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Archives of Toxicology (v.84, #4)

Gene array screening for identification of drugs with low levels of adverse side effects by Hermann M. Bolt; Rosemarie Marchan; Jan G. Hengstler (pp. 253-254).

The involvement of transition metal ions on iron-dependent lipid peroxidation by Marisa G. Repetto; Nidia F. Ferrarotti; Alberto Boveris (pp. 255-262).

The metals iron (Fe) and copper (Cu) are considered trace elements, and the metals cobalt (Co) and nickel (Ni) are known as ultra-trace elements, considering their presence in low to very low quantity in humans. The biologic activity of these transition metals is associated with the presence of unpaired electrons that favor their participation in redox reactions. They are part of important enzymes involved in vital biologic processes. However, these transition metals become toxic to cells when they reach elevated tissue concentrations and produce cellular oxidative damage. Phospholipid liposomes (0.5 mg/ml, phosphatidylcholine (PC)/phosphatidylserine (PS), 60/40) were incubated for 60 min at 37°C with 25 μM of Fe²⁺ in the absence and in the presence of Cu²⁺, Co²⁺, and Ni²⁺ (0–100 μM) with and without the addition of hydrogen peroxide (H₂O₂, 5–50 μM). Iron-dependent lipid peroxidation in PC/PS liposomes was assessed by thiobarbituric acid-reactive substances (TBARS) production. Metal transition ions promoted lipid peroxidation by H₂O₂ decomposition and direct homolysis of endogenous hydroperoxides. The Fe²⁺-H₂O₂-mediated lipid peroxidation takes place by a pseudo-second order process, and the Cu²⁺-mediated process by a pseudo-first order reaction. Co²⁺ and Ni²⁺ alone do not induce lipid peroxidation. Nevertheless, when they are combined with Fe²⁺, Fe²⁺-H₂O₂-mediated lipid peroxidation was stimulated in the presence of Ni²⁺ and was inhibited in the presence of Co²⁺. The understanding of the effects of transition metal ions on phospholipids is relevant to the prevention of oxidative damage in biologic systems.

Keywords: Iron; Copper; Cobalt; Nickel; Lipid peroxidation; Phospholipid oxidative damage

Identification of proteasome gene regulation in a rat model for HIV protease inhibitor-induced hyperlipidemia by Jeffrey F. Waring; Rita Ciurlionis; Kennan Marsh; Larry L. Klein; David A. DeGoey; John T. Randolph; Brian Spear; Dale J. Kempf (pp. 263-270).

Patients treated with highly active antiretroviral therapy may develop metabolic side effects such as hyperlipidemia, insulin resistance, lipoatrophy and lactic acidosis. The pathophysiology of these metabolic abnormalities is unknown, although some, e.g., lactic acidosis and lipoatrophy, are more associated with nucleoside use while protease inhibitors (PIs) have been shown to contribute to hyperlipidemia and insulin resistance. Identifying new PIs that are not associated with dyslipidemia has been hindered by the lack of mechanistic information and the unavailability of relevant animal models. In order to understand the molecular mechanism behind the hyperlipidemia associated with other protease inhibitors, and to develop a more effective, faster screen for compounds with this liability, we have analyzed expression profiles from PI-treated animals. Previously, we have shown that treatment of rats with ritonavir results in increases in the expression of proteasomal subunit genes in the liver. We show this increase is similar in rats treated with bortezomib, a proteasome inhibitor. In addition, we have treated rats with additional protease inhibitors, including atazanavir, which is associated with lower rates of lipid elevations in the clinic when administered in the absence of ritonavir. Our results indicate a strong correlation between proteasomal induction and lipid elevations, and have allowed us to develop a rapid screen for identifying novel PIs that do not induce the proteasome.

Keywords: HIV; Protease inhibitor; Proteasome; Microarray; Hyperlipidemia

Gene expression profiles in the brain of the neonate mouse perinatally exposed to methylmercury and/or polychlorinated biphenyls by Miyuki Shimada; Satomi Kameo; Norio Sugawara; Kozue Yaginuma-Sakurai; Naoyuki Kurokawa; Satomi Mizukami-Murata; Kunihiko Nakai; Hitoshi Iwahashi; Hiroshi Satoh (pp. 271-286).

