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Archives of Toxicology (v.87, #3)

Human bladder cancer risk calculation based on genome-wide analysis of genetic variants by H. M. Bolt (pp. 397-399).

The connection of β-catenin and phenobarbital in murine hepatocarcinogenesis: a critical discussion of Awuah et al., PLoS ONE 7(6):e39771, 2012 by Albert Braeuning (pp. 401-402).

Genotoxicity and carcinogenicity of the light emitted by artificial illumination systems by Silvio De Flora (pp. 403-405).

The light delivered by artificial illumination systems, and in particular by halogen quartz bulbs, contains UVA, UVB, and UVC radiation, is genotoxic to both bacterial and human cells and is potently carcinogenic to hairless mice. Since IARC has classified UV radiation in Group 1, any source of UV light poses a carcinogenic hazard to humans. Suitable regulations would be needed in order to control the safety of the light emitted by artificial light sources.

Genotoxicity and carcinogenicity of the light emitted by artificial illumination systems by Silvio De Flora (pp. 403-405).

Optimal dosing of warfarin and other coumarin anticoagulants: the role of genetic polymorphisms by Ann K. Daly (pp. 407-420).

Coumarin anticoagulants, which include warfarin, acenocoumarol and phenprocoumon, are among the most widely prescribed drugs worldwide. There is now a large body of published data showing that genotype for certain common polymorphisms in the genes encoding the target vitamin K epoxide reductase (G-1639A/C1173T) and the main metabolizing enzyme CYP2C9 (CYP2C9*2 and *3 alleles) are important determinants of the individual coumarin anticoagulant dose requirement. Additional less common polymorphisms in these genes together with polymorphisms in other genes relevant to blood coagulation such as the cytochrome P450 CYP4F2, gamma-glutamyl carboxylase, calumenin and cytochrome P450 oxidoreductase may also be significant predictors of dose, especially in ethnic groups such as Africans where there have been fewer genetic studies compared with European populations. Using relevant genotypes to calculate starting dose may improve safety during the initiation period. Various algorithms for dose calculation, which also take patient age and other characteristics into consideration, have been developed for all three widely used coumarin anticoagulants and are now being tested in ongoing large randomised clinical trials. One recently completed study has provided encouraging results suggesting that calculation of warfarin dose on the basis of individual patient genotype leads to few adverse events and a higher proportion of time within the therapeutic coagulation rate window, but these findings still need confirmation.

Keywords: Coumarin anticoagulant; Pharmacogenetics; Warfarin; Cytochrome P450; Vitamin K epoxide reductase

Optimal dosing of warfarin and other coumarin anticoagulants: the role of genetic polymorphisms by Ann K. Daly (pp. 407-420).

Keywords: Coumarin anticoagulant; Pharmacogenetics; Warfarin; Cytochrome P450; Vitamin K epoxide reductase

Biological markers of exposure to organophosphorus nerve agents by Robin M. Black; Robert W. Read (pp. 421-437).

Organophosphorus nerve agents are the most toxic chemical warfare agents that are known to have been produced, stockpiled and weaponised. Their development, production, stockpiling and use are prohibited under the terms of the Chemical Weapons Convention and, together with their precursors, are subject to strict controls and verification procedures. The detection and identification of biological markers of exposure to nerve agents are required for three main purposes: confirmation of exposure for forensic purposes in cases of alleged use; diagnosis to guide appropriate medical countermeasures in the event of an exposure; and occupational health monitoring of workers in defence laboratories and demilitarisation facilities. Biomarkers of nerve agents fall into two main groups, free metabolites and adducts to proteins. These are reviewed together with analytical methods for their identification. Examples are provided of applications in cases of human exposure.

Keywords: Organophosphorus; Nerve agent; Biomarker; Mass spectrometry; Review

Biological markers of exposure to organophosphorus nerve agents by Robin M. Black; Robert W. Read (pp. 421-437).

