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Selected AbstractsRisk assessment of herbicide mixtures in a large European lakeENVIRONMENTAL TOXICOLOGY, Issue 2 2008Nathalie Chèvre Abstract Lake Geneva is one of the largest European lakes with a surface area of 580 km2. Its catchment area covers 7400 km2, of which ,20% is arable land. Monitoring campaigns have been carried out in 2004 and 2005 to determine the contamination of the lake by pesticides. The results highlight the widespread presence of herbicides in water, the measured concentrations for most substances remaining constant in 2004 and 2005. However, for some individual herbicides the concentrations increased drastically (e.g., the herbicide foramsulfuron). We assessed the environmental risk of the herbicides detected in the lake using water quality criteria recently determined for the Swiss environmental protection agency. Furthermore, we assessed the risk of herbicide mixtures, grouped based upon their mode of action. Generally, the risk estimated for all single substances is low, except for some sulfonylurea compounds. For these substances, the measured concentrations are higher than the predicted no-effect concentration. Impact on the flora of the lake can therefore not be excluded. When mixtures of pesticides with similar mode of action are taken into account, the risk remains lower than the mixture water quality criteria for all groups, but can reach as high as one third of this quality criteria. A further step would therefore be to assess the risk of the total pesticide mixture, including similar and dissimilar modes of action. © 2008 Wiley Periodicals, Inc. Environ Toxicol, 2008. [source] Chronic toxicity of five structurally diverse demethylase-inhibiting fungicides to the crustacean Daphnia magna: A comparative assessmentENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 6 2009Enken Hassold Abstract Demethylase inhibitors (DMIs) are broad-spectrum fungicides that are ubiquitously used in agriculture and medicine. They comprise chemically heterogeneous substances that share a common biochemical target in fungi, the inhibition of a specific step in sterol biosynthesis. Several DMIs are suspected to disrupt endocrine-mediated processes in a range of organisms and to inhibit ecdysteroid biosynthesis in arthropods. It is unclear, however, whether and, if so, to what extent different DMI fungicides have a similar mode of action in nontarget organisms, which in turn would lead to a common chronic toxicity profile. Therefore, we selected a representative of each of the major DMI classes,-the piperazine triforine, the pyrimidine fenarimol, the pyridine pyrifenox, the imidazole prochloraz, and the triazole triadimefon,-and comparatively investigated their chronic toxicity to Daphnia magna. No toxicity was detectable up to the limit of solubility of triforine (61 ,mol/L). All other DMIs reduced reproductive success by delaying molting and development and by causing severe developmental abnormalities among offspring. Prochloraz was most toxic (median effective concentration [EC50] for fecundity reduction, 0.76 ,mol/L), followed by fenarimol (EC50, 1.14 ,mol/L), pyrifenox (EC50, 3.15 ,mol/L), and triadimefon (EC50, 5.13 ,mol/L). Mean effect concentrations for fecundity reduction were related to lipophilicity and followed baseline toxicity. However, triadimefon and fenarimol (but none of the other tested DMIs) caused severe eye malformations among exposed offspring. Affected neonates did survive, but a reduced ecological fitness can be assumed. Offspring exposed to fenarimol in mater matured earlier. The investigated different life-history parameters were affected in a substance-specific manner. These qualitatively different toxicity profiles suggest additional, substance-specific mechanisms of action in D. magna that probably are related to an antiecdysteroid action. [source] Identification of the Rdl mutation in laboratory and field strains of the cat flea, Ctenocephalides felis (Siphonaptera: Pulicidae)PEST MANAGEMENT SCIENCE (FORMERLY: PESTICIDE SCIENCE), Issue 12 2004Chris Bass Abstract In many insect species, resistance to cyclodiene insecticides is caused by amino acid substitutions at a single residue (A302) within the M2 transmembrane region of the ,-aminobutyric acid (GABA) receptor sub-unit termed Rdl (resistance to dieldrin). These mutations (A302S and A302G) have also been shown to confer varying levels of cross-resistance to fipronil, a phenylpyrazole insecticide with a similar mode of action to cyclodienes. To investigate the possible occurrence of these mutations