13 Abstract An environmental pollutant and a human carcinogen benzo[a]pyrene (BaP) is after its activation with cytochrome P450 (CYP) able to covalently bind to DNA. In the thesis, one of the target was to investigate an influence of individual components of mixed function monooxygenase (MFO) system on metabolism of benzo[a]pyrene and generation of adducts of activated BaP with DNA. The study was particularly focused to increase our knowledge on the effect of cyt b5 on metabolism of BaP by cytochrome P450 1A1 (CYP1A1) and its potential to serve as a donor of electrons during the reaction cycle of this cytochrome P450. The effect of cyt b5 on generation of BaP metabolites and adducts of BaP with DNA was investigated. In addition the effect of two different expression systems for cytochrome P450 1A1 (prokaryotic and eukaryotic) was also studied. The influence of cyt b5 on oxidation another xenobiotic compound, a plant alkaloid ellipticine that exhibit antitumor activities, was also investigated. Its pharmacological efficiency, as well as side effects depends on its metabolic activation by cytochrome P450. CYP3A4 is very important for ellipticine activation and therefore this enzyme was used in our experiments. Furthermore, a suitability of rat as a model organism mimicking the metabolic fate of BaP...

6 Abstract Ellipticine (5,11-dimethyl-6H-pyrido[4,3-b]carbazole), an alkaloid isolated from Apocynaceae plants, exhibits significant antitumor and HIV activity. This antitumor agent binds to DNA and forms covalent DNA adducts. Enzymes, which are involved in its enzymatic activation, are cytochromes P450 (CYP) and peroxidases. To elucidate the effect of ellipticine on the expression and enzymatic activity of the individual components of the microsomal mixed function oxidase system in different tissues, we used rat model. Simultaneously, the effect of ellipticine and its cytotoxicity on different tumor cell lines was also investigated. Another part of the presented work was targeted on preparation of anti-peptide antibody against orphan cytochrome P450 2S1, which is highly expressed in many human tumours of the epithelial origin, for its detection in these tissues. For better understanding how CYP2S1 can contribute to the metabolism of xenobiotics, the protein was prepared by heterologous expression in E. coli. Furher, its role in metabolism of an antitumor drug ellipticine, a carcinogenic environmental pollutant benzo[a]pyrene (BaP) and its derivate BaP-7,8-dihydrodiol was examined. Utilizing a mouse model, the impact of pulmonary inflammation on the metabolism of an environmental carcinogen was...

A exposição dos peixes a poluentes provoca danos nos organismos que podem ser identificados precocemente através de respostas biológicas. O presente estudo visou avaliar os efeitos do naftaleno e benzo(a)pireno em pampos da espécie Trachinotus carolinus. Foram avaliados os efeitos citogenotóxicos, histopatológicos e bioquímicos após exposições às concentrações de 0,9 M; 2,7 M e 8,1 M de NAP e BAP por períodos de 12, 24, 48 e 96 horas. O NAP causa quebra no DNA de eritrócitos de pampos em concentrações de 8,1 M e a partir de 12 horas de exposição. O BAP revelou ser genotóxico a partir da menor concentração e de 24 horas. A mutagenicidade de ambos os poluentes, avaliada através da indução de formação de micronúcleos e anormalidades nucleares eritrocitárias, também ocorre a partir de curtos períodos de exposição e freqüências de MN e ANE estão relacionadas com a duração da exposição. O período de exposição aos HPAs foi determinante na intensidade e severidade das lesões observadas nos tecidos dos peixes. A especificidade de CYP1A, observada segundo análise imunohistoquímica, ocorreu de maneira dose-dependente e evidenciada principalmente nos maiores períodos experimentais. Os poluentes orgânicos, nas condições experimentais utilizadas, não provocaram alteração significativa na atividade das enzimas catalase e GST da espécie. Os biomarcadores, citogenotóxicos e histopatológicos utilizados neste estudo, demonstraram ser ferramentas eficientes para aferir a toxicidade, genotoxicidade e mutagenicidade de NAP e BAP como também sua relação dose-resposta na espécie T. carolinus. / Effects of exposure of fish to pollutants can be identified through stress responses. The present study aims to evaluate the effects of naphthalene and benzo(a)pyrene in Florida pompanos, Trachinotus carolinus. Evidences from citogenotoxical, histopathological and biochemical studies showed that alterations caused by exposures to 0.9 M, 2.7 M and 8.1 M of NAP and BAP occurred within 12 to 96 hours. NAP at 8.1 M induced erythrocyte DNA strand breaks in pompanos since early periods of exposure. Genotoxic effects of BAP at the lowest concentration were documented soon after 24 hours of exposure. Mutagenotoxicity of both pollutants, as seen by the induction of MN and ENA, was revealed since early periods and their frequencies are related to the duration of exposure. Exposures to these PAHs, for longer periods, resulted in increased frequency and severity of lesions observed in fish tissues. Specificity of CYP1A, observed through immunohistochemical analyses, was related to the dose of the pollutants and mainly at longer periods of exposure. These organic pollutants, under the experimental conditions, did not interfere with the activity of liver catalase and GST of the species. The citogenotoxic and histopathologic biomarkers used in this study proved to be efficient tools to ascertain the toxicity, genotoxicity and mutagenesis of NAP and BAP, as well as their dose related response, in the species T. carolinus.

