RESUMEN
Exposure of young organisms to oestrogenic endocrine disrupting chemicals (EDCs) can elicit adverse effects, particularly on the reproductive function. In fish, as in other vertebrates, reproduction is controlled by the neuroendocrine gonadotropic axis, whose components are mainly regulated by sex steroids and may then be targets for EDCs. In the present study, we investigated the effects of a xenoestrogen exposure on the ontogenesis of the gonadotropic axis in European sea bass. After exposure of hatching larvae for 8â¯days to 17α-ethinylestradiol (EE2) (0.5â¯nM and 50â¯nM), gene expression for kisspeptins (kiss1, kiss2), gonadotropin-releasing hormones (gnrh1, gnrh2, gnrh3), gonadotropin beta subunits (lhß and fshß) and brain type aromatase (cyp19a1b) were measured using quantitative real-time PCR. Our results demonstrate that EE2 strongly stimulated the expression of brain type aromatase (cyp19a1b) in sea bass larvae. In addition, EE2 exposure also affected the mRNA levels of kiss1, gnrh1 and gnrh3 by inducing a downregulation of these genes during the early developmental stages, while no effect was seen in gnrh2, lhß and fshß. These results reinforce the idea that the larval development is a sensitive critical period in regard to endocrine disruption and that the gonadotropic axis in the developing sea bass is sensitive to xenoestrogen exposure.
Asunto(s)
Lubina , Kisspeptinas , Animales , Aromatasa/genética , Aromatasa/metabolismo , Lubina/fisiología , Etinilestradiol/metabolismo , Etinilestradiol/toxicidad , Gonadotropinas/metabolismo , Kisspeptinas/metabolismoRESUMEN
Regulatory assessment of the effects of chemicals requires the availability of validated tests representing different environments and organisms. In this context, developing new tests is particularly needed for marine species from temperate environments. It is also important to evaluate effects that are generally poorly characterized and seldom included in regulatory tests. In this study, we designed an exposure protocol using European sea bass (Dicentrarchus labrax) larvae. We examined classical toxicological values (LCx) as well as behavioral responses. By comparing different hatching and breeding strategies, we defined the optimal conditions of exposure as non-agitated conditions in 24- or 48-well microplates. Our exposure protocol was then tested with 3,4-dichloroaniline (3,4-DCA), a recommended reference molecule. Based on our results, the 96 h LC50 for 3,4-DCA corresponded to 2.04 mg/L while the 168 h LC50 to 0.79 mg/L. Behavioral analyses showed no effect of 3,4-DCA at low concentration (0.25 mg/L). In conclusion, the present work established the basis for a new test which includes behavioral analysis and shows that the use of sea bass is suitable to early-life stage toxicity tests.
Asunto(s)
Lubina , Animales , Larva , Dosificación Letal Mediana , Pruebas de ToxicidadRESUMEN
Tetrodotoxins (TTXs) are potentially lethal paralytic toxins that have been identified in European shellfish over recent years. Risk assessment has suggested comparatively low levels (44 µg TTX-equivalent/kg) but stresses the lack of data on occurrence. Both bacteria and dinoflagellates were suggested as possible biogenic sources, either from an endogenous or exogenous origin. We thus investigated TTXs in (i) 98 shellfish samples and (ii) 122 bacterial strains, isolated from French environments. We optimized a method based on mass spectrometry, using a single extraction step followed by ultrafiltration without Solid Phase Extraction and matrix-matched calibration for both shellfish and bacterial matrix. Limits of detection and quantification were 6.3 and 12.5 µg/kg for shellfish and 5.0 and 10 µg/kg for bacterial matrix, respectively. Even though bacterial matrix resulted in signal enhancement, no TTX analog was detected in any strain. Bivalves (either Crassostrea gigas or Ruditapes philippinarum) were surveyed in six French production areas over 2.5-3 month periods (2018-2019). Concentrations of TTX ranged from 'not detected' to a maximum of 32 µg/kg (Bay of Brest, 17 June 2019), with events lasting 2 weeks at maximum. While these results are in line with previous studies, they provide new data of TTX occurrence and confirm that the link between bacteria, bivalves and TTX is complex.