in the cat flea, Ctenocephalides felis (Bouché), a 176-bp fragment of the cat flea Rdl gene, encompassing the mutation site, was PCR amplified and sequenced from nine laboratory flea strains. The A302S mutation was found in eight of the nine strains analysed, although the relative frequency of the mutant allele varied between strains. Only one strain (R6) was found to be homozygous for the S302 allele in all the individuals tested, and this correlated with previous reports of low-level fipronil resistance in this strain. A PCR-based diagnostic assay, capable of screening individual fleas for this mutation, was developed and used to survey a range of fleas collected at random from veterinary clinics in the UK and USA. The A302S mutation was present at a high frequency in these domestic pet populations. Copyright © 2004 Society of Chemical Industry [source] Flufenacet herbicide treatment phenocopies the fiddlehead mutant in Arabidopsis thalianaPEST MANAGEMENT SCIENCE (FORMERLY: PESTICIDE SCIENCE), Issue 8 2003Christa Lechelt-Kunze Abstract In order to study the mode of action of herbicides we conducted a pilot study analysing phenotype and gene expression of flufenacet- and benfuresate-treated Arabidopsis thaliana (L) Heynhoe plants. Treatments with either herbicide caused phenocopies of the known Arabidopsis mutant fiddlehead, displaying fused organs and the typical fiddlehead-like inflorescence. Herbicide treatments of other plant species, including monocots, also gave rise to analogous organ fusions, indicating the presence of the target in a broad range of plants. Furthermore, many other herbicides with a proposed similar mode of action, eg chloroacetanilides, produced comparable fusion phenotypes in plants. The fiddlehead gene encodes a putative very-long-chain fatty acid elongase (VLCFAE), which corroborates earlier biochemical results pointing to the inhibition of VLCFA synthesis as mode of action of flufenacet. Gene expression profiles of herbicide-treated plants using the first 8247 gene Arabidopsis gene array of Affymetrix provided additional clues in support of inhibition of VLCFA synthesis. We discuss fiddlehead -like elongases as plant specific targets for flufenacet and many other herbicides. Copyright © 2003 Society of Chemical Industry [source] Design, Synthesis, and Biological Evaluation of 1,5-Diaryl-1,2,4-triazole Derivatives as Selective Cyclooxygenase-2 InhibitorsARCHIV DER PHARMAZIE, Issue 9 2010Bo Jiang Abstract A series of 1,5-diaryl-1,2,4-triazole derivatives were synthesized and evaluated as cyclooxygenase-2 (COX-2) inhibitors. The results of the preliminary biological assays in vivo showed that eight compounds 5b, 6b, 6c, 7c, 8b, 8d, 9c, and 9d have potent anti-inflammatory activity (P,<,0.01), while compounds 6b, 6c, and 9c exhibit marked potency. Compound 6c was then selected for further investigation. In the COX inhibition assay in vitro, compound 6c was identified as a potent and selective inhibitor of COX-2 (COX-2 IC50,=,0.37,µM; SI,=,0.018), being equipotent to celecoxib (COX-2 IC50,=,0.26,µM; SI,=,0.015). In a rat carrageenan-induced paw edema assay, 6c exhibited moderate anti-inflammatory activity (35% inhibition of inflammation) at 2,h after administration of 15,mg/kg as an oral dose. A docking study also revealed that compound 6c binds in the active site of COX-2 in a similar mode to that of the known selective COX-2 inhibitor SC-558. [source] Gonadoinhibitory effects of Neb-colloostatin and Neb-TMOF on ovarian development in the mealworm, Tenebrio molitor L.ARCHIVES OF INSECT BIOCHEMISTRY AND PHYSIOLOGY (ELECTRONIC), Issue 3 2007O. Wasielewski Abstract The gonadostatic action of the peptides Neb-colloostatin (SIVPLGLPVPIGPIVVGPR) and Neb-TMOF (NPTNLH) from Neobellieria bullata was studied in female mealworm Tenebrio molitor. Both peptides potently inhibit ovarian development and terminal oocyte maturation of mated females during their first reproductive cycle. Injection of 4 ,g of Neb-colloostatin or Neb-TMOFNeb-TMOF reduced, at day 4 of the cycle, the size of the terminal oocytes to about half or one third of the normal size in saline-injected controls. In addition, follicular patency was arrested. The injections of Neb-colloostatin and Neb-TMOF also caused a delay to the first ovulation and oviposition as well as a reduction of the number of eggs by about 50% in the first 3 days of the oviposition period. At 4 days after adult emergence, none of the peptides had caused significant changes in protein concentration or composition of the haemolymph. However, both peptides reduced total protein content in