Setenta e três fungos representantes de grupos taxonômicos distintos, isolados de cnidários, coletados no litoral norte do estado de São Paulo, foram submetidos ao teste de descoloração do corante RBBR e ao teste de MIC. Treze fungos selecionados no teste de descoloração foram submetidos ao teste de degradação de pireno e benzo[a]pireno. Sete fungos mostraram resultados satisfatórios de degradação, entretanto, o fungo Aspergillus sulphureus (8.2A) apresentou os melhores resultados: degradou 99,7% de pireno e 73,6% de benzo[a]pireno. Com relação ao teste de MIC, 21 isolados inibiram o crescimento das bactérias: B. subtillis; P. aeruginosa, S.aureus, E. coli EPEC e V. parahaemolyticus. Penicillium sp. (12.12) apresentou o melhor resultado (0,0078 mg/mL). Os 23 isolados que apresentaram potencial biotecnológico foram caracterizados taxonomicamente. Os resultados do presente trabalho sugerem que fungos filamentosos associados a cnidários possuem potencial para aplicação biotecnológica, em particular para biorremediação de ambientes marinhos contaminados com HPAs. / Seventy three fungi representatives of distinct taxonomic groups, isolated from cnidarians collected from north coast of São Paulo State, were submitted to RBBR dye decolorization tests and to MIC. Thirteen fungal selected from the decolorization test were submitted to pyrene and benzo[a]pyrene degradation assays. Seven fungi showed satisfactory PAH degradation results. Among them Aspergillus sulphureus (8.2A) presented the best results degrading pyrene (99.7%) and benzo[a]pyrene (73.6%). Regarding the MIC experiments, 21 isolates were able to inhibit the growth of B. subtilis, P. aeruginosa, S. aureus, E. coli EPEC and V. parahaemolyticus. Penicillium sp. (12.12) presented the best result (0,0078 mg/mL). The 23 isolates that showed potential biotechnologic were taxonomically characterized. Results derived from the present work suggest that cnidarians-derived filamentous fungi have a great potential for biotechnological application, in particular on bioremediation of marine environments contaminated by PAHs.

