Check out our New Publishers' Select for Free Articles

Archives of Toxicology (v.83, #4)

Epoxide hydrolases are not only a molecular sponge sucking up genotoxic epoxides: new roles in control of blood pressure, inflammation as well as nociception and cell proliferation by J. G. Hengstler; J. D. Stewart; H. M. Bolt (pp. 289-291).

A further plea for rigorous science and explicit disclosure of potential conflicts of interest by Rémy Slama; Josef Cyrys; Olf Herbarth; H.-Erich Wichmann; Joachim Heinrich (pp. 293-295).

Mammalian epoxide hydrolases in xenobiotic metabolism and signalling by Martina Decker; Michael Arand; Annette Cronin (pp. 297-318).

Epoxide hydrolases catalyse the hydrolysis of electrophilic—and therefore potentially genotoxic—epoxides to the corresponding less reactive vicinal diols, which explains the classification of epoxide hydrolases as typical detoxifying enzymes. The best example is mammalian microsomal epoxide hydrolase (mEH)—an enzyme prone to detoxification—due to a high expression level in the liver, a broad substrate selectivity, as well as inducibility by foreign compounds. The mEH is capable of inactivating a large number of structurally different, highly reactive epoxides and hence is an important part of the enzymatic defence of our organism against adverse effects of foreign compounds. Furthermore, evidence is accumulating that mammalian epoxide hydrolases play physiological roles other than detoxification, particularly through involvement in signalling processes. This certainly holds true for soluble epoxide hydrolase (sEH) whose main function seems to be the turnover of lipid derived epoxides, which are signalling lipids with diverse functions in regulatory processes, such as control of blood pressure, inflammatory processes, cell proliferation and nociception. In recent years, the sEH has attracted attention as a promising target for pharmacological inhibition to treat hypertension and possibly other diseases. Recently, new hitherto uncharacterised epoxide hydrolases could be identified in mammals by genome analysis. The expression pattern and substrate selectivity of these new epoxide hydrolases suggests their participation in signalling processes rather than a role in detoxification. Taken together, epoxide hydrolases (1) play a central role in the detoxification of genotoxic epoxides and (2) have an important function in the regulation of physiological processes by the control of signalling molecules with an epoxide structure.

Keywords: Epoxide hydrolase; Xenobiotic metabolism; EPHX; ABHD; Lipid signalling; peg1/MEST; EET; Cholesterol; Lipid phosphatase

Subtoxic chlorpyrifos treatment resulted in differential expression of genes implicated in neurological functions and development by Andrea R. Stapleton; Victor T. Chan (pp. 319-333).

Chlorpyrifos (CPF), a commonly used organophosphorus insecticide, induces acetylcholinesterase inhibition and cholinergic toxicity. Subtoxic exposure to CPF has long-term adverse effects on synaptic function/development and behavioral performance. To gain insight into the possible mechanism(s) of these observations, this study aims to investigate gene expression changes in the forebrain of rats treated with subtoxic CPF doses using DNA microarrays. Statistical analysis revealed that CPF treatment resulted in differential expression of 277 genes. Gene ontology and pathway analyses revealed that these genes have important roles in nervous system development and functions including axon guidance, dorso-ventral axis formation, long-term potentiation, synaptic transmission, and insulin signaling. The results of biological associated network analysis showed that Gsk3b is highly connected in several of these networks suggesting its potential role in cellular response to CPF exposure/neurotoxicity. These findings might serve as the basis for future mechanistic analysis of the long-term adverse effects of subtoxic CPF exposure.

Keywords: Chlorpyrifos; Neurotoxicity; Transcriptomic profiling; Pathway analysis; Biological association networks

Protective effect of resveratrol in endotoxemia-induced acute phase response in rats by Hichem Sebai; Mossadok Ben-Attia; Mamane Sani; Ezzedine Aouani; Néziha Ghanem-Boughanmi (pp. 335-340).

