Quantitative structure-activity relationships and mixture-toxicity studies of alcohols and chlorohydrocarbons: reproducibility of effects on growth and reproduction of Daphnia magna

In subacute toxicity experiments for 10 nonreactive organic chemicals, such as alcohols and chlorobenzenes, the effects on growth and reproduction of Daphnia magna were studied. No-observed-effect concentrations (NOEC) for growth and reproduction were found to be approximately equal. For all compounds tested, these values and the median effective concentrations (EC₅₀) on reproduction correlated very well with hydrophobicity (octanol-water partition coefficient, P_oct.) as shown by a quantitative structure-activity relationship (QSAR) study.From one of the QSAR equations, EC₅₀ values for 15 other compounds were predicted, after which the toxicity of mixtures of 10 and 25 compounds was tested. The toxicity was found to be predictable on the basis of concentration addition. Comparing the results of this study with those from earlier experiments, it may be concluded that subacute toxicity data for D. magna are very reproducible and are not very dependent upon the physical condition of the daphnids used.     

Quantitative structure-activity relationships and toxicity studies of mixtures of chemicals with anaesthetic potency: Acute lethal and sublethal toxicity to Daphnia magna

In this study quantitative structure-activity relationships (QSARs) were calculated between hydrophobicity of a group of organic chemicals with anaesthetic potency and toxicity (immobilization, mortality and inhibition of reproduction) to Daphnia magna. Differences in slopes of the high quality QSARs might be explained in terms of possible different sites of action for the three criteria of effect.The combined effects of mixtures of 5–50 chemicals on immobilization and mortality did not deviate from additivity, while the effect on reproduction deviated somewhat from it.     

Quantitative structure-activity relationships in fish toxicity studies Part 1: Relationship for 50 industrial pollutants

LC₅₀-experiments have been conducted using guppies subjected to 72 industrial pollutants. The correlation of the LC₅₀ with several expressions of the hydrophobicity of these chemicals has been studied. Calculated log P_oct-values appeared to satisfy more than HPLC retention indices, solubility data or molecular connectivity indices. One QSAR, with log P_oct as the only variable, gave good estimations of the toxicity of most of the tested compounds with log P_oct < 6. No LC₅₀ could be determined for solutions of compounds with log P_oct > 6.     

定量结构-活性关系在混合体系毒性预测中的发展(英文)

目的:预测麻醉型化合物卤代苯混合体系的毒性。方法:采用发光细菌对卤代苯的单一体系和混合体系进行毒性试验;利用特定的公式计算了混合物的分配系数;建立了混合体系的定量构效关系。结果:(1)建立了单一化合物的正辛醇/水分配系数与毒性的关系。(2)建立了二元混合体系的分配系数与毒性之间的定量结构模型。(3)用二元混合体系的QSAR模型预测了其它不同组份和不同毒性比例的混合体系毒性。结论:QSAR能很好地预测麻醉型化合物卤代苯混合体系的毒性,并且有助于该类化合物的混合体系毒性作用的评价。     

Structure-efficacy relationships of immunostimulatory activity of CpG-containing oligodeoxynucleotides on mouse spleen cells

Aim： To study the relationship between primary structures of oligodeoxynucleotides （ODN） containing unmethylated deoxycytidyl-deoxyguanosine （CpG） dinucleotide motifs and their immunostimulatory activities in mouse spleen cells. Methods： A series of CpG ODN with different primary structures were synthesized. Their capabilities to stimulate mouse spleen cell proliferation were determined by [^3H]thymidine incorporation assay. Cytokine （interleukin [IL]-6, IL-12, and IFN-α） secretion spectra induced by CpG ODN were assessed by ELISA. The ability of CpG ODN to activate natural killer cells was evaluated by standard 4 h ^51Cr-release assay. Flow cytometry was utilized to examine the expressions of various lymphocyte surface molecules on diverse immunocytes. An effective CpG ODN for murine, ODN1826, was set as the template of modification and the positive control. Results： The immunostimulatory activities of CpG ODN with different sequences and compositions varied markedly, both in character and in extent. It was useless for improving the immunostimulatory activity of ODN1826 by simply increasing the functional hexameric CpG motif number, modifying the site of CpG motifs, or changing the distance between multi-CpG motifs. However, an addition of a self- complementary palindrome structure at the 3＇-end, but not the 5＇-end of CpG ODN, aroused marked improvement in its activity. Several designed ODN had superior comprehensive immunostimulatory properties compared to ODN1826. Conclusion： The immunostimulatory activity of a CpG ODN was relevant to its primary structure. It was useless for promoting immunostimulatory activity to simply change CpG motif number, space, or distance. The 3＇-end palindrome structure of CpG ODN is associated with enhanced immunostimulatory activity.     

