM–0.2 mM) in vitro, more than 90% of the total radioactivity was found in the erythrocytes and 25–50% of the radioactivity becomes associated with globin. Evidence was obtained for the presence of several binding sites. One type of binding was identified as L1-induced crosslinking of cysteine residues 93 and 112 of the β-globin chain. A method was developed for extraction of bound and unbound 2-chlorovinylarsonous acid (CVAA), a major metabolite of L1, from whole blood after treatment with 2,3-dimercapto-1-propanol (BAL). Subsequent to derivatization with heptafluorobutyryl imidazole, the CVAA-BAL derivative could be analysed at a 40-fmol level by means of gas chromatography–mass spectroscopy (GC-MS) under electron impact conditions. With this procedure, in vitro exposure of human blood to 1 nM L1 could be determined. The same procedure was applied to the analysis of human urine samples spiked with CVAA. In vivo exposure of guinea pigs could be established at least 240 h after subcutaneous administration of the agent (0.25 mg/kg) by the determination of bound and unbound CVAA in the blood. In the urine of these animals, CVAA could be detected for 12 h after exposure.
Keywords: Lewisite Adducts Haemoglobin Gas chromatography–mass spectroscopy Electrospray mass spectroscopy
No Title by Alyson E. Mitchell; Jeffrey Lakritz; A. Daniel Jones (pp. 215-221).
Acute exposure to naphthalene produces severe bronchiolar epithelial cell necrosis in mice, whereas subchronic exposure to naphthalene (200 mg/kg/7 days) fails to produce epithelial necrosis and renders the animals tolerant to subsequent challenge doses of naphthalene. Mechanisms responsible for the development of tolerance have not been delineated. The few studies exploring naphthalene tolerance focus on expression of microsomal enzymes and have yet to delve into expression of the hepatic detoxification enzymes such as glutathione S-transferases (GSTs; EC 2.5.1.18). Glutathione conjugation catalyzed by GSTs accounts for one of the two primary routes of naphthalene detoxification. In this study, we rigorously quantify levels of individual GST isozymes expressed within the livers and lungs of mice with acquired tolerance to naphthalene. Subchronic exposure to naphthalene increases the abundance of some hepatic GSTs to levels as much as 68% greater than controls. Naphthalene-tolerant mice displayed increases in mGSTM1 (51%), mGSTM2 (58%), and mGSTP1 (66%), whereas no significant difference in mGSTA3 was observed between exposed and control mice. Extracts of pulmonary tissues from naphthalene-tolerant mice showed minor increases in levels of mGSTP1 (7%) and Peak 8 isozyme (27%) and decreases in levels of mGSTM1 (31%), mGSTM2 (17%), and mGSTA3 (8%). The total enzymatic activity for the conjugation of 1-chloro-2,4-dinitrobenzene (CDNB) was 22% lower in lung extracts from naphthalene-tolerant animals than in controls. These results indicate that induction of hepatic GSTs is substantial and may be an important factor in the development of tolerance to naphthalene.
Keywords: Glutathione S-transferase Glutathione S-transferases Naphthalene Electrospray ionization mass spectrometry Mass spectroscopy
No Title by M. Steiner; M. Bastian; W.A. Schulz; T. Pulte; K.H. Franke; A. Röhring; J.M. Wolff; H. Seiter; P. Schuff-Werner (pp. 222-225).
Preliminary evidence suggests that genetic polymorphisms in certain enzymes involved in xenobiotic metabolism and chemical defense could modify a susceptibility to prostate cancer. In the present study, two recently described phenol sulphotransferase SULT1A1 alleles (SULT1A1*1, SULT1A1*2) were investigated using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) approach. Genotyping was performed on DNA isolated from white blood cells from 134 patients with prostate cancer and 184 healthy control subjects. Both the prostate cancer patients and the controls demonstrated similar frequencies of the variant allele SULT1A1*2 (35.1% vs 39.1%). Homozygosity for the variant allele was slightly less frequent in cancer patients than controls (12.7% vs 17.4%). Our study does not support the hypothesis that the phenol sulphotransferase variant allele SULT1A1*2 with a G/A transition at nucleotide 638 is a risk modifier for prostate cancer in the Caucasian population.