Keywords: Organophosphorus; Nerve agent; Biomarker; Mass spectrometry; Review

Enhanced carcinogenicity by coexposure to arsenic and iron and a novel remediation system for the elements in well drinking water by Mayuko Y. Kumasaka; Osamu Yamanoshita; Shingo Shimizu; Shoko Ohnuma; Akio Furuta; Ichiro Yajima; Saika Nizam; Md. Khalequzzaman; Hossain U. Shekhar; Tamie Nakajima; Masashi Kato (pp. 439-447).

Various carcinomas including skin cancer are explosively increasing in arsenicosis patients who drink arsenic-polluted well water, especially in Bangladesh. Although well drinking water in the cancer-prone areas contains various elements, very little is known about the effects of elements except arsenic on carcinogenicity. In order to clarify the carcinogenic effects of coexposure to arsenic and iron, anchorage-independent growth and invasion in human untransformed HaCaT and transformed A431 keratinocytes were examined. Since the mean ratio of arsenic and iron in well water was 1:10 in cancer-prone areas of Bangladesh, effects of 1 μM arsenic and 10 μM iron were investigated. Iron synergistically promoted arsenic-mediated anchorage-independent growth in untransformed and transformed keratinocytes. Iron additionally increased invasion in both types of keratinocytes. Activities of c-SRC and ERK that regulate anchorage-independent growth and invasion were synergistically enhanced in both types of keratinocytes. Our results suggest that iron promotes arsenic-mediated transformation of untransformed keratinocytes and progression of transformed keratinocytes. We then developed a low-cost and high-performance adsorbent composed of a hydrotalcite-like compound for arsenic and iron. The adsorbent rapidly reduced concentrations of both elements from well drinking water in cancer-prone areas of Bangladesh to levels less than those in WHO health-based guidelines for drinking water. Thus, we not only demonstrated for the first time increased carcinogenicity by coexposure to arsenic and iron but also proposed a novel remediation system for well drinking water.

Keywords: Arsenic; Iron; Coexposure; Well drinking water; Remediation

The influence of chronic fluorosis on mitochondrial dynamics morphology and distribution in cortical neurons of the rat brain by Di-Dong Lou; Zhi-Zhong Guan; Yan-Jie Liu; Yan-Fei Liu; Kai-Lin Zhang; Ji-Gang Pan; Jin-Jing Pei (pp. 449-457).

The present study was designed to evaluate the effects of chronic fluorosis on the dynamics (including fusion and fission proteins), fragmentation, and distribution of mitochondria in the cortical neurons of the rat brain in an attempt to elucidate molecular mechanisms underlying the brain damage associated with excess accumulation of fluoride. Sixty Sprague–Dawley rats were divided randomly into three groups of 20 each, that is, the untreated control group (drinking water naturally containing <0.5 mg fluoride/l, NaF), the low-fluoride group (whose drinking water was supplemented with 10 mg fluoride/l) and the high-fluoride group (50 mg fluoride/l). After 6 months of exposure, the expression of mitofusin-1 (Mfn1), fission-1 (Fis1), and dynamin-related protein-1 (Drp1) at both the protein and mRNA levels were detected by Western blotting, immunohistochemistry, and real-time PCR, respectively. Moreover, mitochondrial morphology and distribution in neurons were observed by transmission electron or fluorescence microscopy. In the cortices of the brains of rats with chronic fluorosis, the level of Mfn1 protein was clearly reduced, whereas the levels of Fis1 and Drp1 were elevated. The alternations of expression of the mRNAs encoding all three of these proteins were almost the same as the corresponding changes at the protein levels. The mitochondria were fragmented and the redistributed away from the axons of the cortical neurons. These findings indicate that chronic fluorosis induces abnormal mitochondrial dynamics, which might in turn result in a high level of oxidative stress.

Keywords: Rats; Brains; Fluorosis; Mitochondrial dynamics; Fusion and fission proteins

MicroRNA-210 targets antiapoptotic Bcl-2 expression and mediates hypoxia-induced apoptosis of neuroblastoma cells by Chung-Ching Chio; Jia-Wei Lin; Heien-An Cheng; Wen-Ta Chiu; Yuan-Hung Wang; Jhi-Joung Wang; Chung-Hsi Hsing; Ruei-Ming Chen (pp. 459-468).