Effects of water hardness and humic acid on zinc toxicity to Daphnia magna Straus

The effects of water hardness and humic acid (HA) on the acute and chronic toxicity of zinc to Daphnia magna were evaluated. Increases in either water hardness or HA concentration resulted in proportional decreases in both acute (3-day) and chronic (50-day) zinc toxicity. The effect of either of these variables (hardness or HA) was independent of the other in acute tests. In chronic tests, HA reduced the toxic effect of zinc on reproduction more in soft water than in hard water. In addition to reducing the chronic toxicity of zinc, our data suggest that an increase in water hardness also changes the mode of chronic toxic action of zinc. As previously shown for other metals, this study indicates that a reliance on only reproductive and survival endpoints in short-duration chronic tests may lead to an underestimation of the chronic toxicity of zinc.     

Chronic toxicity of ibuprofen to Daphnia magna: Effects on life history traits and population dynamics

The non-steroidal anti-inflammatory drug (NSAID) ibuprofen (IB) is a widely used pharmaceutical that can be found in several freshwater ecosystems. Acute toxicity studies with Daphnia magna suggest that the 48h EC(50) (immobilisation) is 10-100 mgIBl(-1). However, there are currently no chronic IB toxicity data on arthropod populations, and the aquatic life impacts of such analgesic drugs are still undefined. We performed a 14-day exposure of D. magna to IB as a model compound (concentration range: 0, 20, 40 and 80 mgIBl(-1)) measuring chronic effects on life history traits and population performance. Population growth rate was significantly reduced at all IB concentrations, although survival was only affected at 80 mgIBl(-1). Reproduction, however, was affected at lower concentrations of IB (14-day EC(50) of 13.4 mgIBl(-1)), and was completely inhibited at the highest test concentration. The results from this study indicate that the long-term crustacean population consequences of a chronic IB exposure at environmentally realistic concentrations (ngl(-1) to microgl(-1)) would most likely be of minor importance. We discuss our results in relation to recent genomic studies, which suggest that the potential mechanism of toxicity in Daphnia is similar to the mode of action in mammals, where IB inhibits eicosanoid biosynthesis.     

Influence of water hardness on zinc toxicity in Daphnia magna

Zinc is an essential trace metal required for the maintenance of multiple physiological functions. Due to this, organisms can experience both zinc deficiency and toxicity. Hardness is recognized as one of the main modifying physiochemical factors regulating zinc bioavailability. Therefore, the present study analyzed the effect of hardness on zinc toxicity using Daphnia magna. Endpoint parameters were acute-toxicity, development, reproduction, and expression data for genes involved in metal regulation and oxidative stress. In addition, the temporal expression profiles of genes during the initiation of reproduction and molting were investigated. Water hardness influenced the survival in response to exposures to zinc. A zinc concentration of 50 μg/l in soft water (50 mg CaCO₃/L) caused 73% mortality after 96 h exposure, whereas the same zinc concentration in the hardest water did not cause any significant mortality. Moreover, increasing water hardness from 100 to 200 mg CaCO₃/L resulted in a reduced number of offspring. Fecundity was higher at first brood for groups exposed to higher Zn concentrations. The survival data were used to assess the precision of the bioavailability models (Bio-met) and the geochemical model (Visual MINTEQ). As the Bio-met risk predictions overestimated the Zn toxicity, a competition-based model to describe the effects of hardness on zinc toxicity is proposed. This approach can be used to minimize differences in setting environmental quality standards. Moreover, gene expression data showed that using the toxicogenomic approach was more sensitive than the physiological endpoints. Therefore, data presented in the study can be used to improve risk assessment for zinc toxicity.     