Asunto(s)
Bivalvos/química , Microbiología de Alimentos , Tetrodotoxina/análisis , Animales , Cromatografía Liquida/métodos , Crassostrea/química , Francia , Extracción en Fase Sólida/métodos , Espectrometría de Masas en Tándem/métodosRESUMEN
The mite Varroa destructor is an ectoparasite and has been identified as a major cause of worldwide honey bee colony losses. The use of yearly treatments for the control of varroosis is the most common answer to prevent collapses of honey bee colonies due to the mite. However, the number of effective acaricides is small and the mite tends to become resistant to these few active molecules. In this study, we have been looking for a new original varroacide treatment inhibiting selectively Varroa destructor AChE (vdAChE) with respect to Apis mellifera AChE (amAChE). To do this an original drug design methodology was used applying virtual screening of the CERMN chemolibrary, starting from a vdAChE homology sequence model. By combining the in silico screening with in vitro experiments, two promising compounds were found. In vitro tests of AChE inhibition for both species have confirmed good selectivity toward the mite vdAChE. Moreover, an in vivo protocol was performed and highlighted a varroacide activity without acute consequences on honey bee survival. The two compounds discovered have the potential to become new drug leads for the development of new treatments against the mite varroa. The method described here clearly shows the potential of a drug-design approach to develop new solutions to safeguard honey bee health.
Asunto(s)
Acaricidas/farmacología , Varroidae/efectos de los fármacos , Acaricidas/química , Animales , Simulación por Computador , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacologíaRESUMEN
BACKGROUND: The ectoparasitic honey bee mite Varroa destructor is a main cause of the gradual decline in honey bees Apis mellifera. Beekeepers currently utilize a wide range of different synthetic acaricides, organic acids and essential oils to keep mite populations under control. Previous work has indicated that pirimicarb may be a new varroacide candidate. The aim of this study was to observe chronic effects on feeding activity in worker honey bees after oral exposure to 1.05 mm pirimicarb. The long-term effects of 24 h exposure to pirimicarb were also tested. RESULTS: After three successive trials, no mortality could be detected at the tested concentration, although oral exposure to pirimicarb had a significant effect on honey bees feeding behavior. Pirimicarb added to a sucrose solution led to a rapid decrease in food intake. These tendencies may be reversed when the pesticide is removed. However, recovery seemed to be trial dependent. CONCLUSION: This study highlights seasonal variation in honey bee susceptibility, which should be considered in toxicology studies. © 2018 Society of Chemical Industry.
Asunto(s)
Acaricidas/farmacología , Abejas/efectos de los fármacos , Carbamatos/farmacología , Conducta Alimentaria/efectos de los fármacos , Pirimidinas/farmacología , Administración Oral , Animales , Abejas/fisiologíaRESUMEN
Antidepressants are among the most prescribed pharmaceuticals throughout the world. Their presence has already been detected in several aquatic ecosystems worldwide and their effects on non-target organisms justify the growing concern of both the public and regulatory authorities. These emerging pollutants do not occur as isolated compounds but rather as multi-component mixtures, which may lead to increased adverse effects compared to individual compounds. Freshwater and marine algae seem particularly sensitive to pharmaceuticals, including antidepressants. Studies assessing the toxicity of antidepressant mixture to algae focused mainly on binary mixtures of selective serotonin reuptake inhibitors. In the present experiment, the freshwater algae Raphidocelis subcapitata (formerly known as Pseudokirchneriella subcapitata) and the marine diatom Skeletonema marinoi were exposed to equitoxic mixtures of 9 antidepressants (fluvoxamine, fluoxetine, sertraline, duloxetine, venlafaxine, clomipramine, amitriptyline, and citalopram) at different concentrations. The growth inhibition was measured. Results showed that the toxicity of this mixture was higher than the effects of each individual component, highlighting simple additivity or synergistic effects, whereas tested concentrations were below the 10% inhibition concentration (IC10) of each compound. Moreover, the QSAR analysis highlighted that antidepressants would act through narcosis (non-specific mode of action) towards the two species of algae. However, more specific effects can be observed by differentiating compounds with a primary/secondary amine from those with a tertiary amine. These mixture effects on algal species have to be assessed, especially since any impacts on phytoplankton could ultimately impact higher trophic levels (less food, secondary poisoning).