Methylmercury (MeHg) and polychlorinated biphenyls (PCBs) are environmentally persistent neurodevelopmental toxicants. The primary source of human exposure is the consumption of contaminated fish, seafood and marine mammals. However, little is known about the molecular mechanisms of MeHg and PCB toxicities and interactions between these contaminants. We investigated the functional profiles of differently expressed genes in the brains of offspring mice perinatally exposed to MeHg and/or PCBs to elucidate how these contaminants interact with each other. Pregnant mice (C57BL/6) were divided into four groups by exposure: (1) vehicle control, (2) MeHg alone, (3) PCBs alone, (4) MeHg + PCBs. Gene expression analysis of the brains of offspring mice was carried out with 4 × 44 K whole mouse genome’s microarrays (Agilent) on postnatal day 1. The gene expression pattern of the MeHg exposure-group differed from that of the PCB-exposure group. The MeHg + PCB group expressed a larger number of genes, most of which were not expressed in the MeHg group or PCB group. It was revealed that gene expression was greatly increased, and the most altered genes were found with co-exposure. The genes were related to the functional categories of development, inflammation, calcium ion homeostasis, signal transduction, the ubiquitin–proteasome pathway and detoxication. The ubiquitin–proteasome system and detoxication categories might function for protection against the toxicity induced by co-exposure to MeHg and PCBs. These results suggest that co-exposure does not simply exacerbate the toxicity of MeHg alone or PCB alone, but stimulates a protection system.

Keywords: Methylmercury; Polychlorinated biphenyls; PCBs; Aroclor 1254; Gene expression; Microarray; Brain; Co-exposure; Mouse

Toxicity of penta- and decabromodiphenyl ethers after repeated administration to rats: a comparative study by Elżbieta Bruchajzer; Barbara Frydrych; Stanisław Sporny; Jadwiga A. Szymańska (pp. 287-299).

Until recently, pentabromodiphenyl (PentaBDE) and decabromodiphenyl (DecaBDE) ethers were commonly used as flame retardants in a wide array of products, mostly in the production of plastics utilized in the electric, electronic and textile industries. The aim of this study was to compare the toxicity of PentaBDE and DecaBDE after their repeated (7–28 days) intragastric administration to rats. The compounds were given at doses of 2, 8, 40 or 200 mg/kg/day (PentaBDE) and 10, 100 or 1,000 mg/kg/day (DecaBDE). The repeated administration of PentaBDE disturbed redox homeostasis, which was manifested by lower total antioxidant status and increased activity of glutathione reductase in serum and higher concentrations of glutathione reduced and malondialdehyde in the liver. The occurrence of these effects was not observed after DecaBDE administration. The results of histopathological examination showed fatty degeneration after administration of the highest dose of PentaBDE. The repeated administration of PentaBDE also caused the increase in relative liver mass, dose-dependent increase in the activity of CYP 1A (EROD) and CYP 2B (PROD), 7–12- and 2–8-fold, respectively, as well as enhanced level of CYP 1A1 (5–30-fold) and CYP 4A (2–4.5-fold). The administration of DecaBDE induced much less pronounced changes: a maximum 2.8-fold increase in the activity of CYP 1A, a twofold increase in CYP 2B, and no alterations in other parameters under study. Contrary to DecaBDE, PentaBDE disturbed redox homeostasis, and induced liver microsomal enzymes. Fatty degeneration in liver caused by this compound was also found.

Keywords: PentaBDE; DecaBDE; Oxidative stress; Cytochromes; Repeated administration; Toxicity; Rat

Association of melamine exposure with urinary stone and oxidative DNA damage in infants by Yuebin Ke; Xiaobei Duan; Feiqiu Wen; Xinyun Xu; Gonghua Tao; Li Zhou; Renli Zhang; Baoming Qiu (pp. 301-307).

There is evidence in experimental animals for the urolithiasis and carcinogenicity of melamine, but no evidence for melamine in humans. To evaluate any association between melamine-contaminated powdered formula (MCPF) feeding and urolithiasis, and further the MCPF feeding and oxidative damage to DNA in infants. A cross-sectional study was carried out to assess urolithiasis and urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG) in four groups of infants according to the type of feeding: (1) Infants receiving over 90% of their intake as MCPF. (2) Infants receiving 50–90% of their intake as MCPF. (3) Infants receiving less than 50% of their intake as MCPF. (4) Infants receiving over 90% of their intake as imported milk powdered formula free of melamine contamination. Groups 1 to 3 are the observation groups, and Group 4 is the reference group. There is a significant correlation between urolithiasis and percentage of MCPF intake. The mean urinary 8-OHdG concentrations for Groups 1, 2, 3, and 4 were: 2.03 ± 0.52, 1.67 ± 0.28, 1.90 ± 0.39, and 1.85 ± 0.47 micromoles per mole of creatinine, respectively. There were no significant differences in the mean urinary 8-OHdG concentrations among the observation and control groups. There were also no correlation between mean urinary 8-OHdG excretions and percentage of MCPF intake. Our data suggested that melamine exposure were associated with urolithiasis, but it might not cause any increase in oxidative damage of DNA in infants.

Keywords: Melamine; Powdered formula; Urolithiasis; Oxidative DNA damage; 8-OHdG

Prepubertal exposure to commercial formulation of the herbicide glyphosate alters testosterone levels and testicular morphology by R. M. Romano; M. A. Romano; M. M. Bernardi; P. V. Furtado; C. A. Oliveira (pp. 309-317).