ovaries and induced qualitative changes in ovarian protein patterns. Electrophoretic analyses indicated that Neb-colloostatin and Neb-TMOF caused a loss of two proteins (150, 180 kDa) and a drastic reduction of 4 others (39, 43, 47, 130 kDa), which are the most abundant ones in ovaries of control females. On the other hand, they increased the concentration of 2 other polypeptides (65, 70 kDa), which normally occur in insignificant quantities in ovaries. Our results indicate that both peptides have a very similar mode of action despite the differences in their amino acid sequence. They seem to interfere with vitellogenin production by the fat body as well as with vitellogen uptake by the oocytes through modification of patency. Arch. Insect Biochem. Physiol. 64:131,141, 2007. © 2007 Wiley-Liss, Inc. [source] Structures of BIR domains from human NAIP and cIAP2ACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 11 2009Maria Dolores Herman The inhibitor of apoptosis (IAP) family of proteins contains key modulators of apoptosis and inflammation that interact with caspases through baculovirus IAP-repeat (BIR) domains. Overexpression of IAP proteins frequently occurs in cancer cells, thus counteracting the activated apoptotic program. The IAP proteins have therefore emerged as promising targets for cancer therapy. In this work, X-ray crystallography was used to determine the first structures of BIR domains from human NAIP and cIAP2. Both structures harbour an N-terminal tetrapeptide in the conserved peptide-binding groove. The structures reveal that these two proteins bind the tetrapeptides in a similar mode as do other BIR domains. Detailed interactions are described for the P1,,P4, side chains of the peptide, providing a structural basis for peptide-specific recognition. An arginine side chain in the P3, position reveals favourable interactions with its hydrophobic moiety in the binding pocket, while hydrophobic residues in the P2, and P4, pockets make similar interactions to those seen in other BIR domain,peptide complexes. The structures also reveal how a serine in the P1, position is accommodated in the binding pockets of NAIP and cIAP2. In addition to shedding light on the specificity determinants of these two proteins, the structures should now also provide a framework for future structure-based work targeting these proteins. [source] Community responses to contaminants: Using basic ecological principles to predict ecotoxicological effectsENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 9 2009William H. Clements Abstract Community ecotoxicology is defined as the study of the effects of contaminants on patterns of species abundance, diversity, community composition, and species interactions. Recent discoveries that species diversity is positively associated with ecosystem stability, recovery, and services have made a community-level perspective on ecotoxicology more important than ever. Community ecotoxicology must explicitly consider both present and impending global change and shift from a purely descriptive to a more predictive science. Greater consideration of the ecological factors and threshold responses that determine community resistance and resilience should improve our ability to predict how and when communities will respond to, and recover from, xenobiotics. A better understanding of pollution-induced community tolerance, and of the costs of this tolerance, should facilitate identifying contaminant-impacted communities, thus forecasting the ecological consequences of contaminant exposure and determining the restoration effectiveness. Given the vast complexity of community ecotoxicology, simplifying assumptions, such as the possibility that the approximately 100,000 registered chemicals could be reduced to a more manageable number of contaminant classes with similar modes of action, must be identified and validated. In addition to providing a framework for predicting contaminant fate and effects, food-web ecology can help to identify communities that are sensitive to contaminants, contaminants that are particularly insidious to communities, and species that are crucial for transmitting adverse effects across trophic levels. Integration of basic ecological principles into the design and implementation of ecotoxicological research is essential for predicting contaminant effects within the context of rapidly changing, global environmental conditions. [source] Algal toxicity of nitrobenzenes: Combined effect analysis as a pharmacological probe for similar modes of interactionENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 