Effects of copper pre-exposure routes on the energy reserves and subsequent copper toxicity in Daphnia magna

The hypothesis was tested that copper uptake routes affect the tolerance of Daphnia magna to copper and influence the energy reserves. These were determined in D. magna juveniles that had been exposed for 4 days to water borne and/or dietary copper (algae Pseudokichneriella subcapitata loaded with copper) at nominal concentrations of 0, 10, and 100 nM. Tolerance increased with dietary copper pre-exposure reflected in 24 and 48 h LC50 values of 466 and 398 nM at 100 nM pre-exposure versus 301 and 254 nM in controls, respectively. Control animals (no copper added to their exposure medium and diet) had the lowest lipid content and consequently the lowest energy content. The current study stresses the importance of addressing dietary exposure routes in metal toxicity assessments.     

Chronic toxicity of Great Lakes sediments to Daphnia magna: elutriate effects on survival, reproduction and population growth

Seventeen Great Lakes sediments ranging in degree of expected toxicity were evaluated using a 21 day sediment elutriate bioassay with Daphnia magna. Sediments differed in their effects on survival, age at first reproduction, the number of broods produced and the total number of young produced per adult. Sediments producing low survivorship (50–60%) also had negative effects on reproduction. However, both positive and negative effects on reproduction were found among sediments producing high survivorship. To integrate all test end-points, a stochastic matrix population model was constructed and parameterized with survival and reproduction data from each sediment. By including estimates of variability in vital rates, the model output provided quantitative estimates of uncertainty in projected population size. Sediment effects on survival and reproduction translated into large differences in projected population growth; mean estimates of projected population size at day 28 of the simulations ranged over two orders of magnitude among the 17 sediments. Reproductive timing (e.g. age at first reproduction), followed by fecundity and survivorship, had the largest effect on population growth. Results of this study also indicate that the presence of suspended sediment in elutriates may confound toxicity evaluations using cladocerans. The concentration of total suspended solids was negatively correlated with age at first reproduction and positively correlated with measures of fecundity and population growth. In order to realize the potential benefits of chronic testing we must develop ecologically relevant ways of interpreting sediment bioassay results and expressing the uncertainty associated with our estimates of ecological risk.     

红霉素衍生物抗菌活性构效关系研究进展

为解决抗生素的耐药性问题，近年来在红霉素化学结构修饰方面开展了大量的研究，并发现了诸如酮内酯、酰内酯、双环内酯等多种具有良好抗耐药菌活性的新型大环内酯类化合物。该文对红霉素衍生物抗菌活性研究成果做一概括，并对构效关系研究的某些重要结论加以探讨。     

The developmental toxicity of 1-methyl-3-octylimidazolium bromide on Daphnia magna

The developmental toxicity of 1-methyl-3-octylimidazolium bromide ([C(8)mim]Br) on Daphnia magna was investigated. The 24 and 48 h LC(50) values for [C(8)mim]Br in D. magna were 1.99 and 0.95 mg/L, respectively. A series of multigenerational toxicity tests were then used to explore [C(8)mim]Br effects in D. magna. [C(8)mim]Br significantly inhibited the body lengths of the F0 and F1 1st generations. After 21 days of exposure, [C(8)mim]Br lowered the reproductive ability of the F0 and F1 1st generations. In F1 3rd generation, 21 days of [C(8)mim]Br exposure prolonged the time to bear the first egg and the time to the first brood compared with the control, but the number of first-brood offspring and the number of broods produced by these animals were reduced. After the recovery period all the reproductive parameters returned to normal in F1 1st generation except for the number of broods. The dead neonates increased with prolonged exposure and increasing concentrations, and the dead neonates of the F1 3rd generation went far beyond that of the F1 1st and F0 generations. The intrinsic rate of natural increase (r) values of the three D. magna generations significantly decreased after exposure to higher concentrations of [C(8)mim]Br compared with control groups. Collectively, these results suggest that [C(8)mim]Br exerts a toxic effect on the development of D. magna. This study also highlights the importance of systematically evaluating the potential effects of aquatic ecosystems of ionic liquids that may be released into bodies of water.     