Asunto(s)
Aminas/química , Antidepresivos/toxicidad , Chlorophyta/efectos de los fármacos , Diatomeas/efectos de los fármacos , Contaminantes Químicos del Agua/toxicidad , Antidepresivos/química , Chlorophyta/crecimiento & desarrollo , Diatomeas/crecimiento & desarrollo , Fluoxetina/toxicidad , Sertralina/toxicidad , Clorhidrato de Venlafaxina/toxicidad , Contaminantes Químicos del Agua/químicaRESUMEN
Despite a growing scientific attention on ecological impact of emerging pollutants (EPs) such as pharmaceuticals, personal care products, and pesticides, knowledge gaps remain regarding mixture toxicity and effects on aquatic organisms. Several EPs were screened in seawater (Normandy, France), and the ecotoxicity of five compounds, chosen on their occurrence in ecosystems and use worldwide, was assessed and were the biocides methylparaben (MP) and triclosan (TCS), a pesticide degradation product (AMPA), and the pharmaceuticals venlafaxine (VEN) and carbamazepine (CBZ). The acute or sub-chronic toxicity, alone or in binary/ternary mixtures of three of them (CBZ, AMPA, and MP), was assessed on one marine and two freshwater organisms: Crassostrea gigas, Pseudokirchneriella subcapitata, and Daphnia magna. TCS and AMPA were, respectively, the most (EC50 < 1 mg L-1) and the least (EC50 > 50 mg L-1) toxic chemicals for the four endpoints (algal growth inhibition, daphnia immobilization, oyster embryotoxicity, and metamorphosis). The anxiolytic VEN (EC50 < 1 mg L-1) was particularly toxic to oyster larvae showing sensitivity difference between freshwater and marine organisms. If all the mixtures appeared to be in the same range of toxicity, the joint-toxic effects mainly led to synergistic or antagonistic interactions compared to single-compound toxicity. The data also highlighted species-dependent differing models of toxicity and underscored the need for an awareness of cocktail effects for better ecological risk assessment.
Asunto(s)
Organismos Acuáticos/efectos de los fármacos , Chlorophyta/efectos de los fármacos , Crassostrea/efectos de los fármacos , Daphnia/efectos de los fármacos , Preparaciones Farmacéuticas/análisis , Contaminantes Químicos del Agua/toxicidad , Animales , Francia , Agua Dulce/química , Preparaciones Farmacéuticas/química , Agua de Mar/química , Pruebas de Toxicidad , Contaminantes Químicos del Agua/químicaRESUMEN
A risk assessment for freshwater and marine ecosystems is presented for 48 pharmaceutical compounds, belonging to 16 therapeutic classes, and prescribed in northwestern France. Ecotoxicity data were obtained on two freshwater organisms, i.e., crustacean Daphnia magna and the green algae Pseudokirchneriella subcapitata, and on two marine organisms, i.e., the crustacean Artemia salina and the diatom Skeletonema marinoi. Measured environmental concentrations (MEC), in the Orne River and sea off Merville-Franceville in the Basse-Normandie region, were compared to the predicted environmental concentrations (PEC). Predicted no-effect concentrations (PNEC) were derived from acute data for each compound. Then, a risk assessment for each compound and the mixture was performed by calculating risk quotients (RQ as PEC or MEC/PNEC ratio). Results showed that no immediate acute toxicities were expected even if some compounds displayed strong toxicities at very low concentrations. Antibiotics, antidepressants, and antifungals would deserve attention because of their high or median ecological risk suspected on marine and freshwater ecosystems. Marine ecosystems would be more sensitive to pharmaceutical residues.