Le microbiote intestinal joue un rôle primordial dans l’homéostasie du tractus gastro-intestinal, et plus généralement dans celle de son hôte. A ce titre, de nombreuses pathologies humaines sont associées à une dysbiose de ce microbiote intestinal, tels que les cancers colorectaux, les maladies inflammatoires chroniques de l’intestin (MICI), les troubles du métabolisme ou encore les maladies auto-immunes. Ces pathologies ont une étiologie mal connue et multifactorielle dans laquelle l’environnement semble jouer un rôle clé. Des études récentes ont ainsi mis en évidence un lien entre la pollution atmosphérique et des pathologies humaines telles que les MICI. Parmi les différentes substances polluantes répertoriées, le benzo[a]pyrène (BaP), qui fait partie de la famille des hydrocarbures aromatiques polycycliques, est soumis à une surveillance accrue en raison de ses effets toxiques sur la santé humaine. De par ses propriétés pro-inflammatoires et mutagènes, le BaP pourrait modifier la composition du microbiote intestinal, induisant alors à une réponse inflammatoire et à une altération des fonctions intestinales. Dans le cadre de ce travail de thèse, une surexposition orale et chronique au BaP en modèle murin a conduit à une inflammation modérée principalement au niveau de la muqueuse iléale. L’analyse des amplicons du gène codant l’ARNr 16S a mis en évidence des modifications de la composition et de l’abondance relative des communautés bactériennes fécales et associées à la muqueuse intestinale avec notamment une augmentation et une diminution des taxa pro et anti-inflammatoires respectivement. Ainsi, dans des conditions de susceptibilité génétique et/ou en association avec d’autres facteurs environnementaux, l’exposition à ce polluant pourrait déclencher et/ou accélérer le développement de pathologies inflammatoires. L’identification des potentialités métaboliques des différentes populations bactériennes caractérisées précédemment et impactées par le polluant revêt donc un caractère primordial. La reconstruction de génomes directement à partir de l’écosystème microbien peut permettre d’établir ce lien entre structure et fonction. C’est également dans ce contexte, qu’une approche innovante de capture de gènes en solution a été développée. En effet, cette technique d’enrichissement permet de reconstruire de larges portions génomiques pouvant relier un biomarqueur phylogénétique à des gènes fonctionnels, y compris pour des populations bactériennes présentes en très faible abondance dans l’écosystème. / Gut microbiota plays a primordial role in gastro-intestinal tract and host homeostasis. Numerous pathologies are associated with a gut microbiota dysbioses, such as colorectal cancer, inflammatory bowel diseases (IBD), metabolism disorders or autoimmune diseases. The physiopathology of these diseases has multifactorial aetiology in which environmental factors seem to play a crucial role. Recent evidences have highlighted a link between air pollution and human diseases such as IBD. Among the different pollutant listed, benzo[a]pyrene (BaP), which belong to the family of polycyclic aromatic hydrocarbons, is subject to an increase surveillance due to its toxic effects on human health. By its pro-inflammatory and mutagenic proprieties, BaP could lead to modifications of gut microbiota composition, then inducing an inflammatory response and an alteration of intestinal functions. As part of this thesis, BaP subchronic oral exposure in murine model has led to a moderate inflammation mostly in ileal mucosa. The analysis of ARNr 16S amplicons has highlighted composition and abundance alterations of faecal and mucosa-associated microbiota, especially with increase and decrease of pro and anti- inflammatory taxa respectively. Thus, under conditions of genetic susceptibility and/or in association with other environmental factors, exposure to this pollutant could trigger and/or accelerate the development of inflammatory pathologies. Metabolic potential identification of different bacterial populations previously characterized and affected by the pollutant appears therefore primordial. Genome reconstruction directly from microbial ecosystem could allow to establish this link between structure and function. Also in this context, an innovative approach of gene capture in solution was developed. Indeed, this enrichment technique allows to reconstruct large genomic portions that could link phylogenetic biomarker and functional genes, including for bacterial populations present at very low abundance in the ecosystem.

A exposição dos peixes a poluentes provoca danos nos organismos que podem ser identificados precocemente através de respostas biológicas. O presente estudo visou avaliar os efeitos do naftaleno e benzo(a)pireno em pampos da espécie Trachinotus carolinus. Foram avaliados os efeitos citogenotóxicos, histopatológicos e bioquímicos após exposições às concentrações de 0,9 M; 2,7 M e 8,1 M de NAP e BAP por períodos de 12, 24, 48 e 96 horas. O NAP causa quebra no DNA de eritrócitos de pampos em concentrações de 8,1 M e a partir de 12 horas de exposição. O BAP revelou ser genotóxico a partir da menor concentração e de 24 horas. A mutagenicidade de ambos os poluentes, avaliada através da indução de formação de micronúcleos e anormalidades nucleares eritrocitárias, também ocorre a partir de curtos períodos de exposição e freqüências de MN e ANE estão relacionadas com a duração da exposição. O período de exposição aos HPAs foi determinante na intensidade e severidade das lesões observadas nos tecidos dos peixes. A especificidade de CYP1A, observada segundo análise imunohistoquímica, ocorreu de maneira dose-dependente e evidenciada principalmente nos maiores períodos experimentais. Os poluentes orgânicos, nas condições experimentais utilizadas, não provocaram alteração significativa na atividade das enzimas catalase e GST da espécie. Os biomarcadores, citogenotóxicos e histopatológicos utilizados neste estudo, demonstraram ser ferramentas eficientes para aferir a toxicidade, genotoxicidade e mutagenicidade de NAP e BAP como também sua relação dose-resposta na espécie T. carolinus. / Effects of exposure of fish to pollutants can be identified through stress responses. The present study aims to evaluate the effects of naphthalene and benzo(a)pyrene in Florida pompanos, Trachinotus carolinus. Evidences from citogenotoxical, histopathological and biochemical studies showed that alterations caused by exposures to 0.9 M, 2.7 M and 8.1 M of NAP and BAP occurred within 12 to 96 hours. NAP at 8.1 M induced erythrocyte DNA strand breaks in pompanos since early periods of exposure. Genotoxic effects of BAP at the lowest concentration were documented soon after 24 hours of exposure. Mutagenotoxicity of both pollutants, as seen by the induction of MN and ENA, was revealed since early periods and their frequencies are related to the duration of exposure. Exposures to these PAHs, for longer periods, resulted in increased frequency and severity of lesions observed in fish tissues. Specificity of CYP1A, observed through immunohistochemical analyses, was related to the dose of the pollutants and mainly at longer periods of exposure. These organic pollutants, under the experimental conditions, did not interfere with the activity of liver catalase and GST of the species. The citogenotoxic and histopathologic biomarkers used in this study proved to be efficient tools to ascertain the toxicity, genotoxicity and mutagenesis of NAP and BAP, as well as their dose related response, in the species T. carolinus.

