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Archives of Toxicology (v.82, #2)

Downregulation of arginase II and renal apoptosis by inorganic mercury: overexpression of arginase II reduces its apoptosis by Hironori Kanda; Makoto Kikushima; Shino Homma-Takeda; Daigo Sumi; Akiko Endo; Takashi Toyama; Nobuhiko Miura; Akira Naganuma; Yoshito Kumagai (pp. 67-73).

Inorganic mercury is a toxic metal that accumulates in the proximal tubules of the kidney, causing apoptosis. Arginase II is known to inhibit apoptosis, but its role in the renal apoptosis caused by inorganic mercury is poorly understood. In the present study, we examined the involvement of arginase II in inorganic mercury-dependent apoptosis. A single exposure to mercuric chloride (HgCl₂, 1 mg/kg) in rats resulted in a dramatic time-dependent reduction in the activity of arginase II in the kidney; for example, the activity at 48 h after exposure was 31% of the control level. The decrease in arginase II activity was due to a decrease in the protein level, not to a reduction in gene expression or to direct inhibition of the activity itself. More interestingly, diminished arginase II activity was well correlated with the induction of apoptosis as evaluated by renal DNA fragmentation (r = 0.99). Overexpression of arginase II in LLC-PK₁ cells blocked cell death during exposure to inorganic mercury. These results suggest that inorganic mercury causes a reduction in protein levels of arginase II, and that impaired arginase II activity is, at least in part, associated with the apoptotic cell damage caused by this heavy metal.

Keywords: Inorganic mercury; Arginase II; Apoptosis; Proximal tubule; Accumulation

Induction of CYP1A1 in rat liver after ingestion of mussels contaminated by Erika fuel oils by Sylvie Chaty; François Rodius; Marie-Claire Lanhers; Daniel Burnel; Paule Vasseur (pp. 75-80).

Polycyclic aromatic hydrocarbons (PAH) are known to be specific inducers of CYP1A1 expression in vertebrates. CYP1A1 induction has been widely studied in mammal cell cultures or in vivo, in conditions of exposure to single PAH chemicals. Here, we studied the possible transfer of PAH to rats via the food chain in environmentally-relevant conditions. Rats were fed for 2 days with PAH-contaminated mussels sampled on coasts polluted by the Erika oil-tanker wreck. CYP1A1 expression was investigated by measuring mRNA levels and EROD enzymatic activity over the 84 h following the last ingestion. CYP1A1 expression in treated rats was compared to controls fed with mussels free from PAH contamination. The results showed that ingestion of PAH-contaminated mussels induced CYP1A1 mRNA and EROD activity. Increase of transcriptional level and of EROD activity was transient with a peak within 12 h and a return to basal levels within 36 h.

Keywords: Polycyclic aromatic hydrocarbons; Trophic chain; CYP1A1; EROD; RT-PCR

Induction of apoptosis in rabbit oral mucosa by 1.23% acidulated phosphate fluoride gel by Chia-Ling Tsai; Jui-Wei Lin; Hsi-Kung Kuo; Ming-Hong Tai; Yi-Chen Wu; Chih-Rong Shyr; Pei-Chang Wu (pp. 81-87).

Applying of 1.23% acidulated phosphate fluoride (APF) gel to prevent caries in children has become very popular among dental practitioners. When applied to dental surfaces, however, APF often comes into contact with the oral mucosa. Due to the possibility of local toxic effect, we aimed to investigate the effects of APF on rabbit oral mucosa. Rabbits were sacrificed 1, 5 and 8 days after topical application of 1.23% APF on the oral buccal mucosa for 4 min. The nuclei with DNA strand breaks of the basal epithelial cell layer was estimated using terminal-deoxynucleotidyl-transferase-mediated deoxyuridine-triphospate-biotin nick end labeling (TUNEL). Epithelial cells were analyzed by transmission electron microscopy. The number of basal epithelial cells with DNA strand breaks increased with time in rabbits treated with 1.23% APF. Transmission electron microscopy revealed evidence of apoptosis in the parabasal and basal epithelial cells showed, with loss of cell-to-cell contact, nuclear chromatin condensation and apoptotic bodies. The results demonstrate in vivo that 1.23% APF induced apoptosis in basal epithelial cells of rabbit oral mucosa. It suggests the possible necessity to prevent oral mucosa contact when APF applied on teeth.

