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Archives of Toxicology (v.82, #3)

Arsenic-induced oxidative myocardial injury: protective role of arjunolic acid by Prasenjit Manna; Mahua Sinha; Parames C. Sil (pp. 137-149).

Arsenic, one of the most harmful metalloids, is ubiquitous in the environment. The present study has been carried out to investigate the protective role of a triterpenoid saponin, arjunolic acid (AA) against arsenic-induced cardiac oxidative damage. In the study, NaAsO₂ was chosen as the source of arsenic. The free radical scavenging activity and the effect of AA on the intracellular antioxidant power were determined from its 2,2-diphenyl-1-picryl hydrazyl radical scavenging ability and ferric reducing/antioxidant power assay, respectively. Oral administration of NaAsO₂at a dose of 10 mg/kg body weight for 2 days caused significant accumulation of arsenic in cardiac tissues of the experimental mice in association with the reduction in cardiac antioxidant enzymes activities, namely superoxide dismutase, catalase, glutathione-S-transferase, glutathione reductase and glutathione peroxidase. Arsenic intoxication also decreased the cardiac glutathione (GSH) and total thiol contents and increased the levels of oxidized glutathione (GSSG), lipid peroxidation end products and protein carbonyl content. Treatment with AA at a dose of 20 mg/kg body weight for 4 days prior to NaAsO₂ intoxication protected the cardiac tissue from arsenic-induced oxidative impairment. In addition to oxidative stress, arsenic administration increased total cholesterol level as well as the reduced high-density lipoprotein cholesterol level in the sera of the experimental mice. AA pretreatment, however, could prevent this hyperlipidemia. Histological studies on the ultrastructural changes in cardiac tissue supported the protective activity of AA also. Combining all, results suggest that AA could protect cardiac tissues against arsenic-induced oxidative stress probably due to its antioxidant property.

Keywords: NaAsO₂ ; Arsenic poisoning; Cardiac hyperlipidemia and oxidative stress; Arjunolic acid; Antioxidant; Cardioprotection

Tissue distribution and toxicity of intravenously administered titanium dioxide nanoparticles in rats by Eric Fabian; Robert Landsiedel; Lan Ma-Hock; Karin Wiench; Wendel Wohlleben; Ben van Ravenzwaay (pp. 151-157).

The tissue distribution and toxicity of intravenously administered nanoparticles of titanium dioxide (TiO₂) (>10 wt.% at <100 nm size) were investigated because of the fundamental importance to obtain information on the kinetics of this widely used nanoparticle in a situation of 100% bioavailability. Male Wistar rats were treated with single intravenous injections of a suspension of TiO₂ in serum (5 mg/kg body weight), and the tissue content of TiO₂ was determined 1, 14, and 28 days later. Biochemical parameters and antigens in serum were also assessed to determine potential pathological changes. The health and behavior of the animals were normal throughout the study. There were no detectable levels of TiO₂ in blood cells, plasma, brain, or lymph nodes. The TiO₂ levels were highest in the liver, followed in decreasing order by the levels in the spleen, lung, and kidney, and highest on day 1 in all organs. TiO₂ levels were retained in the liver for 28 days, there was a slight decrease in TiO₂ levels from day 1 to days 14 and 28 in the spleen, and a return to control levels by day 14 in the lung and kidney. There were no changes in the cytokines and enzymes measured in blood samples, indicating that there was no detectable inflammatory response or organ toxicity. Overall, rats exposed to TiO₂nanoparticles by a route that allows immediate systemic availability showed expected tissue distribution, no obvious toxic health effects, no immune response, and no change in organ function. Therefore, even with 100% bioavailability of the 5 mg/kg TiO₂ dose afforded by the intravenous route of administration, there were no remarkable toxic effects evident in the experimental animals. These results indicate that TiO₂ nanoparticles could be used safely in low doses.

Keywords: Nano-TiO2; Tissue distribution; Adverse effects; Toxicokinetics; Cytokines

Species differences in 3-methylsulphonyl-DDE bioactivation by adrenocortical tissue by Veronica Lindström; Ingvar Brandt; Örjan Lindhe (pp. 159-163).

The CYP11B1-activated adrenocortical toxicant 3-methylsulphonyl-DDE (3-MeSO₂-DDE) is proposed as a lead compound for an improved chemotherapy for adrenocortical carcinoma. We compared the binding of 3-MeSO₂-[¹⁴C]DDE in the adrenal cortex of four rodent species; hamster, guinea pig, mouse and rat, using a precision-cut adrenal slice culture system ex vivo. Localization and quantification of the bound radioactivity were carried out using light microscopy autoradiography and radioluminography. The results revealed major species differences since 3-MeSO₂-[¹⁴C]DDE was extensively bound to the hamster adrenal tissue while the guinea pig adrenals were devoid of binding. A high binding in mouse adrenal cortex was confirmed while binding in rat adrenal cortex was very weak. The results support previous observations that metabolic activation of 3-MeSO₂-DDE is highly species dependent. Since CYP11B1 could be expressed in tissues other than the adrenal cortex, final toxicological characterization should be carried out in a species that can bioactivate this compound.