Les activités industrielles sont à l’origine d’un grand nombre de sites et sols pollués en France. Parmi les polluants retrouvés, les hydrocarbures aromatiques polycycliques (HAP), notamment ceux de haut poids moléculaire, posent un réel problème environnemental et de santé publique en raison de leur toxicité et de leur persistance dans les sols. Les techniques biologiques de remédiation qui stimulent la dégradation microbienne des HAP en utilisant des plantes (phyto/rhizoremédiation), des nutriments (biostimulation), ou encore des microorganismes (bioaugmentation), apparaissent comme des stratégies intéressantes car elles sont plus respectueuses de l’environnement et moins onéreuses que les méthodes physico-chimiques. Dans ce contexte, la capacité de la plante Miscanthus x giganteus (MxG) à améliorer la dissipation du benzo(a)anthracène (BaA), un HAP de haut poids moléculaire peu étudié en remédiation, a été évaluée par une approche pluridisciplinaire en réalisant deux types d’expérimentations à partir d’un sol artificiellement contaminé. La première a consisté à analyser l’influence rhizosphérique de la plante (phyto/rhizoremédiation) au cours d’une période de 12 mois. Les résultats ont montré que la présence de MxG conduisait en fin d’exposition à une réduction 3 fois plus importante de la teneur en BaA dans le sol grâce à une augmentation de la biodisponibilité du contaminant et à un effet positif sur les communautés microbiennes via une modification de leur diversité et une augmentation de leur densité de gènes ARNr 16S et PAH-RHDα GP. Afin d’améliorer la compréhension de ce phénomène, une deuxième expérimentation a été mise en place sur une durée de 105 jours dans le but d’étudier spécifiquement l’influence de certaines molécules exsudées au niveau du système racinaire de la plante (biostimulation) et de microorganismes spécifiques, associés à sa rhizosphère, ayant la capacité de dégrader le BaA (bioaugmentation). Ces essais ont témoigné de la complexité des mécanismes rhizosphériques et de la nécessité d’approfondir ce type d’analyses afin d’améliorer la compréhension des processus de biodégradation dans la rhizosphère de la plante. L’ensemble de ces résultats a alors montré que MxG était une candidate idéale pour la phyto/rhizoremédiation de sols contaminés par des HAP de haut poids moléculaires mais que des études supplémentaires étaient encore nécessaires pour comprendre les processus intervenant dans sa rhizosphère / Industrial activities result of a large number of contaminated sites and soils in France. Among the pollutants found, polycyclic aromatic hydrocarbons (PAHs), and especially those of high molecular weight, are a real environmental and public health problem because of their toxicity and persistence in soils. Biological remediation techniques which stimulate microbial degradation of PAHs using plants (phyto/rhizoremediation), nutrients (biostimulation), or microorganisms (bioaugmentation), appear as interesting strategies because they are more environmental friendly and less expensive than physico-chemical methods. In this context, the ability of the plant Miscanthus x giganteus (MxG) to improve benzo(a)anthracene (BaA) dissipation, a high molecular weight PAH few studied in remediation, was assessed with a multidisciplinary approach through two types of experimentations using an artificially contaminated soil. The first one was to analyze the rhizospheric influence of the plant (phyto/rhizoremediation) over a period of 12 months. Results showed that the presence of MxG led to a 3-fold reduction in BaA concentration in soil at the end of exposure thanks to an increase in pollutant bioavailability, and a positive effect on microbial communities due to a modification of their diversity and an increase in their 16S rRNA and PAH-RHDα GP genes density. In order to improve the understanding of this phenomenon, a second experiment was carried out for 105 days to study specifically the influence of certain molecules exuded in the plant’s root system (biostimulation), and specific microorganisms associated with its rhizosphere having the capacity to degrade BaA (bioaugmentation). These tests demonstrated the complexity of rhizospheric mechanisms, and the necessity to explore this type of analysis to improve the understanding of biodegradation processes in plant rhizosphere. All these results showed that MxG was an ideal candidate for phyto/rhizoremediation of soils contaminated with high molecular weight PAH, but that further studies were still needed to understand processes involved in its rhizosphere