Keywords: Phenol sulphotransferase Polymorphism Molecular epidemiology Prostate cancer
No Title by C.D. Anuradha; S. Kanno; S. Hirano (pp. 226-230).
Even though fluoride toxicity is increasingly being considered to be important, very little information is available on the mechanism of action of fluoride. In the present study, the toxicity of fluoride on human leukemia (HL-60) cells was investigated and the involvement of caspase-3 was also studied. Fluoride induced apoptosis in HL-60 cells in a dose- and time-dependent manner. Annexin staining and DNA ladder formation on agarose gel electrophoresis further revealed that HL-60 cells underwent apoptosis on exposure to 2–5 mM fluoride. Western blotting using polyclonal anti-caspase-3 antibody and mouse anti-human poly(ADP-ribose) polymerase (PARP) monoclonal antibody was performed to investigate caspase-3 and PARP activity. Fluoride led to the activation of caspase-3 which was evident by the loss of the 32 kDa precursor and appearance of the 17 kDa subunit. Furthermore, intact 116 kDa PARP was cleaved by fluoride treatment as shown by the appearance of a cleaved 89 kDa fragment. The results clearly suggest that fluoride causes cell death in HL-60 cells by causing the activation of caspase-3 which in turn cleaves PARP leading to DNA damage and ultimately cell death.
Keywords: Fluoride Caspase-3 Apoptosis HL-60 PARP
No Title by Elke Röhrdanz; Barbara Obertrifter; Sandra Ohler; Quynh-Hoa Tran-Thi; Regine Kahl (pp. 231-237).
The cytostatic Adriamycin and the herbicide paraquat form reactive oxygen species during enzymatic activation. Adriamycin, but not paraquat, is also able to intercalate into DNA and to interfere with DNA synthesis and transcription. We investigated the influence of both substances on antioxidant enzyme expression in primary rat hepatocytes. Treatment of hepatocytes with Adriamycin led to an increase in catalase and a decrease in MnSOD mRNA expression. In contrast, exposure of hepatocytes to paraquat resulted in an increase in both catalase and MnSOD message levels. CuZnSOD mRNA was not responsive to either treatment. Adriamycin almost completely inhibited RNA synthesis, but paraquat did not change either RNA or protein synthesis. Both substances induced lipid peroxidation as measured by the accumulation of malondialdehyde in the medium. These findings indicate that catalase and MnSOD are not regulated coordinately in hepatocytes and that ROS-producing agents can differentially influence expression of antioxidant enzymes depending on their capacity to inhibit transcription.
Keywords: Catalase Superoxide dismutase Adriamycin Paraquat Hepatocytes
No Title by Raghubir P. Sharma; Neetesh Bhandari; Masashi Tsunoda; R.T. Riley; K.A. Voss (pp. 238-248).
Our previous studies have indicated that tumour necrosis factor α (TNFα) is involved in fumonisin B1 (FB1)-induced toxic responses. To investigate the role of TNFα in FB1 toxicity further we employed male transgenic mice expressing human TNFα gene (TG) and their wild-type equivalent C57BL/6 (WT). It was hypothesized that TG animals would have enhanced response to FB1. Repeated subcutaneous treatment of animals with 2.25 mg/kg per day of FB1 for 5 days caused minimal changes in body weight, organ weights, blood cell counts, and TNFα levels in plasma 1 day after the last injection. The mRNA for TNFα in liver increased in both TG and WT after FB1 treatment, providing evidence that FB1 induces hepatic TNFα expression. Liver and kidney lesions were found in TG after FB1 treatment; however, liver lesions seen in FB1-treated TG were considerably less than those observed in WT. The decreased hepatotoxicity in TG after FB1 treatment correlated with plasma concentrations of alanine aminotransferase and aspartate aminotransferase. Free sphinganine levels increased significantly in both the liver and kidney of WT and TG mice treated with FB1. The increase of free sphinganine in the liver from TG mice was 40% less than in WT mice and paralleled the changes in serum liver enzymes. Regional brain neurotransmitters and their metabolites were increased to a similar extent by FB1 in both WT and TG mice. Since the data did not support the original hypothesis, we investigated the levels of NFκB in liver. The cytosolic NFκB was significantly higher in TG compared with WT. Induction of NFκB, caused by increased endogenous production of TNFα, is a possible explanation of decreased FB1 hepatotoxicity in TG. The results suggest a protective role for NFκB in FB1-induced liver damage.
