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Archives of Toxicology (v.84, #9)
Deoxynivalenol: mechanisms of action, human exposure, and toxicological relevance by James J. Pestka (pp. 663-679).
The trichothecene mycotoxin deoxynivalenol (DON) is produced in wheat, barley and corn following infestation by the fungus Fusarium in the field and during storage. Colloquially known as “vomitoxin” because of its emetic effects in pigs, DON has been associated with human gastroenteritis. Since DON is commonly detected in cereal foods, there are significant questions regarding the risks of acute poisoning and chronic effects posed to persons ingesting this trichothecene. A further challenge is how to best manage perceived risks without rendering critical food staples unavailable to an ever-expanding world population. In experimental animal models, acute DON poisoning causes emesis, whereas chronic low-dose exposure elicits anorexia, growth retardation, immunotoxicity as well as impaired reproduction and development resulting from maternal toxicity. Pathophysiologic effects associated with DON include altered neuroendocrine signaling, proinflammatory gene induction, disruption of the growth hormone axis, and altered gut integrity. At the cellular level, DON induces ribotoxic stress thereby disrupting macromolecule synthesis, cell signaling, differentiation, proliferation, and death. There is a need to better understand the mechanistic linkages between these early dose-dependent molecular effects and relevant pathological sequelae. Epidemiological studies are needed to determine if relationships exist between consumption of high DON levels and incidence of both gastroenteritis and potential chronic diseases. From the perspective of human health translation, a particularly exciting development is the availability of biomarkers of exposure (e.g. DON glucuronide) and effect (e.g. IGF1) now make it possible to study the relationship between DON consumption and growth retardation in susceptible human populations such as children and vegetarians. Ultimately, a fusion of basic and translational research is needed to validate or refine existing risk assessments and regulatory standards for this common mycotoxin.
Keywords: Mycotoxin; Trichothecene; Gastroenteritis; Fungus; Fusarium
Chronic oral LOAEL prediction by using a commercially available computational QSAR tool by Bernd Rupp; Klaus E. Appel; Ursula Gundert-Remy (pp. 681-688).
In the absence of toxicological data, as it is the case for, e.g. naturally occurring substances and chemicals underlying the new European chemicals legislation, distinct tools to derive quantitative toxicological data are of particular interest with regard to risk assessment of substances humans are repeatedly exposed. The software package TOPKAT 6.2 version 3.1 (Accelrys Inc., San Diego, USA) is a commercially available tool containing a (sub)chronic oral low observed adverse level (LOAEL) prediction model constructed by using structures and LOAELs of 393 chemicals contained in publicly accessible data banks. Applying this tool, we tested the prediction of (sub)chronic LOAELS for 807 industrial chemicals (purity ≥ 95%) by comparing the predicted values with their experimental LOAELs derived from repeated dose animal experiments performed according to standard guidelines. For 460 chemicals, a prediction could not be performed because of exclusion criteria defined in the system. They had either a lower LD50 as the predicted LOAEL (n = 214) were outside the optimum prediction space which defines the domain of applicability (n = 175), were used in the training data set (n = 155), were not known to the system (n = 50) or fulfilled other criteria for data exclusion (n = 21). Of the remaining 347 substances, 34 to 62% LOAELs were predicted within a range of 1/5 and fivefold of the experimental LOAEL (factor 5), whereas 84 and 99% of the predicted LOAELs were within a range of 1/100 and 100-fold indicating high uncertainty of the prediction. Hence, a refined prediction tool is highly warranted. However, the uncertainty of the prediction could be accounted for if an additional factor of 100 is applied in addition to standard default adjustment factor of 100 which would result in an adjustment factor of 10,000 to be able to use a predicted NOAEL for risk assessment..
Keywords: Prediction of LOAELs; Intelligent testing strategy; REACH; Naturally occurring substances; Repeated exposure
Proteasome inhibitor MG132 reduces growth of As4.1 juxtaglomerular cells via caspase-independent apoptosis by Yong Hwan Han; Woo Hyun Park (pp. 689-698).