Les propriétés spectrales des composants fluorescents de la matière organique d’un sol naturel ont été étudiées dans les trois fractions physiques ; substances humiques, acide fulvique et acide humique, par la méthode des matrices d’excitation et d’émission de fluorescence couplée à l’algorithme Parallel Factor analysis (PARAFAC). Les modifications spectrales de ces composants ont été suivies (forme et pseudo-concentrations) en présence d’un contaminant de type hydrocarbure aromatique polycyclique (le benzo(a)pyrène (BaP), toxique et à caractère cancérigène) : (1) en faisant varier les volumes d’une solution pure de BaP dans chaque fraction de même concentration en matières organiques, (2) en faisant varier les concentrations en matière organique pour des concentrations fixes de BaP, qui ont été suivies dans le temps. Les résultats ont montré que le BaP influence d’une manière différente les fluorophores présents dans les trois fractions et ont permis de clarifier le type d’interactions avec une fraction ou l’autre. D’autre part, une discussion a été menée sur les paramètres de validation du nombre de composants pour le choix des modèles de PARAFAC. / The spectral properties of the fluorescent components of the organic matter of a natural soil were studied in the three physical fractions; humic substances, fulvic acid and humic acid, by the method of the excitation and fluorescence emission matrices coupled to the Parallel Factor Analysis (PARAFAC) algorithm. The spectral modifications of these components were studied (form and pseudo-concentrations) in the presence of a polycyclic aromatic hydrocarbon contaminant (benzo (a) pyrene (BaP), toxic and carcinogenic): (1) by varying the volumes of a pure solution of BaP in each fraction having the same concentration of organic matter, (2) by varying the concentrations of organic matter for fixed concentrations of BaP, which were followed over time. The results showed that the BaP influences the fluorophores present in the three fractions in a different way and clarified the type of interactions with one fraction or the other. On the other hand, a discussion was held on parameters for validating the number of components for the selection of PARAFAC models.

L’HBP et le cancer de la prostate constituent les deux maladies prostatiques les plus répandues chez l’homme âgé. La compréhension de leur étiologie et de leur pathogenèse est nécessaire afin de permettre la prévention mais aussi la recherche et le développement de nouveaux agents thérapeutiques. Notre but est d’étudier l’implication du stress oxydatif dans l’HBP et d’étudier l’effet de l’extrait de propolis sur le cancer de la prostate in vivo chez le rat Wistar et in vitro sur les cellules LNCaP. Nous avons montré que : 1) Le stress oxydatif joue le rôle de promoteur dans le développement de l’HBP, 2) Le benzo(a)pyrène administré aux rats Wistar induit le développement du cancer de la prostate, 3) La propolis induit la diminution de la prolifération, de l’expression du Ki-67 (-49 %) et de l’expression de AhR chez le rat Wistar, 4) La propolis possède un effet antiprolifératif sur les cellules LNCaP via le blocage de la signalisation de AR. / BPH and prostate cancer are the two most prevalent prostatic diseases in elders. Understanding their etiology and pathogenesis is necessary in order to prevent them and to enhance both research and development of new therapeutic agents. Our goal is to study the implication of oxidative stress in BPH and to study the effect of propolis extract on prostate cancer in vivo in Wistar rats and in vitro on LNCaP cells. We have shown that: 1) Oxidative stress acts as a promoter in the development of BPH, 2) Benzo(a)pyrene administered to Wistar rats induces the development of prostate cancer, 3) Propolis induces a decrease in proliferation, Ki-67 expression (-49%) and AhR expression in the Wistar rat, (4) Propolis has an antiproliferative effect on LNCaP cells via AR signaling blockade.