Asunto(s)
Chlorophyta/efectos de los fármacos , Daphnia/efectos de los fármacos , Monitoreo del Ambiente , Preparaciones Farmacéuticas/análisis , Contaminantes Químicos del Agua/toxicidad , Animales , Ecosistema , Francia , Agua Dulce/química , Medición de Riesgo , Contaminantes Químicos del Agua/análisisRESUMEN
The acute toxicities of 36 pharmaceuticals towards green algae were estimated from a set of quantile regression models representing the first global quantitative structure-activity relationships. The selection of these pharmaceuticals was based on their predicted environmental concentrations. An agreement between the estimated values and the observed acute toxicity values was found for several families of pharmaceuticals, in particular, for antidepressants. A recent classification (BDDCS) of drugs based on ADME properties (Absorption, Distribution, Metabolism and Excretion) was clearly correlated with the acute ecotoxicities towards algae. Over-estimation of toxicity from our QSAR models was observed for classes 2, 3 and 4 whereas our model results were in agreement for the class 1 pharmaceuticals. Clarithromycin, a class 3 antibiotic characterized by weak metabolism and high solubility, was the most toxic to algae (molecular stability and presence in surface water).
Asunto(s)
Antagonistas Adrenérgicos beta/toxicidad , Antidepresivos/toxicidad , Chlorophyta/efectos de los fármacos , Preparaciones Farmacéuticas/clasificación , Contaminantes Químicos del Agua/toxicidad , Claritromicina/toxicidad , Relación Estructura-Actividad Cuantitativa , Análisis de Regresión , Solubilidad , Pruebas de Toxicidad Aguda , AguaRESUMEN
The low levels of antidepressants detected in surface waters currently raise concern about their potential long-term risks to nontarget aquatic organisms. We investigated the transgenerational effects of sertraline, a selective serotonin reuptake inhibitor, and venlafaxine, a serotonin-norepinephrine reuptake inhibitor, on the life traits of Daphnia magna over two generations under environmentally realistic concentrations. We also studied the reversibility of the effect using recovery experiments. We assessed daphnid survival, growth, and reproduction over 21 days and evidenced detectable effects of the antidepressants. Sertraline increased the F0-daphnid fecundity whereas it decreased the offspring number of F1-daphnids. Transfer to clean medium caused negative effects on the offspring of daphnids exposed to 0.3 µg L(1), but improved the fecundity of offspring of daphnids exposed to 100 µg L(1). Venlafaxine exposure decreased the offspring number of F0-daphnids and resulted in drug tolerance in the F1 generation. Sertraline, unlike venlafaxine, may turn out to be a true environmental threat due to its accumulation in algae and the physiological weakness observed over generations. These effects across generations point out to the need to perform multigeneration tests to assess the environmental risk of pharmaceuticals in nontarget organisms.
Asunto(s)
Antidepresivos/efectos adversos , Daphnia/efectos de los fármacos , Fertilidad/efectos de los fármacos , Sertralina/efectos adversos , Clorhidrato de Venlafaxina/efectos adversos , Animales , Ambiente , Femenino , Exposición Materna , Dinámica Poblacional , Reproducción/efectos de los fármacosRESUMEN
The potential of quantile regression (QR) and quantile support vector machine regression (QSVMR) was analyzed for the definitions of quantitative structure-activity relationship (QSAR) models associated with a diverse set of chemicals toward a particular endpoint. This study focused on a specific sensitive endpoint (acute toxicity to algae) for which even a narcosis QSAR model is not actually clear. An initial dataset including more than 401 ecotoxicological data for one species of algae (Selenastrum capricornutum) was defined. This set corresponds to a large sample of chemicals ranging from classical organic chemicals to pesticides. From this original data set, the selection of the different subsets was made in terms of the notion of toxic ratio (TR), a parameter based on the ratio between predicted and experimental values. The robustness of QR and QSVMR to outliers was clearly observed, thus demonstrating that this approach represents a major interest for QSAR associated with a diverse set of chemicals. We focused particularly on descriptors related to molecular surface properties.