Glyphosate is a herbicide widely used to kill weeds both in agricultural and non-agricultural landscapes. Its reproductive toxicity is related to the inhibition of a StAR protein and an aromatase enzyme, which causes an in vitro reduction in testosterone and estradiol synthesis. Studies in vivo about this herbicide effects in prepubertal Wistar rats reproductive development were not performed at this moment. Evaluations included the progression of puberty, body development, the hormonal production of testosterone, estradiol and corticosterone, and the morphology of the testis. Results showed that the herbicide (1) significantly changed the progression of puberty in a dose-dependent manner; (2) reduced the testosterone production, in semineferous tubules’ morphology, decreased significantly the epithelium height (P < 0.001; control = 85.8 ± 2.8 μm; 5 mg/kg = 71.9 ± 5.3 μm; 50 mg/kg = 69.1 ± 1.7 μm; 250 mg/kg = 65.2 ± 1.3 μm) and increased the luminal diameter (P < 0.01; control = 94.0 ± 5.7 μm; 5 mg/kg = 116.6 ± 6.6 μm; 50 mg/kg = 114.3 ± 3.1 μm; 250 mg/kg = 130.3 ± 4.8 μm); (4) no difference in tubular diameter was observed; and (5) relative to the controls, no differences in serum corticosterone or estradiol levels were detected, but the concentrations of testosterone serum were lower in all treated groups (P < 0.001; control = 154.5 ± 12.9 ng/dL; 5 mg/kg = 108.6 ± 19.6 ng/dL; 50 mg/dL = 84.5 ± 12.2 ng/dL; 250 mg/kg = 76.9 ± 14.2 ng/dL). These results suggest that commercial formulation of glyphosate is a potent endocrine disruptor in vivo, causing disturbances in the reproductive development of rats when the exposure was performed during the puberty period.

Keywords: Glyphosate; Roundup; Endocrine disruption; Prepubertal exposure; Testosterone; Testicular morphology

Induction of GST-P-positive proliferative lesions facilitating lipid peroxidation with possible involvement of transferrin receptor up-regulation and ceruloplasmin down-regulation from the early stage of liver tumor promotion in rats by Sayaka Mizukami; Ryohei Ichimura; Sayaka Kemmochi; Eriko Taniai; Keisuke Shimamoto; Takumi Ohishi; Miwa Takahashi; Kunitoshi Mitsumori; Makoto Shibutani (pp. 319-331).

To elucidate the role of metal-related molecules in hepatocarcinogenesis, we examined immunolocalization of transferrin receptor (Tfrc), ceruloplasmin (Cp) and metallothionein (MT)-1/2 in relation to liver cell foci positive for glutathione-S-transferase placental form (GST-P) in the early stage of tumor promotion by fenbendazole (FB), phenobarbital, piperonyl butoxide or thioacetamide in a rat two-stage hepatocarcinogenesis model. To estimate the involvement of oxidative stress responses to the promotion, immunolocalization of 4-hydroxy-2-nonenal, malondialdehyde and acrolein was similarly examined. Our findings showed that MT-1/2 immunoreactivity was not associated with the cellular distribution of GST-P and proliferating cell nuclear antigen, suggesting no role of MT-1/2 in hepatocarcinogenesis. We also found enhanced expression of Tfrc after treatment with strong tumor-promoting chemicals. With regard to Cp, the population showing down-regulation was increased in the GST-P-positive foci in relation to tumor promotion. Up-regulation of Tfrc and down-regulation of Cp was maintained in GST-P-positive neoplastic lesions induced after long-term promotion with FB, suggesting the expression changes occurring downstream of the signaling pathway involved in the formation of GST-P-positive lesions. Furthermore, enhanced accumulation of lipid peroxidation end products was observed in the GST-P-positive foci by promotion. Post-initiation treatment with peroxisome proliferator-activated receptor α agonists did not enhance any such distribution changes in GST-P-negative foci. The results thus suggest that facilitation of lipid peroxidation is involved in the induction of GST-P-positive lesions by tumor promotion from an early stage, and up-regulation of Tfrc and down-regulation of Cp may be a signature of enhanced oxidative cellular stress in these lesions.

Keywords: Transferrin receptor (Tfrc); Ceruloplasmin (Cp); Metallothionein (MT)-1/2; Rat hepatocarcinogenesis; Tumor promotion; Oxidative stress

Is computational toxicology withering on the vine? by R. D. Combes (pp. 333-336).

The difficulties of developing predictive computational models of toxicity are discussed in relation to their internal and external validation, the selection of relevant physicochemical data and the need to characterise the structure–activity relationship landscapes obtained with training sets of chemicals by using recently published methods. It is concluded that the developers of in silico systems for toxicity prediction should apply such methods to ensure adequate and continuous sampling of chemical space, especially when external validation cannot be undertaken due to lack of sufficient test chemicals not used in the training set. This, combined with discriminate selection of molecular descriptors, and the use of reliable toxicity data, should improve model predictivity.

Keywords: Computational toxicity; In silico methods; Toxicity prediction; Structure activity landscapes; Validation

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Archives of Toxicology (v.84, #4)