Keywords: 3-MeSO₂-DDE; Hamster; Guinea pig; CYP450; Irreversible binding; Adrenal; Tissue-slice

n-Hexane toxicity in Jurkat T-cells is mediated by reactive oxygen species by Catherine McDermott; Maria Hutch O’Donoghue; James J. A. Heffron (pp. 165-171).

Here we assess the role of reactive oxygen species (ROS) formation in the manifestation of n-hexane toxicity in Jurkat T-cells and the chemo-protective potential of the antioxidants epigallocatechin-3-gallate (EGCG) and thymoquinone (TQ) against n-hexane toxicity in vitro. n-Hexane is an important industrial solvent and ambient air pollutant. Subchronic exposure to n-hexane results in a concentration-dependent increase in ROS formation with a corresponding decrease in Jurkat T-cell proliferation. Results from time–course studies indicate that ROS formation plays a causal role in n-hexane induced alterations in Jurkat T-cell proliferation and membrane integrity. Treatment of cells with EGCG, at a concentration reached in plasma, reduced the ROS formation caused by exposure to n-hexane and inhibited the decrease in cell proliferation. Similar effects were obtained with TQ. Both EGCG and TQ significantly reduced n-hexane-induced LDH leakage to control levels. The combined results show that oxidative stress plays a role in the development of n-hexane toxicity.

Keywords: n-Hexane; Reactive oxygen species; Antioxidants; Membrane permeability

Chromosomal instability in bladder cancer by Andrea R. Florl; Wolfgang A. Schulz (pp. 173-182).

Chromosomal instability (CIN) distinguishes invasive urothelial carcinomas from less malignant papillary subtypes. Recent results implicate checkpoint dysfunction as a crucial factor underlying the emergence of aneuploidy in urothelial carcinogenesis. It may moreover contribute to DNA repair defects. Therefore, defects in cell cycle regulation, p53 function, and checkpoint signaling initially caused by carcinogens in the urothelium could ultimately elicit CIN. Among several mechanisms contributing to aneuploidy, breakage-fusion-bridge (BFB) cycles initiated by defective telomeres may be particularly relevant. The mechanism generating large interstitial deletions, prominently at 9p21, appears to be distinct. New experimental approaches are required to address important unresolved questions such as the precise relationship between telomere erosion and telomerase activation, the influence of checkpoint defects on DNA double-strand repair by non-homologous and homomologous recombination repair systems, and the mechanism responsible for megabase-sized interstitial deletions.

Keywords: Carcinogen; Interstitial deletion; Telomere; DNA double-strand break; DNA repair; Checkpoint signaling

The inhibitory effects of garlic and Panax ginseng extract standardized with ginsenoside Rg3 on the genotoxicity, biochemical, and histological changes induced by ethylenediaminetetraacetic acid in male rats by Wagdy K. B. Khalil; Kawkab A. Ahmed; Myung H. Park; Yong T. Kim; Hyung H. Park; Mosaad A. Abdel-Wahhab (pp. 183-195).

Ethylenediaminetetraacetic acid (EDTA) is widely used in food and other industries to sequester metal ions and to prevent their disadvantageous effects. The objective of the current study was to evaluate the protective effect of Panax ginseng extract standardized with ginsenoside Rg3 (ginsenoside Rg3 content was 3.6% w/w, i.e., 36 μg/mg P. ginseng extract) and garlic against EDTA-induced biochemical, genotoxic, and histological changes in rats. Forty male rats were divided into eight treatment groups and treated for 7 days as follows: the control group, the group treated with EDTA (20 mg/kg b.w) and the groups treated with P. ginseng extract (20 mg/kg b.w), garlic (5 mg/kg b.w), P. ginseng plus garlic alone or in combination with EDTA. In vivo bone marrow micronucleus test and random amplified polymorphism DNA-PCR (RAPD-PCR) method were performed to assess the antigenotoxic effect of both protective agents. The results indicated that EDTA administration caused a significant decrease in the serum biochemical parameters and antioxidant enzymes activity. The administration also increased lipid peroxidation and the incidence of micronucleated polychromatic erythrocytes (MnPCEs), caused appearance of some changes in polymorphism band patterns, and induced different histopathological lesions in the livers, kidneys, and testis. Treatment with P. ginseng, garlic alone or plus EDTA significantly improved all the tested parameters. Moreover, P. ginseng extract was found to be more effective than garlic in restoring the parameters that were altered by EDTA.

Keywords: Ethylenediaminetetraacetic acid; Panax ginseng ; Garlic; Genotoxicity; Protection

Ethanol, the forgotten artifact in cell culture by Helena Pontes; Márcia Carvalho; Paula Guedes de Pinho; Helena Carmo; Fernando Remião; Félix Carvalho; Maria Lourdes Bastos (pp. 197-198).

Environmental toxicology in North Rhine-Westphalia, Germany: interdisciplinary research activities in toxicology, statistics, hygiene and medicine by Klaus Golka; Katja Ickstadt; Michael Wilhelm (pp. 199-202).

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Archives of Toxicology (v.82, #3)