Keywords: Apoptosis; Oral mucosa; Keratinocytes; Acidulated phosphate fluoride; Bcl-2; Bax

Detection of early signals of hepatotoxicity by gene expression profiling studies with cultures of metabolically competent human hepatocytes by Thomas Thum; Jürgen Borlak (pp. 89-101).

Xenobiotic induced liver injury is a leading cause for drug withdrawal and toxicogenomics may help to identify molecular causes. Here we report studies with cultures of human hepatocytes to detect early responses of liver toxicity upon treatment with the hepatotoxin Aroclor 1254. We studied transcript abundance of 302 genes with biological functions in detoxification, cell proliferation, tumor development, stress response, signal transduction, apoptosis and cell cycle regulation. More than 40 genes were regulated by at least twofold change, the majority coding for xenobiotic defense. In the case of CYP monooxygenases induction of coded protein was confirmed by Western immunoblotting whereas catalytic activities were determined by assaying for testosterone hydroxylase activity. There was good agreement between gene and protein expression and enzyme activity of CYP monooxygenases. In conclusion, xenobiotic induced hepatotoxicity may arise via several mechanisms and gene expression profiling helps to pinpoint location and pathways perturbed by drugs and chemicals.

Keywords: Hepatotoxicity; Toxicogenomics; Gene expression

Quantitative analysis of liver GST-P foci promoted by a chemical mixture of hexachlorobenzene and PCB 126: implication of size-dependent cellular growth kinetics by Yasong Lu; Manupat Lohitnavy; Micaela Reddy; Ornrat Lohitnavy; Elizabeth Eickman; Amanda Ashley; Lisa Gerjevic; Yihua Xu; Rory B. Conolly; Raymond S. H. Yang (pp. 103-116).

The objectives of this study were twofold: (1) evaluating the carcinogenic potential of the mixture of two persistent environmental pollutants, hexachlorobenzene (HCB) and 3,3′,4,4′,5-pentachlorobiphenyl (PCB 126), in an initiation-promotion bioassay involving the development of π glutathione S-transferase (GST-P) liver foci, and (2) analyzing the GST-P foci data using a biologically-based computer model (i.e., clonal growth model) with an emphasis on the effect of focal size on the growth kinetics of initiated cells. The 8-week bioassay involved a series of treatments of initiator, two-thirds partial hepatectomy, and daily oral gavage of the mixture of two doses in male F344 rats. The mixture treatment significantly increased liver GST-P foci development, indicating carcinogenic potential of this mixture. Our clonal growth model was developed to simulate the appearance and development of initiated GST-P cells in the liver over time. In the model, the initiated cells were partitioned into two subpopulations with the same division rate but different death rates. Each subpopulation was further categorized into single cells, mini- (2–11 cells), medium- (12–399 cells), and large-foci (>399 cells) with different growth kinetics. Our modeling suggested that the growth of GST-P foci is size-dependent; in general, the larger the foci, the higher the rate constants of division and death. In addition, the modeling implied that the two doses promoted foci development in different manners even though the experimental foci data appeared to be similar between the two doses. This study further illustrated how clonal growth modeling may facilitate our understanding in chemical carcinogenic process.

Keywords: Hexachlorobenzene; PCB126; Chemical mixture; Clonal growth model; Liver GST-P foci

Protective effects of ginsenoside Rg₃ against cyclophosphamide-induced DNA damage and cell apoptosis in mice by Qiu Hua Zhang; Chun Fu Wu; Lian Duan; Jing Yu Yang (pp. 117-123).