Lipopolysaccharide (LPS), a glycolipid component of the cell wall of gram-negative bacteria can elicit a systemic inflammatory process leading to septic shock and death. Acute phase response is characterized by fever, leucocytosis, thrombocytopenia, altered metabolic responses and redox balance by inducing excessive reactive oxygen species (ROS) generation. Resveratrol (trans-3,5,4′ trihydroxystilbene) is a natural polyphenol exhibiting antioxidant and anti-inflammatory properties. We investigated the protective effect of resveratrol on endotoxemia-induced acute phase response in rats. When acutely administered by i.p. route, resveratrol (40 mg/kg b.w.) counteracted the effect of a single injection of LPS (4 mg/kg b.w.) which induced fever, a decrease in white blood cells (WBC) and platelets (PLT) counts. When i.p. administered during 7 days at 20 mg/kg per day (subacute treatment), resveratrol abrogated LPS-induced erythrocytes lipoperoxidation and catalase (CAT) activity depression to control levels. In the plasma compartment, LPS increased malondialdehyde (MDA) via nitric monoxide (NO) elevation and decreased iron level. All these deleterious LPS effects were reversed by a subacute resveratrol pre-treatment via a NO independent way. Resveratrol exhibited potent protective effect on LPS-induced acute phase response in rats.

Keywords: Resveratrol; Lipopolysaccharide; Oxidative stress; Hematological parameters; Nitric Oxide; Iron

Histopathologic effects of maternal 4-tert-octylphenol exposure on liver, kidney and spleen of rats at adulthood by Nurhayat Barlas; Müfide Aydoğan (pp. 341-349).

The present study was performed to investigate the potential toxic effects of prenatal exposure to 4-tert-octylphenol (OP) on liver, kidney, spleen, and hematologic parameters of male and female rats in adult life. The rats were treated with OP subcutaneously in utero at doses of control (vehicle, corn oil), 100 or 250 mg/kg per day. After birth, the rats were allowed to grow until adulthood and then liver, kidney and spleen were investigated histopathologically. Also the blood collected from rats were analyzed for any hematologic changes. The red blood cells of male and female rats were decreased in 250 mg/kg per day OP-treated group compared with the control group. μ-RBC of male rats in high dose treatment groups were increased significantly compared with the controls and 100 mg/kg per day treatment groups. μ-RBC of female rats in treatment groups were increased in a dose-dependent manner compared with the controls. In liver, kidney and spleen of male and female rats treated with OP, degeneration of hepatic parenchyma, tubular degeneration and hemorrhage were observed in histopathologic examination. The hemosiderin deposition in spleen of the high-dose group was increased in both male and female rats. In conclusion, findings of this study demonstrate that maternal administration of high doses of OP causes adverse effects on spleen and liver tissues of male and female offsprings at adulthood. Specifically, OP caused decreases in the number of red blood cells indicated by increased destruction in the spleen.

Keywords: Octylphenol; Hematology; Environmental estrogens; Endocrine disrupters; Spleen; Liver; Kidney; Rat

Association of GSTM3 intron 6 variant with cigarette smoking, tobacco chewing and alcohol as modifier factors for prostate cancer risk by Pravin Kesarwani; Ranjana Singh; Rama Devi Mittal (pp. 351-356).

Variations in glutathione-S-transferases (GSTs) genes may alter the catalytic efficiency of GST isoenzymes leading to potential increase in susceptibility to carcinogens present in cigarette smoke and tobacco. The present study aimed to explore the association of GSTM3 intron 6 polymorphism with susceptibility to prostate cancer (PCa), and to assess risks associated with cigarette smoking, tobacco chewing and alcohol consumption in PCa patients of North India. The study included 135 PCa patients and 169 controls. All subjects were genotyped for 3-bp deletion in intron 6 of GSTM3. Risk of developing prostate cancer associated with GSTM3 AB + BB was 2.5-fold (OR = 2.51, P = 0.028) as compared to AA genotype. Patients who were either smokers and/or had alcohol habits demonstrated a strong association with GSTM3 (AB + BB) genotype (OR = 4.11, P = 0.046; OR = 4.38, P = 0.027, respectively). Our results suggested GSTM3 (AB + BB) genotype to be significantly associated with PCa risk. The risk was even more apparent in case of cigarette smokers and alcohol consumers.

Keywords: Glutathione-S-transferases (GSTs) genes; Prostate cancer; Cigarette smoking; Polymorphism

Vitamin D metabolism impairment in the rat’s offspring following maternal exposure to ¹³⁷cesium by E. Tissandie; Y. Guéguen; J. M. A. Lobaccaro; L. Grandcolas; S. Grison; J. Aigueperse; M. Souidi (pp. 357-362).