MicroRNAs (miRNAs) can regulate cell survival and death by targeting apoptosis-related gene expression. miR-210 is one of the most hypoxia-sensitive miRNAs. In this study, we evaluated the roles of miR-210 in hypoxia-induced insults to neural cells. Treatment of neuro-2a cells with oxygen/glucose deprivation (OGD) induced cell apoptosis in a time-dependent manner. In parallel, OGD time-dependently increased cellular miR-210 levels. Knocking down miR-210 expression using specific antisenses significantly attenuated OGD-induced neural apoptosis. Concurrently, OGD increased hypoxia-inducible factor (HIF)-1α mRNA and protein syntheses. Pretreatment with YC-1, an inhibitor of HIF-1α, reduced OGD-caused cell death. Sequentially, OGD specifically decreased antiapoptotic Bcl-2 mRNA and protein levels in neuro-2a cells. A search by a bioinformatic approach revealed that miR-210-specific binding elements exist in the 3′-untranslated region of Bcl-2 mRNA. Application of miR-210 antisenses simultaneously alleviated OGD-involved inhibition of Bcl-2 mRNA expression. In comparison, overexpression of miR-210 synergistically diminished OGD-caused inhibition of Bcl-2 mRNA expression and consequently induced greater cellular insults. Taken together, this study shows that OGD can induce miR-210 expression through activating HIF-1α. And miR-210 can mediate hypoxia-induced neural apoptosis by targeting Bcl-2.

Keywords: Hypoxia; Neural apoptosis; HIF-1α; miR-210; Bcl-2

Neuropeptide Y Y1 receptor knockdown can modify glutathione peroxidase and c-AMP response element-binding protein in phenylpropanolamine-treated rats by Yih-Shou Hsieh; Pei-Ni Chen; Meng-Hsien Kuo; Dong-Yih Kuo (pp. 469-479).

It has been reported that antioxidative enzymes, neuropeptide Y (NPY), and c-AMP response element-binding protein (CREB) are involved in regulating phenylpropanolamine (PPA)-mediated appetite suppression. Here, we investigated whether Y1 receptor (Y1R) might be involved in this regulation. Rats were daily treated with PPA for 4 days. Changes in the contents of NPY, Y1R, glutathione peroxidase (GP), and CREB were assessed and compared. Results showed that Y1R, GP, and CREB increased, with a maximal increase about 100, 200, and 150 %, respectively, on Day 2. By contrast, NPY decreased with a biggest reduction about 48 % on Day 2 and the pattern of expression during PPA treatment was opposite to those of Y1R, GP, and CREB. Central knockdown (using antisense) or inhibition (using antagonist) of Y1R expression modulated the anorectic response of PPA and the reciprocal regulation between NPY and GP (or CREB), revealing an essential role of Y1R in regulating NPY, GP, and CREB. These results suggest that Y1R participates in the reciprocal regulation of NPY, GP, and CREB in the hypothalamus during PPA treatment in conscious rats. The present results may aid the therapeutic research of PPA and related antiobesity drugs.

Keywords: NPY-Y1 receptor; Oxidative stress; CREB; Appetite

Apoptosis initiation of β-ionone in SGC-7901 gastric carcinoma cancer cells via a PI3K-AKT pathway by Qian Liu; Hong-Wei Dong; Wen-Guang Sun; Ming Liu; Juan C. Ibla; Lian-Xin Liu; John W. Parry; Xiao-Hui Han; Ming-Song Li; Jia-Ren Liu (pp. 481-490).

β-ionone has been shown to hold potent anti-proliferative and apoptosis induction properties in vitro and in vivo. To investigate the effects of β-ionone on apoptosis initiation and its possible mechanisms of action, we qualified cell apoptosis, proteins related to apoptosis and a phosphatidylinositol 3-kinase (PI3K)—AKT pathway in human gastric adenocarcinoma cancer SGC-7901 cells. The results demonstrated that β-ionone-induced apoptosis in a dose-dependent manner in SGC-7901 cells treated with β-ionone (25, 50, 100 and 200 μmol/L) for 24 h. β-ionone was also shown to induce the expression of cleaved-caspase-3 and inhibit bcl-2 expression in SGC-7901 cells in a dose-dependent manner. The significantly decreased levels of p-PI3K and p-AKT expression were observed in SGC-7901 cells after β-ionone treatments in a time- and dose-dependent manner (P < 0.01). Thus, the apoptosis induction in SGC-7901 cells by β-ionone may be regulated through a PI3K-AKT pathway. These results demonstrate a potential mechanism by which β-ionone to induce apoptosis initiation in SGC-7901 cells.