Asunto(s)
Chlorophyta/efectos de los fármacos , Ecotoxicología/métodos , Pruebas de Toxicidad Aguda , Contaminantes Químicos del Agua/toxicidad , Chlorophyta/crecimiento & desarrollo , Estructura Molecular , Análisis de Componente Principal , Relación Estructura-Actividad Cuantitativa , Análisis de Regresión , Reproducibilidad de los Resultados , Máquina de Vectores de Soporte , Propiedades de Superficie , Factores de Tiempo , Contaminantes Químicos del Agua/clasificaciónRESUMEN
The hazards linked to pharmaceutical residues like antidepressants are currently a major concern of ecotoxicology because they may have adverse effects on non-target aquatic organisms. Our study assesses the ecotoxicity of three antidepressants (fluoxetine, sertraline and clomipramine) using a battery of marine and freshwater species representing different trophic levels, and compares the bioassay sensitivity levels. We selected the following bioassays: the algal growth inhibition test (Skeletonema marinoi and Pseudokirchneriella subcapitata), the microcrustacean immobilization test (Artemia salina and Daphnia magna), development and adult survival tests on Hydra attenuata, embryotoxicity and metamorphosis tests on Crassostrea gigas, and in vitro assays on primary cultures of Haliotis tuberculata hemocytes. The results showed high inter-species variability in EC50-values ranging from 43 to 15,600 µg/L for fluoxetine, from 67 to 4,400 µg/L for sertraline, and from 4.70 µg/L to more than 100,000 µg/L for clomipramine. Algae (S. marinoi and P. subcapitata) and the embryo-larval stages of the oyster C. gigas were the most sensitive taxa. This raises an issue due to their ecological and/or economic importance. The marine crustacean A. salina was the least sensitive species. This difference in sensitivity between bioassays highlights the importance of using a test battery.
Asunto(s)
Antidepresivos/toxicidad , Pruebas de Toxicidad/métodos , Contaminantes Químicos del Agua/toxicidad , Animales , Organismos Acuáticos/efectos de los fármacos , Artemia/efectos de los fármacos , Chlorophyta/efectos de los fármacos , Crassostrea/efectos de los fármacos , Daphnia/efectos de los fármacos , Diatomeas/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Agua Dulce/química , Ostreidae/efectos de los fármacos , Agua de Mar/química , Sensibilidad y EspecificidadRESUMEN
The present study was conducted to determine the toxicity of different polychlorinated biphenyls (PCBs) on the green algae, Pseudokirchneriella subcapitata and the haemocytes from the European abalone, Haliotis tuberculata. Using the algal growth inhibition test, the green algae median Effective Concentration (EC50) values ranged from 0.34µM for PCB28 to more than 100µM for PCBs 101 and 153. Considering the MTT viability test, the abalone EC50 values ranged from 1.67µM for PCB153 to 89µM for PCB28. Our results in contrast to previous observation in vertebrates did not show significant differences between the dioxin like- and non dioxin like-PCBs toxicities regardless of the model used. However, our results demonstrated that the toxicities of PCBs were species dependent. For example, PCB28 was the most toxic compound for P. subcapitata whereas PCBs 1, 180 and 153 were less toxic for that species. On the contrary, PCB153 was reported as the most toxic for H. tuberculata haemocytes and PCB28 the least toxic. To investigate the mode of action of these compounds, we used an in silico method. Our results suggested that PCBs have a non-specific mode of action (e.g., narcosis) on green algae, and another mode of action, probably more specific than narcosis, was reported for PCBs on the abalone haemocytes.
