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Archives of Toxicology (v.81, #9)
Bias in toxicology by Birgitte Wandall; Sven Ove Hansson; Christina Rudén (pp. 605-617).
The potential for bias, i.e., influences that cause results to deviate systematically from the truth is substantial both in toxicological research and in the performance of standardized toxicological testing. In this contribution, major potential sources of bias in toxicological research and testing are identified. Due to the lack of empirical studies of bias in toxicology, very little is known about its prevalence and impact. Areas to consider for such studies are pointed out, and it is suggested that such investigations should be given priority.
Keywords: Bias; Systematic errors; Toxicity testing; Chemicals control; Guideline tests
Arsenite induced oxidative damage in mouse liver is associated with increased cytokeratin 18 expression by M. E. Gonsebatt; L. M. Del Razo; M. A. Cerbon; O. Zúñiga; L. C. Sanchez-Peña; P. Ramírez (pp. 619-626).
Cytokeratins (CK) constitute a family of cytoskeletal intermediate filament proteins that are typically expressed in epithelial cells. An abnormal structure and function are effects that are clearly related to liver diseases as non-alcoholic steatohepatitis, cirrhosis and hepatocellular carcinoma. We have previously observed that sodium arsenite (SA) induced the synthesis of CK18 protein and promotes a dose-related disruption of cytoplasmic CK18 filaments in a human hepatic cell line. Both abnormal gene expression and disturbance of structural organization are toxic effects that are likely to cause liver disease by interfering with normal hepatocyte function. To investigate if a disruption in the CK18 expression pattern is associated with arsenite liver damage, we investigated CK18 mRNA and protein levels in liver slices treated with low levels of SA. Organotypic cultures were incubated with 0.01, 1 and 10 μM of SA in the absence and presence of N-acetyl cysteine (NAC). Cell viability and inorganic arsenic metabolism were determined. Increased expression of CK18 was observed after exposure to SA. The addition of NAC impeded the oxidative effects of SA exposure, decreasing the production of thiobarbituric acid-reactive substances and significantly diminishing the up regulation of CK18 mRNA and protein. Liver arsenic levels correlated with increased levels of mRNA. Mice treated with intragastric single doses of 2.5 and 5 mg/kg of SA showed an increased expression of CK18. Results suggest that CK18 expression may be a sensible early biomarker of oxidative stress and damage induced by arsenite in vitro and in vivo. Then, during SA exposure, altered CK expression may compromise liver function.
Keywords: Arsenic; Cytokeratin 18; Oxidative damage; N-acetyl cysteine
Phosphylated tyrosine in albumin as a biomarker of exposure to organophosphorus nerve agents by Nichola H. Williams; John M. Harrison; Robert W. Read; Robin M. Black (pp. 627-639).
The organophosphorus nerve agents sarin, soman, cyclosarin and tabun phosphylate a tyrosine residue on albumin in human blood. These adducts may offer relatively long-lived biological markers of nerve agent exposure that do not ‘age’ rapidly, and which are not degraded by therapy with oximes. Sensitive methods for the detection of these adducts have been developed using liquid chromatography-tandem mass spectrometry. Adducts of all four nerve agents were detected in the blood of exposed guinea pigs being used in studies to improve medical countermeasures. The tyrosine adducts with soman and tabun were detected in guinea pigs receiving therapy 7 days following subcutaneous administration of five times the LD50 dose of the respective nerve agent. VX also forms a tyrosine adduct in human blood in vitro but only at high concentrations.
Keywords: Biomarkers; Nerve agents; Phosphylated tyrosine; Albumin
Microsomal epoxide hydrolase genotype and risk of myocardial infarction by Marilyn C. Cornelis; Ahmed El-Sohemy; Hannia Campos (pp. 641-645).
DNA damage caused by mutagens found in tobacco smoke may contribute to the development of coronary heart disease (CHD). Microsomal epoxide hydrolase (EPHX1) is involved in the metabolism of tobacco smoke mutagens and an amino acid substitution (H139R) in exon 4 of the EPHX1 gene is associated with increased enzyme activity. The objective of this study was to investigate the effect of EPHX1 genotype on risk of myocardial infarction (MI) and to determine whether smoking interacts with genotype to modify risk. Cases (n = 2,022) with a first acute non-fatal MI and population-based controls (n = 2,022) living in Costa Rica, matched for age, sex and area of residence were genotyped by RFLP-PCR. Smoking status was determined by questionnaire. The frequency of the R139 allele was 17% for both cases and controls. EPHX1 genotype was not associated with risk of MI, regardless of smoking status. Compared to individuals with the HH genotype, the multivariate adjusted odds ratio (95% confidence interval) for risk of MI was 0.95 (0.81–1.11) for individuals with the HR genotype and 1.18 (0.79–1.76) for those with the RR genotype. These results suggest that EPHX1 does not play a significant role in the development of CHD.
Keywords: Microsomal epoxide hydrolase; DNA damage; Genotype; Smoking; Myocardial infarction
Gene expression analyses of the liver in rats treated with oxfendazole by Yasuaki Dewa; Jihei Nishimura; Masako Muguruma; Sayaka Matsumoto; Miwa Takahashi; Meilan Jin; Kunitoshi Mitsumori (pp. 647-654).