Keywords: β-ionone; SGC-7901 cells; PI3K-AKT pathway; Apoptosis initiation

Aryl hydrocarbon receptor-mediated disruption of contact inhibition is associated with connexin43 downregulation and inhibition of gap junctional intercellular communication by Zdeněk Andrysík; Jiřina Procházková; Markéta Kabátková; Lenka Umannová; Pavlína Šimečková; Jiří Kohoutek; Alois Kozubík; Miroslav Machala; Jan Vondráček (pp. 491-503).

The aryl hydrocarbon receptor (AhR) contributes to the control of cell-to-cell communication, cell adhesion, migration or proliferation. In the present study, we investigated the regulation of connexin43 (Cx43) and Cx43-mediated gap junctional intercellular communication (GJIC) during the AhR-dependent disruption of contact inhibition in non-tumorigenic liver epithelial cells. The contact inhibition of cell proliferation is a process restricting the cell division of confluent non-transformed cells, which is frequently abolished in cancer cells; however, the mechanisms contributing to its disruption are still only partially understood. Disruption of contact inhibition, which was induced by toxic AhR ligands 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or polycyclic aromatic hydrocarbons in epithelial WB-F344 cells, reduced Cx43 protein levels, possibly via enhanced proteasomal degradation, significantly decreased the amount of gap junction plaques and downregulated GJIC, in an AhR-dependent manner. Although both intracellular and membrane Cx43 pools were markedly reduced in cells released from contact inhibition by TCDD, siRNA-mediated Cx43 knock-down was not sufficient to stimulate proliferation in contact-inhibited cells. Our data suggest that downregulation of Cx43/GJIC in non-transformed epithelial cells is an inherent part of disruption of contact inhibition, which occurs at the post-transcriptional level. This process runs in parallel with alterations of other forms of cell-to-cell communication, thus suggesting that toxic AhR agonists may simultaneously abrogate contact inhibition and reduce GJIC, two essential mechanisms linked to deregulation of cell-to-cell communication during tumor promotion and progression.

Keywords: Aryl hydrocarbon receptor; Contact inhibition; Gap junctions; Connexin43; Liver epithelial cells

Benzo[a]pyrene-induced transcriptomic responses in primary hepatocytes and in vivo liver: Toxicokinetics is essential for in vivo–in vitro comparisons by P. C. E. van Kesteren; P. E. Zwart; M. M. Schaap; T. E. Pronk; M. H. M. van Herwijnen; J. C. S. Kleinjans; B. G. H. Bokkers; R. W. L. Godschalk; M. J. Zeilmaker; H. van Steeg; M. Luijten (pp. 505-515).

The traditional 2-year cancer bioassay needs replacement by more cost-effective and predictive tests. The use of toxicogenomics in an in vitro system may provide a more high-throughput method to investigate early alterations induced by carcinogens. Recently, the differential gene expression response in wild-type and cancer-prone Xpa ^−/− p53 ^+/− primary mouse hepatocytes after exposure to benzo[a]pyrene (B[a]P) revealed downregulation of cancer-related pathways in Xpa ^−/− p53 ^+/− hepatocytes only. Here, we investigated pathway regulation upon in vivo B[a]P exposure of wild-type and Xpa ^−/− p53 ^+/− mice. In vivo transcriptomics analysis revealed a limited gene expression response in mouse livers, but with a significant induction of DNA replication and apoptotic/anti-apoptotic cellular responses in Xpa ^−/− p53 ^+/− livers only. In order to be able to make a meaningful in vivo–in vitro comparison we estimated internal in vivo B[a]P concentrations using DNA adduct levels and physiologically based kinetic modeling. Based on these results, the in vitro concentration that corresponded best with the internal in vivo dose was chosen. Comparison of in vivo and in vitro data demonstrated similarities in transcriptomics response: xenobiotic metabolism, lipid metabolism and oxidative stress. However, we were unable to detect cancer-related pathways in either wild-type or Xpa ^−/− p53 ^+/− exposed livers, which were previously found to be induced by B[a]P in Xpa ^−/− p53 ^+/− primary hepatocytes. In conclusion, we showed parallels in gene expression responses between livers and primary hepatocytes upon exposure to equivalent concentrations of B[a]P. Furthermore, we recommend considering toxicokinetics when modeling a complex in vivo endpoint with in vitro models.