Dans notre étude, la biosurveillance de la lagune de Tunis a été réalisée durant une année enemployant une approche combinant les analyses chimiques et biologiques et en utilisant lapalourde Ruditapes decussatus comme espèce bioindicatrice. Cette approche a permis demettre en évidence la forte contamination de la lagune de Tunis par les métaux traces et leshydrocarbures aromatiques polycycliques (HAPs). La variation saisonnière des niveaux debioaccumulation de ces contaminant par la palourde s’avère être fortement associée auxchangements des paramètres physico-chimiques du milieu et aux processus physiologiques del’animal. L’étude de la réponse biologique basée sur l’utilisation d’une batterie debiomarqueurs d’exposition et d’effet situés à différents niveaux de l’organisation biologique :moléculaire (l’expression de cinq gènes d’intérêt), biochimique (les activités benzo(a)pyrènehydroxylase, glutathion S-transférase, acétylcholinestérase, catalase et taux demalondialdéhyde) et tissulaire (altérations histopathologiques), a permis de mettre enévidence une modulation des processus de défense contre les perturbations induites par lapollution et l’identification des altérations histopathologiques (structurales) au niveau desbranchies et de la glande digestive impliquant un impact sévère des contaminants sur l’état desanté de la palourde. L’étude des interactions spatio-temporelles entre les facteurs abiotiqueset biotiques a permis d’identifier la température et la reproduction comme paramètresprincipaux affectant la réponse biochimique de défense et d’effet. L’analyse en composanteprincipale (ACP), regroupant tous les paramètres analysés pendant le printemps, nous apermis d’identifié le site Z2 comme le site le plus affecté par la pollution. Dans un secondtemps, le benzo(a)pyrène (BaP), déjà identifié dans la lagune de Tunis, a été employé dansdes conditions contrôlées au laboratoire afin de caractériser les réponses moléculaires etbiochimiques chez les bivalves (Ruditapes philippinarum et Crassostrea gigas) face à desexpositions subaiguës et aiguës à ce contaminant. Cette étude nous a permis d’identifier unemodulation des biomarqueurs biochimiques de métabolisation, de stress oxydant et deneurotoxicité et de l’expression des gènes impliqués dans les processus de métabolisation, derespiration mitochondriale, de défense antioxydante, de reproduction et de défenseimmunitaire. L’analyse de l’altération de l’ADN a révélé un pouvoir génotoxique précoce etélevé du BaP chez les deux bivalves. / Firstly, biomonitoring of Tunis lagoon was conducted during one year using an approach combining chemicals and biological analyses and the bioindicator species Ruditapesdecussatus. This approach high lighted the high contamination of the Tunis lagoon by tracemetals and polycyclic aromatic hydrocarbons (PAHs). Seasonal variation of contaminant bioaccumulation levels in clam was found to be strongly associated with physico chemical changes in surrounding environment and physiological processes in organism. Biological responses investigated through a battery of exposure and effect biomarkers located at differentlevels of biological organisation: molecular (expression of five genes), biochemical(benzo(a)pyrene hydroxylase, glutathione S-transferase, acetylcholinesterase and catalase activities and malondialdehyde concentration) and tissular (histopathological damages),demonstrated a defense process modulation by pollution and showed histopathological alterations in gills and digestive gland involving severe impact of contaminants on health stateof clam. The study of spatio temporal interactions between abiotic and biotic factors identified temperature and reproduction as main parameters affecting defense and effect biochemical response. The principal component analysis (PCA), using all analyzed parameters during thespring, allowed to identify site Z2 as the most affected by pollution. Secondly,benzo(a)pyrene (BaP), already identified in Tunis lagoon, was used in controlled conditions at the laboratory in order to characterize the molecular and biochemical responses in bivalves(Ruditapes philippinarum and Crassostrea gigas) facing a subacute and acute exposures tothis contaminant. This study showed a modulation of biochemical biomarkers of metabolism,oxidative stress and neurotoxicity and expression of genes involved in process of metabolisation, mitochondrial respiration, antioxidant defense, reproduction and immune defense. The analysis of DNA damages revealed a high and early genotoxicity effect of BaPin both bivalves.