2 2005Rolf Altenburger Abstract An analysis regarding the effects of the mixture toxicity of different nitrobenzenes on the reproduction of the green alga Scenedesmus vacuolatus was undertaken using the concepts of concentration addition and response addition. Using lipophilicity-based quantitative structure-activity relationship (QSAR) modeling for nitrobenzenes, the assumption is held that mononitrobenzenes may exert narcotic effects as a common type of action, whereas dinitrobenzenes show a somewhat greater toxicity. From the literature, QSARs based on quantum chemical parameters suggest that some mononitrobenzenes may be effective through additional other modes of action. The toxicity of a mixture of 14 nitrobenzenes clearly exceeds the predicted combined effects, as expected for the sum of toxic units from a uniform narcotic mode of action. Moreover, the observed combined effect is smaller than that predicted from similarly acting compounds calculated on the basis of the parameterized dose-response functions using concentration addition. Further modeling of the combined effect, joining the models of concentration addition for components with anticipated similar modes of action and of response addition for those with independent action, led us to propose that not all nitrobenzenes follow the same mode of action. This idea is in line with the hypothesis derived from quantum chemical QSAR considerations. Most interestingly, the methodology introduced here uses combined effect analysis as a pharmacological probe to test for similarity in the mode of action of mixture components. [source] Functional screening of traditional antidepressants with primary cortical neuronal networks grown on multielectrode neurochipsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 2 2006Alexandra Gramowski Abstract We optimized the novel technique of multielectrode neurochip recordings for the rapid and efficient screening of neuroactivity. Changes in the spontaneous activity of cultured networks of primary cortical neurons were quantified to evaluate the action of drugs on the firing dynamics of complex network activity. The multiparametric assessment of electrical activity changes caused by psychoactive herbal extracts from Hypericum, Passiflora and Valeriana, and various combinations thereof revealed a receptor-specific and concentration-dependent inhibition of the firing patterns. The spike and burst rates showed significant substance-dependent effects and significant differences in potency. The effects of specific receptor blockades on the inhibitory responses provided evidence that the herbal extracts act on gamma-amino butyric acid (GABA) and serotonin (5-HT) receptors, which are recognized targets of pharmacological antidepressant treatment. A biphasic effect, serotonergic stimulation of activity at low concentrations that is overridden by GABAergic inhibition at higher concentrations, is apparent with Hypericum alone and the triple combination of the extracts. The more potent neuroactivity of the triple combination compared to Hypericum alone and the additive effect of Passiflora and Valeriana suggest a synergy between constituent herbal extracts. The extracts and their combinations affected the set of derived activity parameters in a concomitant manner suggesting that all three constituent extracts and their combinations have largely similar modes of action. This study also demonstrates the sensitivity, selectivity and robustness of neurochip recordings for high content screening of complex mixtures of neuroactive substances and for providing multiparametric information on neuronal activity changes to assess the therapeutic potential of psychoactive substances. [source] Altered gene expression in the brain and liver of female fathead minnows Pimephales promelas Rafinesque exposed to fadrozoleJOURNAL OF FISH BIOLOGY, Issue 9 2008D. L. Villeneuve The fathead minnow Pimephales promelas is a small fish species widely used for ecotoxicology research and regulatory testing in North America. This study used a 2000 gene oligonucleotide microarray to evaluate the effects of the aromatase inhibitor, fadrozole, on gene expression in the liver and brain tissue of exposed females. Reproductive measures, plasma vitellogenin and gene expression data for the brain isoform of aromatase (cytP19B), vitellogenin precursors and transferrin provided evidence supporting the efficacy of the fadrozole exposure. Unsupervised analysis of the microarray results identified 20 genes in brain and 41 in liver as significantly up-regulated and seven genes in brain and around 45 in