Keywords: Toxicogenomics; Carcinogenesis; Benzo[a]pyrene; Xpa ^−/− p53 ^+/− ; Physiologically based kinetic modeling

Repeat oral dose toxicity studies of melamine in rats and monkeys by Richard J. Early; Hong Yu; Xueyan Peter Mu; Haiyan Xu; Lei Guo; Qingxue Kong; Junma Zhou; Bruce He; Xiuying Yang; Hailiang Huang; Edward Hu; Ying Jiang (pp. 517-527).

Melamine is an important and widely used organic industrial chemical. Recently, clinical findings of renal failure and kidney stones in infants have been associated with ingestion of melamine-contaminated infant formula. To understand the toxicity and clinical outcome of melamine exposure, repeated oral dose studies in rats and monkeys were performed to characterize the subchronic toxicity of melamine. Assessment of toxicity was based on mortality, clinical signs, body weights, ophthalmic findings, clinical pathology, gross pathology, organ weights, and microscopic observations. The first rat study was intended to be a 14-day oral study followed by an 8-day recovery period. The dose levels were 140, 700, and 1,400 mg/kg/day (lowered to 1,000 mg/kg/day subsequently due to mortality). Oral administration of melamine at 700 mg/kg/day for 14 consecutive days in rats produced compound-related clinical signs (red urine), decreased body weights, and changes in clinical pathology (increased serum urea nitrogen and creatinine) and anatomical pathology (renal tubular cell debris, crystal deposition, and hyperactive regeneration of renal tubular epithelium). The kidney was identified as the target organ. Oral administration at 1,400 mg/kg/day (subsequently lowered to 1,000 mg/kg/day) resulted in animal death and moribundity. There were no treatment-related findings in the 140 mg/kg/day group. There were no compound-related findings in the high-dose recovery animals. The second rat study was a 5-day oral toxicity study with genomic biomarkers assayed in the kidney tissues. At the top dose of 1,050 mg/kg/day, similar clinical and anatomical pathology findings as described above were observed. The genes measured, Kim-1, Clu, Spp1, A2m, Lcn2, Tcfrsf12a, Gpnmb, and CD44, were significantly up-regulated (fivefold to 550-fold), while Tff3 was significantly down-regulated (fivefold). These results indicated that genomic markers could sensitively diagnose melamine-induced kidney injury. A 3-month oral study with 4-week recovery in monkeys was also conducted. In this monkey study, the animals were treated with melamine at doses of 60, 200, or 700 mg/kg/day. The administration of 700 mg/kg/day melamine by nasal-gastric gavage to monkeys resulted in test article-related clinical signs including turbid and whitish urine, urine crystals, red blood cell changes, increased serum alanine aminotransferase and kidney and/or liver weights, and microscopic findings including nephrotoxicity, pericarditis, and increased hematopoiesis. Nephrotoxicity was also noted at 200 mg/kg/day. It was concluded that the kidney is the primary target organ and the NOAEL was estimated to be 140 mg/kg/day in rats following a 14-day oral administration and 60 mg/kg/day in the monkey study.

Keywords: Melamine; Nephrotoxicity; Biomarker

Induction of nuclear anomalies in exfoliated buccal cells of coca chewers: results of a field study by Armen Nersesyan; Michael Kundi; Georg Krupitza; Gustavo Barcelos; Miroslav Mišík; Georg Wultsch; Juan Carrion; Gladys Carrion-Carrera; Siegfried Knasmueller (pp. 529-534).