Despite the significant anti-tumor activities, cyclophosphamide (CP) also shows cytotoxicity to normal cells. In order to explore the protective effects of drugs against CP-induced adverse effects, 20(S)-ginsenoside Rg₃ was tested for its possibly protective activities on CP-induced DNA damage and cell apoptosis in mouse bone marrow cells or peripheral lymphocyte cells. In the current study, the alkaline single cell gel electrophoresis (comet assay), flow cytometry assay with annexin V-FITC/PI and AO/EB staining assay were employed to measure DNA strand breakage and cell apoptosis, respectively. The activities of SOD and GPx and the contents of MDA were also tested by the various colormetric methods. The results showed that CP at a dose of 100 mg/kg, i.p. significantly caused DNA damages in both mouse bone marrow cells and peripheral lymphocyte cells, and markedly inhibited the activities of GPx and SOD and increased MDA contents in mouse blood. Moreover, CP at a dose of 200 mg/kg, i.p. triggered apoptosis in mouse bone marrow cells. On the other hand, 20(S)-ginsenoside Rg₃ orally administered at a dose of 20 mg/kg to the animals once a day for 2 days significantly inhibited CP-induced DNA damages in mouse bone marrow cells and peripheral lymphocyte cells, decrease the apoptotic numbers of bone marrow cells, antagonized the reduction of the activities of SOD and GPx, and the increase in MDA contents. In conclusion, 20(S)-ginsenoside Rg₃ showed the significant protective effects on CP-induced cell DNA damage and apoptosis. These effects might be partially attributed to its protective actions against CP-induced oxidative stress.

Keywords: 20(S)-Ginsenoside Rg₃ ; Cyclophosphamide; DNA damage; Apoptosis; Anti-oxidant enzyme; MDA

Hematological effects of four ethylene glycol monoalkyl ethers in short-term repeated exposure in rats by Andrzej Starek; Wieslaw Szymczak; Lidia Zapor (pp. 125-136).

This study was carried out to compare the hematological effects of 2-methoxyethanol (ME), 2-ethoxyethanol (EE), 2-isopropoxyethanol (IPE), and 2-butoxyethanol (BE) in short-term studies in rats. Male rats were subcutaneously treated with ME or EE at a dosage of 0, 1.25, 2.5 and 5.0 mM/kg in saline, 5 days per week, for 4 weeks. Other rats were exposed to IPE or BE at doses of 0, 0.25, 0.5, 0.75 and 1.25 mM/kg in the same manner. Administration of each chemical, except of ME, resulted in a time- and dose-dependent swelling of erythrocytes as evidenced by an increase in mean corpuscular volume (MCV). Subsequently, red blood cells (RBC), packed cell volumes (PCV), hemoglobin concentration (HGB), and mean cell hemoglobin concentration (MCHC) decreased. Furthermore, an increase in mean cell hemoglobin (MCH) and reticulocyte counts was observed. The onset of hemolysis induced by EE, IPE or BE was faster than after ME administration. While in rats exposed to ME hematological changes were strongly pronounced and progressively increased with exposure time beginning from the day 11, those in animals treated with EE were rather persisted at low constant level for all exposure period. In contrast, the rats exposed to IPE and BE demonstrated the dramatic hematological changes more pronounced in case of BE than IPE at the beginning of exposure (on day 4). Despite of exposure duration, these changes were regressed, although the decrease in RBC and MCHC and the increase in MCV and MCH in rats treated with highest doses of both compound (0.5, 0.75, and 1.25 mM/kg) were more persistent, probably due to selective hemolysis of the aged erythrocytes. In addition, significant leukopenia due to reduction of lymphocytes in rats exposed to ME was observed. In summary, this study demonstrated no tolerance to ME- and EE-induced intravascular hemolysis developed under these experimental conditions. On the contrary, tolerance to IPE- and BE-induced hemolysis in rats exposed to these compounds was prompted.

Keywords: Ethylene glycol alkyl ethers; Short-term exposure; Hematotoxicity; Hemolysis; Tolerance

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Archives of Toxicology (v.82, #2)

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Archives of Toxicology (v.82, #2)