Keywords: Fumonisin B1 Hepatotoxicity Nuclear factor κB Sphingolipids Tumour necrosis factor α
No Title by Annukka Kärki; Eero Mäntylä; Yrjö Hirsimäki; Stefan Karlsson; Sakari Toikkanen; Pirkko Hirsimäki (pp. 249-256).
The hepatoproliferative and cytochrome P450 enzyme inducing effects of two antiestrogens, tamoxifen and toremifene, were compared in female Sprague-Dawley rats using immunohistochemical staining methods. Equimolar doses of the antiestrogens (tamoxifen 45 mg/kg and toremifene 48 mg/kg) were given by oral administration to 6-week-old rats for 12 months including a 3-month recovery period. Controls received the vehicle carboxymethylcellulose. Altogether 90 rats were used in the study. Five rats per dose group were killed after 14 days, 5 weeks, 3, 6 and 12 months of treatment as well as after the 3-month recovery period. Hepatocellular carcinoma was found in four out of five rats after 12 months of tamoxifen treatment. After the 3-month recovery period all tamoxifen-treated rats had large liver tumors (diameter up to 3 cm). No tumors were observed in toremifene-treated rats. Liver cell proliferation was measured by the index of proliferating cell nuclear antigen (PCNA) expression. Immunohistochemical staining with the placental form of glutathione S-transferase (GST-P) was used as a marker for preneoplastic foci. Cytochrome P450 induction was measured using specific antibodies to isoenzymes. Tamoxifen increased the incidence of GST-P-positive foci significantly by 3 months of treatment but toremifene did not as compared with the controls. Liver cell proliferation increased significantly only in the liver tumors of tamoxifen-treated rats after 12 months of treatment and during the recovery period. Both antiestrogens induced the isoenzymes CYP2B1/2 and CYP3A1 within 14 days although tamoxifen was a more powerful inducer. Immunohistochemistry of rat liver sections showed a centrilobular localization of these induced enzyme proteins. The expression of CYP2B1/2 and 3A1 could also be observed in foci after 3 and 6 months of administration and in liver adenomas and in some carcinomas after 12 months of administration with tamoxifen. The results show that tamoxifen, but not toremifene, has the potential to induce and promote the development of rat hepatocarcinogenesis in this experimental model.
Keywords: Antiestrogens Tamoxifen Toremifene Hepatocellular carcinoma Immunohistochemistry Enzyme induction
No Title by Jürgen Pauluhn (pp. 257-269).