The effect of oxfendazole (OX), a benzimidazole anthelmintic, on hepatic gene expression was investigated in the liver of rats as a preliminary study to elucidate the possible mechanism of its non-genotoxic hepatocarcinogenesis. The liver from a male F344/N rat given a diet containing 500 ppm of OX for 3 weeks was examined by global gene expression analysis in comparison with an untreated rat. Microarray analysis revealed that phase I and phase II detoxifying enzymes were up-regulated in an OX-treated rat. In addition to these genes, the expressions of several upregulated genes related to xenobiotic metabolism and oxidative stress [e.g. Cyp1a1; NAD(P)H dehydrogenase, quinone 1 (Nqo1); glutathione peroxidase 2 (Gpx2); glutathione S-transferase Yc2 subunit (Yc2)], were confirmed by real-time reverse transcription polymerase chain reaction (RT-PCR). Furthermore, rats were administered 500 or 1,000 ppm of OX for 9 weeks, and the effect of OX on oxidative stress responses was evaluated by real-time RT-PCR along with conventional toxicological assays, including lipid peroxidation (thiobarbituric acid-reactive substance; TBARS). A longer treatment period and/or a higher dose of OX tended to increase the gene expressions of not only phase I (Cyp1a1 and Cyp1a2) but also phase II (Nqo1, Gpx2, Yc2, and Akr7a3) drug metabolizing enzymes. Toxicological parameters, such as TBARS, serum aspartate aminotransferase (AST), and serum alkaline phosphatase (ALP), showed slight but significant increases after treatment with OX for 9 weeks. These results indicate that OX elicits adaptive responses against oxidative stress in the liver and suggest that the imbalance in redox status might be one of the factors triggering the initial step of OX-induced non-genotoxic carcinogenesis in the liver of rats.
Keywords: Oxfendazole; Cytochrome P450 induction; Oxidative stress; Rat
Protective effects of ibuprofen on testicular torsion/detorsion-induced ischemia/reperfusion injury in rats by Dikmen Dokmeci; Mehmet Kanter; Mustafa Inan; Nurettin Aydogdu; Umit Nusret Basaran; Omer Yalcin; Fatma Nesrin Turan (pp. 655-663).
The aim of this study was to investigate the protective effect of ibuprofen on testicular torsion/detorsion-induced ischemia/reperfusion (I/R) injury. A total of 48 prepubertal male Wistar albino rats were divided into two models: early and late orchiectomy. Testicular torsion was created by rotating the right testis 720° in a clockwise direction. The ischemia period was 5 h and orchiectomy was performed after 5 h of detorsion in the early orchiectomy model (EOM). In the late orchiectomy model (LOM), the ischemia period was 5 h and orchiectomy was performed after 7 days of detorsion. In the EOM, ibuprofen (70 mg/kg, po) was administrated only once, 40 min prior to detorsion. In the LOM, ibuprofen (70 mg/kg, po) was administered 40 min before detorsion, once daily for 7 days. Bilateral orchiectomy was performed in all groups to measure the tissue levels of malondialdehyde (MDA) and to microscopically investigate light and electrons. The presence of endothelial nitric oxide synthase (eNOS) activity was shown with immunohistochemical studies. Spermatogenesis and mean seminiferous tubule diameter (MSTD) were significantly decreased in ipsilateral and contralateral testis when both early and late I/R groups were compared to the sham groups. Furthermore, ibuprofen-treated animals showed an improved histological appearance in both models of testicular torsion. Ibuprofen treatment prevented lipid peroxidation resulting in decreased MDA accumulation in the testes of both models. After I/R, eNOS immunoreactivity was increased in the testicular tissues. Ibuprofen treatment decreased eNOS immunoreactivity in the germ cells of the tubules in the contralateral testes, but intense eNOS immunoreactivity was shown in the ipsilateral testes of the LOM. Electron microscopy of the testes of rats demonstrated that ibuprofen pretreatment was particularly effective in preventing the mitochondrial degeneration in both Sertoli and spermatid cells in the LOM. Because of its anti-inflammatory and antioxidant effects, ibuprofen pretreatment may have protective effects in the experimental testicular torsion/detorsion model in rats.
Keywords: Ibuprofen; Testicular torsion; Ischemia/reperfusion; Antioxidant; eNOS
Pre- and postnatal toxicity of the commercial glyphosate formulation in Wistar rats by Eliane Dallegrave; Fabiana D. Mantese; Rosemari T. Oliveira; Anderson J. M. Andrade; Paulo R. Dalsenter; Augusto Langeloh (pp. 665-673).
Glyphosate is the active ingredient and polyoxyethyleneamine is the surfactant present in the herbicide Roundup® formulation commercialized in Brazil. The aim of this study was to assess the reproductive effects of glyphosate-Roundup® on male and female offspring of Wistar rats exposed during pregnancy and lactation. Dams were treated orally with water or 50, 150 or 450 mg/kg glyphosate during pregnancy (21–23 days) and lactation (21 days). These doses do not correspond to human exposure levels. The results showed that glyphosate-Roundup® did not induce maternal toxicity but induced adverse reproductive effects on male offspring rats: a decrease in sperm number per epididymis tail and in daily sperm production during adulthood, an increase in the percentage of abnormal sperms and a dose-related decrease in the serum testosterone level at puberty, and signs of individual spermatid degeneration during both periods. There was only a vaginal canal-opening delay in the exposed female offspring. These findings suggest that in utero and lactational exposure to glyphosate-Roundup® may induce significant adverse effects on the reproductive system of male Wistar rats at puberty and during adulthood.
Keywords: Male reproductive effects; Glyphosate; Polyoxyethyleneamine; Roundup® ; Wistar rats