Asunto(s)
Chlorophyta/efectos de los fármacos , Contaminantes Ambientales/toxicidad , Gastrópodos/efectos de los fármacos , Hemocitos/efectos de los fármacos , Bifenilos Policlorados/toxicidad , Animales , Chlorophyta/fisiología , Gastrópodos/citología , Gastrópodos/fisiología , Hemocitos/citología , Dibenzodioxinas PolicloradasRESUMEN
Currently, the hazard posed by pharmaceutical residues is a major concern of ecotoxicology. Most of the antidepressants belong to a family named the Cationic Amphipathic Drugs known to have specific interactions with cell membranes. The present study assessed the impact of eight antidepressants belonging to selective serotonin reuptake inhibitors or serotonin norepinephrine reuptake inhibitors by the combination of multi-approaches (in vivo, in vitro, in silico) and gives some insights on the mode of action for these molecules. Antidepressants were from the most to the least toxic compound for Daphnia magna: Sertraline (EC50=1.15 mg L(-1))>Clomipramine (2.74 mg L(-1))>Amitriptyline (4.82 mg L(-1))>Fluoxetine (5.91 mg L(-1))>Paroxetine (6.24 mg L(-1))>Mianserine (7.81 mg L(-1))>Citalopram (30.14 mg L(-1)) and Venlafaxine (141.28 mg L(-1)). These acute toxicities were found correlated to Log Kow coefficients (R=0.93, p<0.001) and to cytotoxicity assessed on abalone hemocytes through the neutral red uptake assay (R=0.96, p<0.001). If narcosis as mode of action is typically expected during acute ecotoxicity bioassays, we showed by molecular modeling that particular interactions can exist between antidepressants and phosphatidylcholine, a major component of cell membranes, leading to a more specific mode of action corresponding to a potential acidic hydrolysis of ester functions.
Asunto(s)
Antidepresivos/toxicidad , Daphnia/efectos de los fármacos , Contaminantes Ambientales/toxicidad , Gastrópodos/efectos de los fármacos , Inhibidores Selectivos de la Recaptación de Serotonina/toxicidad , Animales , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Daphnia/metabolismo , Gastrópodos/citología , Hemocitos/citología , Hemocitos/efectos de los fármacos , Lisosomas/efectos de los fármacos , Lisosomas/metabolismo , Modelos Moleculares , Fosfatidilcolinas/metabolismoRESUMEN
Thiophene derivatives, a class of compounds widely used in products such as pharmaceuticals, agrochemicals or dyestuffs, represent chemicals of concern. Indeed, the thiophene ring is often considered as a structural moiety that may be involved in toxic effects in humans. We primarily focus on the genotoxic/mutagenic and carcinogenic potentials of the methyl 3-amino-4-methylthiophene-2-carboxylate (1), a precursor of the articaine local anesthetic (4) which falls within the scope of the European REACH (Registration, Evaluation, Authorisation and restriction of CHemicals) legislation. To discern some structure-toxicity relationships, we also studied two related compounds, namely the 3-amino 4-methylthiophene (2) and the 2-acetyl 4-chlorothiophene (3). Techniques employed to assess mutagenic and DNA-damaging effects involved the Salmonella mutagenicity assay (or Ames test) and the single-cell gel electrophoresis assay (or Comet assay). In the range of tested doses, none of these derivatives led to a positive response in the Ames tests and DNA damage was only observed in the Comet assay after high concentration exposure of 2. The study of their carcinogenic potential using the in vitro SHE (Syrian Hamster Embryo) cell transformation assay (CTA) highlighted the activity of compound 2. A combination of experimental data with in silico predictions of the reactivity of thiophene derivatives towards cytochrome P450 (CYP450), enabled us to hypothesize possible pathways leading to these toxicological profiles.
Asunto(s)
Carcinógenos/toxicidad , Daño del ADN/efectos de los fármacos , Tiofenos/toxicidad , Animales , Carcinogénesis/efectos de los fármacos , Transformación Celular Neoplásica , Células Cultivadas , Ensayo Cometa , Cricetinae , Femenino , Humanos , Persona de Mediana Edad , Pruebas de Mutagenicidad , Salmonella typhimurium/efectos de los fármacosRESUMEN
Pharmaceutical compounds like antidepressants found in surface waters raise concerns due to their potential toxicity on non-target aquatic organisms. This study aimed at investigating the in vitro cytotoxicity and immunomodulatory properties of four common antidepressants, namely Amitriptyline, Clomipramine, Citalopram and Paroxetine, on primary cultures of abalone hemocytes (Haliotis tuberculata), after 48 h-exposure. Effects on immunocompetence (phagocytosis, levels of reactive oxygen species, esterase activity and lysosomal membrane destabilization) were assessed. Results obtained by MTT assays revealed that acute toxicity is unlikely to occur in the environment since the LC50s of the four antidepressants are at the mg/L level. The different immunological endpoints displayed a biphasic response, with an increase at the lowest concentration (i.e. 1 µg/L) followed by a decrease at higher concentrations. Overall, Amitriptyline and Clomipramine, the two tricyclic antidepressants, had higher immunomodulatory capacities than the two selective serotonin reuptake inhibitors Citalopram and Paroxetine. Amitriptyline was the most potent and Citalopram the least potent drug in altering immune function in H. tuberculata.