Previous works clearly showed that chronic contamination by ¹³⁷cesium alters vitamin D metabolism. Since children are known to be a high-risk group for vitamin D metabolism disorders, effects of ¹³⁷Cs on vitamin D biosynthetic pathway were investigated in newborn rats. The experiments were performed in 21-day-old male offspring of dams exposed to ¹³⁷Cs in their drinking water at a dose of 6,500 Bq/l (150 Bq/rat/day) during the lactation period. Significant modifications of blood calcium (−7%, P < 0.05), phosphate (+80%, P < 0.01) and osteocalcin (−25%, P < 0.05) levels were observed in contaminated offspring, associated with an increase of blood vitamin D₃ (+25%, P < 0.01). Besides, decreased expression levels of cyp2r1 and cyp27b1 (−26 and −39%, respectively, P < 0.01) were measured in liver and kidney suggesting a physiological adaptation in response to the rise in vitamin D level. Expressions of vdr, ecac1, cabp-d28k, ecac2 and cabp-9k involved in renal and intestinal calcium transport were unaffected. Altogether, these data show that early exposure to post-accidental doses of ¹³⁷Cs induces the alteration of vitamin D metabolism, associated with a dysregulation of mineral homeostasis.

Keywords: ¹³⁷Cesium; Chronic contamination; Cytochrome P450; Vitamin D₃ ; Maternal exposure

Mechanisms participating in oxidative damage of isolated rat hepatocytes by Zuzana Červinková; Pavla Křiváková; Anna Lábajová; Tomáš Roušar; Halka Lotková; Otto Kučera; René Endlicher; Miroslav Červinka; Zdeněk Drahota (pp. 363-372).

The aim of the study was to evaluate time course and dose dependence of peroxidative damage induced by tert-butyl hydroperoxide (tBHP) in rat hepatocytes cultured in suspension and in monolayer. At the lowest (0.1 mM) concentration, decrease of cytosolic glutathione and discharge of mitochondrial membrane potential (MMP) could be detected. Significant increases in leakage of lactate dehydrogenase and in malondialdehyde concentrations together with decrease of pyruvate-dependent respiration were detected at higher tBHP concentrations (above 0.5 mM) and after longer periods of incubation. Changes in plasma membrane integrity were observed at 1 mM concentration of tBHP. Succinate-dependent oxidation was most resistant to peroxidative damages. Opening of the mitochondrial permeability transition pore was responsible for the discharge of mitochondria membrane potential. In the presence of cyclosporine A and succinate, the membrane potential could be restored. Our data showed that the most sensitive indicators of the peroxidative damage are changes of cytosolic glutathione concentration and MMP.

Keywords: Hepatocytes; Oxidative damage; Mitochondrial enzymes

Diazinon oxon affects the differentiation of mouse N2a neuroblastoma cells by Erasmia Sidiropoulou; Magdalini Sachana; John Flaskos; Wayne Harris; Alan J. Hargreaves; Zerai Woldehiwet (pp. 373-380).

The aim of this study was to assess the neurotoxicity of diazinon oxon (DZO), a major in vivo metabolite of the phosphorothionate insecticide diazinon (DZ), on differentiating mouse N2a neuroblastoma cells. When used at concentrations of 1, 5 and 10 μM, DZO did not cause cell death but it impaired the outgrowth of axon-like processes after 24 h. Densitometric scanning of Western blots of lysates of N2a cells revealed that exposure to 5 or 10 μM DZO for 24 h increased the expression of phosphorylated neurofilament heavy chain (NFH) compared to controls, while there was no significant change in total NFH. By contrast, treatment of N2a cells with 1–10 μM DZO resulted in marked reductions in the expression of the axon growth-associated protein GAP-43. DZO-treated cells also showed an increased expression of the heat shock protein HSP-70 compared to controls. The above biochemical changes were not temporally related to inhibition of acetylcholinesterase (AChE). These data suggest that biologically relevant, subcytotoxic levels of DZO may exert neurotoxic effects on differentiating cells and that the mechanisms involved are different from those attributed to its parent compound.

Keywords: Diazinon oxon; N2a neuroblastoma cells; Neurite outgrowth; NFH; GAP-43; HSP-70

Protect effect of bicyclol on cisplatin-induced nephrotoxicity in mice by Ying-Nan Yu; Hui Chen; Yan Li (pp. 381-387).