Study on acute toxicity and structure-activity relationship of Daphnia magna exposed to naphthoquinones

The acute toxicities of the six naphthoquinone compounds on Daphnia magna (D. magna) at 48 h were classified as harmful, toxic, and very toxic. The results indicated that logP played an important part in the toxicity of compounds to organism. And 1-carbonyl or the other hydrophobic substituents of the naphthoquinone compounds are likely to mediate the binding of the compound to the target via hydrogen bonding and hydrophobic interactions. Our results provided a foundation for further investigation using 3D-QSAR and HQSAR to evaluate the aquatic ecological risk and the mechanism of toxicity of naphthoquinones.     

Chronic toxicity of chlordane to Daphnia magna and Ceriodaphnia dubia: A comparative study

Chronic toxicity of chlordane, an organochlorine insecticide, was assessed on Ceriodaphnia dubia under standardized conditions of testing. Results were compared to Daphnia magna to determine the sensitivity of the two freshwater cladoceran species to this persistent organic pollutant (POP) and to explore the possibility of using the 7‐day C. dubia test as an alternative to the 21‐day D. magna test in chronic toxicity assessment of POPs. The NOEC‐7d value of chlordane on reproduction of C. dubia (2.9 μg/L) was much higher than the NOEC‐21d value of D. magna (0.18 μg/L), attesting that the 7‐day test on C. dubia was less sensitive than the 21‐day reproduction test on D. magna to chlordane. However, extending the period of exposure of C. dubia to chlordane from 7 to 14 days led to a NOEC‐14d value similar to the NOEC‐21d value in D. magna (0.18 μg/L). This study highlights the usefulness of prolonging the exposure time of the reproduction test in C. dubia from 7 to 14 days to increase the performances of the reproduction test on C. dubia for assessing chronic toxicity of POPs. © 2010 Wiley Periodicals, Inc. Environ Toxicol, 2012.     

Effects of chronic internal alpha irradiation on physiology, growth and reproductive success of Daphnia magna

Daphnids were chronically exposed to waterborne Am-241, an alpha-emitting radionuclide, ranging in concentration from 0.4 to 40 Bq ml(-1). Am-241 amounts were monitored in the medium, daphnid tissues and cuticles. Corresponding average dose rates of 0.02, 0.11 and 0.99 mGy h(-1) were calculated for whole organisms with internal alpha-radiation contributing 99% of total dose rates. Effects of internal alpha irradiation on respiration and ingestion rates, adult, egg and neonate individual dry masses, fecundity and larval resistance to starvation were examined in 23-day experiments. Daphnids showed increased respiratory demand after 23 days at the highest dose rate, suggesting increased metabolic cost of maintenance due to coping with alpha radiological stress. Although no effect was detected on ingestion rates between contaminated and control daphnids, exposure to dose rates of 0.11 mGy h(-1) or higher, resulted in a significant 15% reduction in body mass. Fecundity remained unchanged over the 23-day period, but individual masses of eggs and neonates were significantly smaller compared to the control. This suggested that increased metabolic expenditure in chronically alpha-radiated daphnids came at the expense of their energy investment per offspring. As a consequence, neonates showed significantly reduced resistance to starvation at every dose rate compared to the control. Our observations are discussed in comparison with literature results reported for cadmium, a chemical toxicant which affects feeding activity and strongly reduces individual energy uptake.     

黄酮类化合物生物活性及其构效关系的研究进展

黄酮类化合物是广泛存在于自然界中的一类多酚化合物,具有十分广泛的药理活性,如抗肿瘤、抗炎、抗菌、抗病毒、抗阿尔茨海默病、调血脂等。近几十年来,关于该类化合物的相关研究较多。本文主要从生物活性和构效关系方面综述了近年来黄酮类化合物的研究进展,并对其中存在的相关问题进行了初步探讨和展望。     

Identification of the motilide pharmacophores using quantitative structure activity relationships