The leaves of coca (Erythroxylum coca var. coca), a South American shrub which contains cocaine, other alkaloids and phenolics are widely used by indigenous populations of the Andes. It is currently not known if coca consumption causes genotoxic effects in humans. This information is important to predict potential long-term toxic effects such as cancer induction. Therefore, the buccal cytome assay was used to analyze oral cells from 45 uni- and bilateral chewers and 23 controls living in the Altiplano of the Peruvian Andes. In total, 123,471 cells were evaluated from chewers and 57,916 from controls. Information concerning the consumption levels and habits and also use of lime were collected with questionnaires. Chewing of the leaves did not induce nuclear anomalies reflecting genetic damage such as micronuclei (MNi) and nuclear buds; in the highest exposure group (but not in the overall group) even a significant decrease in the frequencies of cells with MNi (by 64 %) was observed. However, we found significantly elevated levels of other nuclear anomalies (karyorrhexis and karyolysis) which reflect cytotoxic effects in the coca users. The frequencies of these anomalies increased with the daily consumption and when lime was used to improve the release of the alkaloids. In contrast to other chewing habits (betel, tobacco and khat), consumption of coca leaves does not induce genetic instability in cells from the oral cavity and our findings indicate that no adverse health effects take place in chewers which are associated with DNA damage. However, the significant increase in certain anomalies shows that acute toxic effects are caused by coca consumption.

Keywords: Coca leaves; Chewing; Buccal cells; Cytome assay; Genotoxicity; Cytotoxicity

Crystal structure and activating effect on RyRs of AhV_TL-I, a glycosylated thrombin-like enzyme from Agkistrodon halys snake venom by Fuxing Zeng; Bing Shen; Zhongliang Zhu; Ping Zhang; Yonghua Ji; Liwen Niu; Xu Li; Maikun Teng (pp. 535-545).

A snake venom thrombin-like enzyme (SVTLE) from Agkistrodon halys pallas venom was isolated by means of a two-step chromatographic procedure. The purified enzyme, named AhV_TL-I, showed fibrinogenolytic activity against both the Aα and Bβ chains of bovine fibrinogen. Unlike the other SVTLEs, AhV_TL-I has poor esterolytic activity upon BAEE substrate. The N-terminal sequence of AhV_TL-I was determined to be IIGGDEXNINEHRFLVALYT, and the molecular mass was confirmed to 29389.533 Da by MALDI-TOF mass spectrometry. Its complete cDNA and derived amino acid sequence were obtained by RT-PCR. The crystal structure of AhV_TL-I was determined at a resolution of 1.75 Å. A disaccharide was clearly mapped in the structure, which involved in regulating the esterolytic activity of AhV_TL-I. The presence of the N-glycan deformed the 99-loop, and the resulting steric hindrances hindered the substrates to access the active site. Furthermore, with the carbohydrate moiety, AhV_TL-I could induce mouse thoracic aortic ring contraction with the EC₅₀ of 147 nmol/L. Besides, the vasoconstrictor effects of AhV_TL-I were also independent of the enzymatic activity. The results of [Ca²⁺]_i measurement showed that the vasoconstrictor effects of AhV_TL-I were attributed to Ca²⁺ releasing from Ca²⁺ store. Further studies showed that it was related to the activation of ryanodine receptors (RyRs). These offer new insights into the snake SVTLEs functions and provide a novel pathogenesis of A. halys pallas venom.

Keywords: Glycosylation; Ryanodine receptor; Ca²⁺ release; Thrombin-like enzyme

Comment: Carcinogenicity of diesel-engine exhaust (DE) by Dirk Pallapies; Dirk Taeger; Frank Bochmann; Peter Morfeld (pp. 547-549).

Internal exposure to carcinogenic polycyclic aromatic hydrocarbons and DNA damage by Sofia Pavanello; Marcello Lotti (pp. 551-553).

Second symposium on Environmental Toxicology in North Rhine-Westphalia, Germany—interdisciplinary research activities in toxicology, statistics, hygiene and medicine: meeting report on a symposium held in Dortmund May 19–20, 2011 by Klaus Golka; Katja Ickstadt; Silvia Selinski; Jan G. Hengstler; Michael Wilhelm (pp. 555-561).

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Archives of Toxicology (v.87, #3)