This study investigated the protective effects of bicyclol against cisplatin-induced nephrotoxicity and the possible mechanisms in mice. Bicyclol (250 mg/kg, p.o., 5 days) showed significant protection as evidenced by the decrease of elevated serum creatine and blood urea nitrogen, and improvement of histopathological injury induced by cisplatin. The formation of kidney malondialdehyde with a concomitant reduction of reduced glutathione were also inhibited by bicyclol, while the activities of kidney superoxide dismutase, catalase and glutathione peroxidase were all increased, respectively. Bicyclol also inhibited the increase of kidney and serum nitric oxide induced by cisplatin. In addition, induction of induced nitric oxide synthase and nitrotyrosine were suppressed by bicyclol. Bicyclol suppressed cisplatin-induced extracelluar signal regulated kinases 1/2 and p38 mitogen-activated protein kinase activation in the kidney of mice. Results obtained demonstrate that bicyclol pre-administration can prevent the nephrotoxicity induced by cisplatin.

Keywords: Cisplatin; Nephrotoxicity; Bicyclol; Oxidative stress; Lipid peroxidation

Cytotoxicity and decreased corticosterone production in adrenocortical Y-1 cells by 3-methylsulfonyl-DDE and structurally related molecules by Vendela Asp; Veronica Lindström; Jan A. Olsson; Ulrika Bergström; Ingvar Brandt (pp. 389-396).

The persistent environmental pollutant 3-methylsulfonyl-DDE (3-MeSO₂-DDE) undergoes bioactivation by cytochrome P450 11B1 (CYP11B1) in the adrenal cortex of several animal species in vivo and causes decreased glucocorticoid production and cell death in the zona fasciculata. This study presents extended investigations of the cytotoxic and endocrine disrupting effects of 3-MeSO₂-DDE and some structurally related molecules in the mouse adrenocortical cell line Y-1. Both 3-MeSO₂-DDE and, to a lesser extent, 3,3′(bis)-MeSO₂-DDE decreased corticosterone production and produced CYP11B1-dependent cytotoxicity in Y-1 cells. Neither 2-MeSO₂-DDE nor p,p′-DDE had any significant effect on either cell viability or corticosterone production, indicating that the presence and position of the methylsulfonyl moiety of 3-MeSO₂-DDE is crucial for its biological activity. The adrenocortical toxicant o,p′-DDD decreased corticosterone production but was not cytotoxic in this cell line. None of the compounds altered Cyp11b1 gene expression, indicating that 3-MeSO₂-DDE inhibits CYP11B1 activity on the protein level.

Keywords: Adrenal cortex; Metabolic activation; Toxicity; Corticosterone; DDE; CYP11B1

The use of Fluoro-Jade in primary neuronal cell cultures by Gabriele Schmuck; Regine Kahl (pp. 397-403).

Fluoro-Jade (FJ) and its derivatives are widely used for histological staining of neurons undergoing neurodegeneration. With this dye, the entire structure of these neurons can be stained in a fast and reliable way in histopathological slices of the brain, with results comparable to those obtained with other methods such as the Nissle technique or silver staining. The question arose as to whether this method might be useful for in vitro neuronal cell cultures. Primary cortical neuronal cell cultures have been used as a sensitive and reliable system to detect compounds which induce neurodegenerative lesions (Schmuck et al. 2000). Additionally, various biochemical endpoints in this system allow the mode of action of these compounds to be identified. The target mechanism of FJ staining is unknown, and it may therefore be useful to compare FJ staining with one of the central endpoints in compound-induced neurodegeneration, interaction with the cytoskeleton as demonstrated by accumulations of neurofilaments (200 kD). Cortical neuronal cells were cultivated under standardized serum-free conditions. Once they had developed a stable network, the cells were treated with acrylamide, mipafox, diethyldithiocarbamate, glutamate, paraquat, paraoxon, and IDPN (ß,ß-imino dipropionitrile) for 7 days in the concentration range of 0.1–50 μg/ml. One half of the cell culture samples were tested directly after 7 days, the others were allowed to recover during a 7-day treatment-free period. Subsequently viability testing and quantification for FJ staining were performed. All compounds except paraoxon increased FJ staining after 7 days, and this signal increased slightly during the recovery period with glutamate and acrylamide. With mipafox and IDPN the signal decreased slightly. Paraoxon increased FJ staining only after the recovery period. The intensity of FJ staining did not always correlate with neurofilament destruction or cytotoxicity. It can therefore be assumed that FJ targets a different cellular endpoint. Interestingly, paraoxon, a compound which does not induce neurodegeneration, increased FJ staining only in the recovery phase; this pointed to a neurotoxic mechanism which sets it apart from the other model compounds.

Keywords: Fluoro-Jade; Neurodegeneration; Cortical neurons; Viability; Neurofilaments

Sections

Personal tools

Archives of Toxicology (v.83, #4)

Sections

Personal tools

Local resources

Archives of Toxicology (v.83, #4)