liver as significantly down-regulated. Differentially expressed genes were associated with a broad spectrum of biological functions, many with no obvious relationship to aromatase inhibition. However, in brain, fadrozole exposure elicited significant up-regulation of several genes involved in the cholesterol synthesis, suggesting it as a potentially affected pathway. Gene ontology-based analysis of expression changes in liver suggested overall down-regulation of protein biosynthesis. While real-time polymerase chain reaction analyses supported some of the microarray responses, others could not be verified. Overall, results of this study provide a foundation for developing novel hypotheses regarding the system-wide effects of fadrozole, and other chemical stressors with similar modes of action, on fish biology. [source] A new genotype 2 subcluster identified among GBV-C strains circulating in the Lisbon metropolitan area of PortugalJOURNAL OF MEDICAL VIROLOGY, Issue 3 2010Cristina Branco Abstract The rate of infection by the GBV-C virus was investigated in a group of 214 individuals at high risk of infection with parenterally transmitted viruses, and all living in the Lisbon metropolitan area (Portugal). RNA was extracted from plasma samples, and a fragment of the 5,-UTR was amplified by RT-PCR, disclosing a high prevalence of infection (40.7%). Most probably due to similar modes of viral transmission, the majority of GBV-C (+) individuals were found to be coinfected with HIV and/or HCV. A genomic region covering part of the E1/E2 glycoprotein coding sequence was amplified from approximately half of the GBV-C positive samples (44/87). Phylogenetic analysis of nucleotide sequences showed segregation of Portuguese GBV-C strains with genotype 1 (G1, n,=,10) and genotype 2 (G2, n,=,24) references. Genotype 1 was significantly associated with the African descent of those infected. Curiously, some of the strains assigned to genotype 2 were shown to form a separate cluster (designated G2*) in both neighbor-joining and Bayesian phylogenetic trees, which was confirmed by multivariate principal coordinate analysis. However, analysis of the distribution of intra- and intergenotype genetic distances support the hypothesis that rather than corresponding to a new viral genotype, G2* is a geographical subcluster within the genotype 2 radiation. J. Med. Virol. 82:452,459, 2010. © 2010 Wiley-Liss, Inc. [source] Healing of subfailure ligament injury: comparison between immature and mature ligaments in a rat modelJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 5 2002Paolo P. Provenzano This study evaluated biomechanical properties of healing ligament following subfailure (grade II) injury by comparing young and mature animals in a rat lateral collateral ligament (LCL) model. One randomly selected LCL was stretched in situ using a custom designed device in eighteen young (21 days) and eighteen skeletally mature (8 months) male rats. Animals were euthanized at 0, 7, and 14 days post-surgery, and ligament ultimate stress, strain at failure and laxity were determined (n = 6 pairs per group). At time 0 after introduction of stretch injury, ligament laxity was present in both groups. The mature rats had 54 ± 9% strength of the control while the immature rats had 58 ± 11% of the strength of the control, representing a consistent and significant injury. The immature and mature ligaments showed similar patterns of cellular damage post-injury and had similar modes of mechanical failure. Ligament laxity decreased in each group as healing time increased, however ligament laxity did not completely recover in either group after 2 weeks of healing. After 7 and 14 days of healing, the mature rats, respectively, had only 63 ± 14% and 80 ± 8% strengths of the controls while the immature rats had 94 ± 6% and 94 ± 10%. Hence, mechanical data showed that immature animals recovered their strength after a grade II sprain at a faster rate than mature animals. However, ligament laxity was still present in both groups two weeks after the injury and was not completely removed by growth in the immature group. These findings are clinically relevant since joint laxity after injury is common, and these results may explain the presence of continued instability in a joint injured at a young age. Hence, this study, with a new injury model, showed differences in ligament healing associated with maturity and quantified the clinically observed persistance of ligament laxity. © 2002 Orthopaedic Research Society. Published by Elsevier Science Ltd. All rights reserved. [source] | ||||||||||||||||