The early acute pulmonary response of Wistar rats exposed nose-only to respirable polymeric diphenyl-methane 4,4′-diisocyanate (MDI) aerosol was examined. This study investigated the time course of the relationship between acute pulmonary irritation and ensuing disturbances of the air/blood barrier in rats exposed to concentrations of 0.7, 2.4, 8, or 20 mg MDI/m3. The duration of exposure was 6 h. The time-response relationship of MDI-induced acute lung injury was examined 0 h (directly after cessation of exposure), 3 h, 1 day, 3 days, and 7 days after exposure. Bronchoalveolar lavage (BAL) fluid was analyzed for markers indicative of injury of the bronchoalveolar region, i.e., angiotensin-converting enzyme, protein, alkaline phosphatase, lactate dehydrogenase, γ-glutamyltranspeptidase, and sialic acid. Phosphatidylcholine and acid phosphatase were determined in BAL fluid and cells. Glutathione was determined in BAL fluid and lung tissue. This analysis revealed no latent period of effects except a transiently delayed influx of cells and increased lung weights on postexposure days 1 and 3. Markedly loaded BAL cells with phosphatidylcholine were observed on day 1 only. In most instances, changes returned to the level of the air exposed control on day 7, except increased glutathione in lung tissue. The findings suggest that the most sensitive markers of dysfunction of the air/blood barrier are angiotensin-converting enzyme and protein, including alkaline phosphatase. The statistically significant increase in intracellular phosphatidylcholine and decreased intracellular acid phosphatase on the exposure day suggest that increased amounts of phospholipids are phagocytized by alveolar macrophages, associated with protracted lysosomal catabolism. Partially glutathione-depleted rats exposed to 20 mg/m3 experienced a more pronounced increase in BAL protein than normal rats. In summary, this study suggests that respirable polymeric MDI aerosol interacts directly with the air/blood barrier causing increased extravasation of plasma constituents as a result of increased permeability of capillary endothelial cells. Overall, a transient dysfunction of the pulmonary epithelial barrier occurred at level as low as 0.7 mg/m3 and appears to be related a dysfunction of pulmonary surfactant. Nonprotein sulfhydryl constituents appear to play a role as portal-of-entry specific modifying factors.
Keywords: Diisocyanate inhalation Pulmonary edema Thiol protectants Surfactant Angiotensin-converting enzyme
No Title by A. Lafuente; N. Márquez; Y. Pousada; D. Pazo; A.I. Esquifino (pp. 270-275).
Methoxychlor (MTX) is a pesticide currently used as a substitute for dichloro-diphenyl-trichloroethane (DDT). This organochloride insecticide has some estrogenic properties, and may modify the feedback mechanisms of steroids on the hypothalamus and pituitary. This work was undertaken to explore the possible effects of MTX on the episodic prolactin release and to analyze whether these effects are mediated by dopamine (DA), luteinizing hormone (LH), and/or testosterone. Adult male Sprague-Dawley rats were administered 25 mg/kg/day of MTX in sesame oil for 30 days. Control animals received vehicle only. The episodic prolactin release and plasma testosterone levels were measured as well as the dopamine (DA) content in the median eminence (ME) and in the anterior (AH), mediobasal (MBH), and posterior (PH) hypothalamus. The mean serum prolactin levels and absolute pulse amplitude of the hormone increased after the xenobiotic administration, whereas its relative pulse amplitude diminished. The frequency and duration of prolactin peaks and its half-life were not modified by the treatment with the pesticide. On the other hand, methoxychlor decreased the DA content in ME, increased it in AH, and did not change it in MBH or PH. MTX decreased plasma levels of LH and testosterone compared with controls. These data suggest estrogenic and antiandrogenic effects of MTX on the episodic prolactin secretion; the changes observed in prolactin release could be explained, at least in part, by some of the changes of DA at the hypothalamus and of LH at the pituitary, but not by changes of testosterone at the testicular level.
Keywords: Methoxychlor Prolactin Dopamine Testosterone Luteinizing hormone
No Title by Shawn McGuire; Elaine Bostad; Les Smith; Mark Witten; Frank L. Siegel; Steven Kornguth (pp. 276-280).
The current study was designed to determine whether exposure of mice to aerosolized jet fuel (JP8+100) resulted in changes in the cellular distribution or immunoreactivity of the enzyme glutathione-S-transferase (GST), a biomarker of toxicant exposure. Male mice were exposed to JP8+100 at 1000 mg/m3 or 2500 mg/m3 in aerosol for 1 h per day for 7 days and then sacrificed. The retinas were studied by immunohistochemical methods. The JP8+100 exposure caused a marked increase in the immunoreactivity of anti-GSTM antibodies with the radial glial cells of the retina, the Müller cells. These results are consistent with the hypothesis that JP8+100 acts as a toxicant to mouse retina by permitting the flux of materials across the blood-retina barrier. The findings are relevant to humans because recent studies indicate that Air Force personnel assigned to clean and maintain fuel pods may be exposed to concentrations of JP8+100 exceeding 1000 mg/m3.
Keywords: Glutathione-S-transferase Jet fuel Toxicant Retina Müller cell