The proteasome inhibitor MG132 has been shown to induce apoptotic cell death through the formation of reactive oxygen species (ROS). Here, we investigated the molecular mechanisms of MG132 in As4.1 juxtaglomerular cell death in relation to apoptosis and levels of ROS and glutathione (GSH). MG132 inhibited the growth of As4.1 cells with an IC50 of approximately 0.3–0.4 μM at 48 h and induced cell death, accompanied by the loss of mitochondrial membrane potential (MMP; ∆Ψm), Bcl-2 decrease, activations of caspase-3 and caspase-8, and PARP cleavage. MG132 increased intracellular ROS levels and GSH-depleted cell numbers. However, caspase inhibitors, especially Z-VAD (pan-caspase inhibitor) intensified cell growth inhibition, cell death, MMP (∆Ψm) loss, and Bcl-2 decrease in MG132-treated As4.1 cells. Z-VAD also slightly intensified increases in ROS levels and GSH depletion in MG132-treated As4.1 cells. In conclusion, MG132 reduced the growth of As4.1 cells via caspase-independent apoptosis. The changes in ROS and GSH levels by MG132 and caspase inhibitors partially influenced the growth inhibition and death of As4.1 cells.
Keywords: MG132; Apoptosis; As4.1; ROS; GSH
Involvement of Hsp70, a stress protein, in the resistance of long-term culture of PC12 cells against sodium nitroprusside (SNP)-induced cell death by Carmen Romero; Juana Benedí; Angel Villar; Sagrario Martín-Aragón (pp. 699-708).
Sodium nitroprusside (SNP)-treated PC12 cell line is being used in our laboratory as a cell model of nitric oxide (NO)-mediated damage for in vitro evaluation of potential neuroprotective compounds, thus cell response to SNP must be standardized to gain reproducible data. The NO-donor SNP has been shown to induce cell death at high concentrations in undifferentiated PC12 cells. Differences were found in sensitivity to SNP between cells from short- and long-term cultured cells. After 24-h exposure to 100–500 μM SNP, a decrease of cell viability was observed in both short- (17, 21 and 23rd passages) and long-term cultures (46, 49 and 50th passages), with IC50 values of 312.72 and 462.90 μM, respectively. In cells from early passages, SNP-induced cell death was accompanied by significant increases of LDH leakage, nitrite production, malondialdehyde (MDA) levels, catalase (CAT) activity, cleavage of poly(ADP-ribose)polymerase (PARP) and caspase-3 activation in comparison with those from late passages. Furthermore, untreated and SNP-treated cells from long-term cultures displayed an increase of the stress protein Hsp70 levels when compared with those from short-term cultures. Up-regulated levels of Hsp70 may be associated with cell survival. Therefore, cells may acquire a certain resistance to SNP-induced toxicity associated with an increase in cell passage-dependent Hsp70. The protein Hsp70 might modulate the cellular response to the toxic insult by increasing CAT and GSH-Px activities and decreasing caspase-3 activation. Finally, it is crucial for the standardization of this cell model of neurotoxicity, at least in part, the use of PC12 cells in an optimum and reliable range of passages.
Keywords: Resistance; Short-term culture; Long-term culture; Hsp70; Sodium nitroprusside (SNP); PC12 cell line
Study of the sensitising potential of various textile dyes using a biphasic murine local lymph node assay by V. Ahuja; T. Platzek; H. Fink; A. Sonnenburg; R. Stahlmann (pp. 709-718).
Disperse dyes, which are suitable for dyeing synthetic fibres, are responsible for the great majority of allergic contact dermatitis (ACD) cases to textile dyes. The aim of the present study was to investigate the sensitising potential of various disperse dyes using a biphasic protocol of the local lymph node assay (LLNA). Briefly, mice were shaved over a surface of approximately 2 cm2 on their backs and treated using a “sensitisation-challenge protocol”. The shaved surface was treated once daily on days 1–3 with 50 μl of the test solution. Animals remained untreated on days 4–14. On days 15–17, mice were treated with 25 μl of the test solution on the dorsum of both ears. Mice were killed on day 19 with deep CO2 anaesthesia, the lymph nodes prepared and various end points, such as ear thickness, ear punch weight, lymph node weight, lymph node cell count and the proportion of various lymphocyte subpopulations, were determined by flow cytometry. The results were compared to control group treated with the vehicle alone. Our results showed that almost all of the tested textile dyes caused a significant increase in lymph node cell count and lymph node weight. We also observed an increase in ear thickness and ear punch weight in most of the concentrations tested for various textile dyes. We observed a decrease in CD4+ and CD8+ cells and an increase in CD19+, CD45+ and CD45+/1A+ cells in most of the cases, which is characteristic for allergens. The CD4+/CD69+ cells increased in only few experiments mainly with Disperse Blue 124 and Disperse Blue 106. Based on our results, the disperse dyes could be arranged in four groups on the basis of their sensitising potency in the following decreasing order (in parenthesis: lowest concentration causing a significant increase in lymph node cell number): group 1, strong: Disperse Blue 124 and Disperse Blue 106 (0.003%); group 2, moderate: Disperse Red 1 and Disperse Blue 1 (3%); group 3, weak: Disperse Orange 37 and Disperse Blue 35 (10%); and group 4, very weak: Disperse yellow 3 and Disperse Orange 3 (increase at 30% or no increase at 30%). In conclusion, our study shows that the biphasic LLNA protocol was proficient enough to study the sensitisation potential of tested textile dyes and provides data allowing to discriminate them according to their potency.