Erythromycin A and some derivatives have been shown to act as agonists at the motilin receptor site (motilides) and a structural similarity between these molecules and the N-terminal fragment of motilin has been proposed. Conformational analysis and three-dimensional quantitative structure-activity relationship (3D-QSAR) methods have been used to determine the homology between a series of erythromycin A derivatives and motilin 1-10. A total of 18 compounds has been studied to correlate the gastrointestinal motor stimulating (GMS) activity with the structure-related parameters determined by 3D-QSAR. Two models with good predictive power of the GMS activity are presented, leading to the prediction of motilin 1-10 activity. The models are consistent with the majority of the data available. The most significant parameters for GMS activity are a favorable dispersion interaction from the quaternary ammonium group of the desosamine ring. In motilin 1-10, the aromatic side chains of Phe¹ and Tyr⁷ seem to play the same role as the quaternary ammonium group in models 1 and 2, respectively. Some hydroxyl groups of erythromycin A derivatives and hydrophobic groups of the Val² and lie⁴ side chains of motilin also contribute to the GMS activity. The experimental GMS activities measured are in good agreement with the predicted values, with correlation coefficient values of 0.98 and 0.94 in models 1 and 2, respectively.     

Multi-parametric analysis of ciprofloxacin toxicity at ecologically relevant levels: Short- and long-term effects on Daphnia magna

The increased presence of emergent compounds, such as pharmaceuticals drugs, in the aquatic compartment has been acknowledged as an evolving environmental issue whose consequences are not yet fully characterized. Specific classes of pharmaceutical drugs, such as fluoroquinolone antibiotics, can exert toxic effects to non-target species with ecological significance, since these compounds are environmentally stable and persistent, and may interact with some of the key physiologic processes of organisms. Despite such characteristics, knowledge about the effects of these drugs is still scarce, especially to non-target organisms. The present study aimed to evaluate the effects of chronic and acute exposures of the cladoceran Daphnia magna to the fluoroquinolone antibiotic ciprofloxacin. Putative toxic effects were assessed, following acute and chronic exposures to ecologically relevant concentrations of ciprofloxacin, through enzymatic (cholinesterase – ChEs, catalase – CAT, glutathione S-transferases – GSTs) and non-enzymatic (thiobarbituric acid reactive substances – TBARS, glycogen – Gly) biomarkers. In addition, we also determined behavioural (swimming distance – SD) and morphological (body length of the first brood – BL1B) endpoints in animals exposed to this drug. Ciprofloxacin acute exposure resulted in increased CAT and ChEs activities, and inhibited GSTs activity. After chronic exposure, ChEs activity was significantly inhibited, while GSTs activity was significantly enhanced. TBARS levels were only increased at higher concentrations of ciprofloxacin. CAT activity and Gly content did not evidence a clear and significant pattern of variation. SD was slightly inhibited during dark cycles. BL1B presented a significant decrease for animals subjected to an intermediate concentration. Results showed that even ecologically relevant concentrations of ciprofloxacin may cause oxidative stress in individuals of D. magna. The present study showed important data that corroborate the occurrence of significant biochemical alterations in key features of an aquatic organism when exposed to relevant levels of a widely used antibiotic, establishing essential links between environmental exposure to this specific drug and putative toxic challenges that may result in irreversible changes and damages, especially at the individual level. However, changes in the size of neonates suggest that population alterations are likely to occur under real scenarios of chronic contamination by this drug.     

新型阿片受体部分激动剂－噻吩诺啡及其衍生物的构效关系研究

为了探讨新型阿片受体部分激动剂——噻吩诺啡药理作用的结构基础, 本研究在大鼠热辐射甩尾和小鼠热板致痛模型上, 评价了噻吩诺啡镇痛作用的强度与有效时间, 并通过其与一系列衍生物的相互比较, 分析该类化合物的构效关系。结果显示, 噻吩诺啡为强效、长效的阿片受体部分激动剂; N位上的环丙甲基决定了噻吩诺啡部分激动剂的特性; 改变噻吩环与侧链的连接位点对镇痛活性没有显著影响; 侧链中含有噻吩环的衍生物有效时间均较长, 用吡啶环、苯环替换侧链中的噻吩环, 使化合物的有效时间明显缩短, 提示噻吩环可能与长效作用密切相关。本研究为新结构类型的长效阿片化合物的开发提供了一些线索。