Asunto(s)
Antidepresivos/toxicidad , Gastrópodos/efectos de los fármacos , Contaminantes Químicos del Agua/toxicidad , Animales , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Activación Enzimática/efectos de los fármacos , Esterasas/metabolismo , Gastrópodos/enzimología , Gastrópodos/inmunología , Hemocitos/efectos de los fármacos , Hemocitos/enzimología , Inmunidad Innata/efectos de los fármacos , Dosificación Letal Mediana , Fagocitosis/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismoRESUMEN
The widespread use of different pesticides generates adverse effects on non target organisms like honeybees. Organophosphorous and carbamates kill honeybees through the inactivation of acetylcholinesterase (AChE), thereby interfering with nerve signaling and function. For this class of pesticides, it is fundamental to understand the relationship between their structures and the contact toxicity for honeybees. A Quantitative Structure-Activity Relationship (QSAR) study was carried out on 45 derivatives by a genetic algorithm approach starting from more than 2500 descriptors. In parallel, a new 3D model of AChE associated to honeybees was defined. Physicochemical properties of the receptor and docking studies of the derivatives allow understanding the meaningful of three descriptors and the implication of several amino acids in the overall toxicity of the pesticides.
Asunto(s)
Inhibidores de la Colinesterasa/toxicidad , Acetilcolinesterasa/metabolismo , Algoritmos , Secuencia de Aminoácidos , Animales , Abejas , Carbamatos/química , Carbamatos/toxicidad , Inhibidores de la Colinesterasa/química , Modelos Químicos , Datos de Secuencia Molecular , Compuestos Organofosforados/química , Compuestos Organofosforados/toxicidad , Relación Estructura-Actividad CuantitativaRESUMEN
Starting from a random set of structures taken from the European Chemical Bureau (ECB) Web site, an estimation of the classification by acute category in ecotoxicology was carried out. This estimation was based on two approaches. One approach consists in starting with global quantitative structure-activity relationship (QSAR) equations, analyzing the results and defining an interpretation in terms of overall results and mode of action. The other starts with the notion of emerging fragments and more specifically with the introduction of a particular concept: the jumping fragments. This publication studies the scopes and limitations of each approach for the classification of the derivatives. A promising combination of the two methods is proposed for the classification and also for bringing new information about the importance, for the ecotoxicity, of specific chemical fragments considered alone or in association with others.
Asunto(s)
Ecotoxicología/métodos , Contaminantes Ambientales/química , Contaminantes Ambientales/efectos adversos , Modelos Biológicos , Estructura Molecular , Relación Estructura-Actividad CuantitativaRESUMEN
Under REACH legislation, alternative methods (in silico or in vitro) like QSAR (Quantitative Structure-Activity Relationships) models are expected to play a significant role. QSARs are based on the assumption that substances with similar chemical structures may have the same biological activities. However, identification of chemical classes could be problematic because chemicals often exhibit different chemical moieties, thereby confounding efforts to achieve a meaningful classification. This publication is focus on the notion of global model with the integration of a recent genetic algorithm for the generation of QSAR models. Starting from three datasets (EPAFHM, ECBHPV, AQUIRE), prediction of acute toxicity for fish (Pimephales promelas) with a global consensus model was carried out leading to very interesting statistics. The integration of the notion of Mode of Action was the second point of this study. A Bayesian classification associated to the genetic algorithm for consensus models was created leading to a good estimation of toxicity associated to derivatives with nonspecific MOA.