Keywords: Textile dye; Sensitisation; Local lymph node assay; Dermatitis
Carcinogenicity study of 3-monochloropropane-1, 2-diol (3-MCPD) administered by drinking water to B6C3F1 mice showed no carcinogenic potential by Jayoung Jeong; Beom Seok Han; Wan-Seob Cho; Mina Choi; Chang-Su Ha; Byoung-Seok Lee; Yong-Bum Kim; Woo-Chan Son; Choong-Yong Kim (pp. 719-729).
3-Monochloropropane-1, 2-diol (or 3-chloro-1,2-propanediol, 3-MCPD) is a well-known food processing contaminant found in a wide range of foods and ingredients. It has been classified as non-genotoxic carcinogen but its carcinogenic potential in the rodents has been controversial. The carcinogenicity to B6C3F1 mice by drinking water administration was assessed over a period of 104 weeks. Three groups, each comprising 50 male and 50 female mice received 3-MCPD at dosages of 30, 100 or 300 ppm up to Day 100 and 200 ppm onward (4.2, 14.3 and 33.0 mg/kg for males; 3.7, 12.2, and 31.0 mg/kg for females), were allocated. Survival was good, with at least 80% of males and 72% of females in each group surviving 104 weeks. Body weights and body weight gain were decreased in males and females receiving 200 ppm. Water and food consumptions of both sexes at 300/200 ppm were lowered. Emaciated or crouching position was observed for animals of both sexes exposed to 200 ppm. There were some differences in hematology and serum biochemistry compared with controls, although there was no histopathological evidence to support those changes. Histopathological examination did not reveal any neoplastic or non-neoplastic findings attributable to treatment with 3-MCPD. It is concluded that drinking water administration of 3-MCPD for 104 weeks revealed no evidence of carcinogenic potential.
Keywords: 3-monochloropropane-1,2-diol; B6C3F1 mice; Carcinogenicity
EP4 upregulation of Ras signaling and feedback regulation of Ras in human colon tissues and cancer cells by Cheng-Hsun Wu; Yuan-Wei Shih; Chun-Hua Chang; Ting-Tsz Ou; Chi-Chou Huang; Jeng-Dong Hsu; Chau-Jong Wang (pp. 731-740).
Previous studies indicate that COX-2 and prostaglandin E2 (PGE2) receptor subtypes are involved in intestinal carcinogenesis and activation of downstream pathways. In this report, we try to understand the association of PGE2 receptor and K-ras cellular mechanism during the development of colorectal cancer. We collected 21 colorectal cancer patients and compared the protein expression of tumor tissues and normal mucosa tissues by using immunoblot. Furthermore, we transferred empty vector and pcDNA-K-ras into Ras-HT29 colon cancer cells. Result showed that phosphorylation of Akt and EP1/EP4 were over-expressed in the colorectal tumor tissue. K-ras induces HT29 cells proliferation through the expressions of COX-2, EP1/EP4, pAkt, GSK3β and increases Tcf transcriptional factor activation. Additionally, Ras protein was suppressed when treated with EP4 inhibitor in Ras-HT29 cell. In cell cycle assay, K-ras mutation causing cell cycle S phase was prolonged with an increase in the G2/M phase ratio. In conclusion, we suggested that Ras overexpression leads to cell proliferation through activating Ras/PI3K/GSK3β/EP4 PGE2 receptor signals and caused a feedback regulation of Ras by EP4 in colorectal tumor progression.
Keywords: Colorectal cancer (CRC); K-ras; Cyclooxygenase-2 (COX-2); Prostaglandin E2 receptor (PGE2 receptor)