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Immunotoxic Impact of Pharmaceuticals on Harbor Seal (Phoca Vitulina) Leukocytes

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Immunotoxic Impact of Pharmaceuticals on Harbor Seal (Phoca Vitulina) Leukocytes Université du Québec Institut National de la Recherche Scientifique Centre Institut Armand-Frappier Immunotoxic Impact of Pharmaceuticals on Harbor Seal (Phoca vitulina) Leukocytes Par Christine Kleinert Thèse présentée pour l’obtention du grade de Philosophiae doctor (Ph.D.) en Biologie Jury d’évaluation Président du jury et Cathy Vaillancourt examinateur interne INRS-Institut Armand-Frappier Examinateur externe André Lajeunesse Dép. de chimie-biochimie et physique Université du Québec à Trois-Rivières Examinateur externe Daniel Martineau Dép. de pathologie et microbiologie Faculté de médecine vétérinaire Université de Montréal Directeur de recherche Michel Fournier INRS-Institut Armand-Frappier Codirecteur de recherche Sylvain De Guise Department of Pathobiology University of Connecticut © Droits réservés de Christine Kleinert, 2017 This thesis is dedicated to the seals of Eastern Canada. I love you dearly. 0 ACKNOWLEDGEMENTS First and foremost, none of this work would have been possible without the financial support of the Institut National de la Recherche Scientifique-Institut Armand-Frappier and the Canada Research Chair in Immunotoxicology (obtained by Prof. Michel Fournier). I was personally also supported by the German Academic Exchange Service (DAAD) and the Fondation Armand- Frappier with one-year scholarships and would like to thank these organizations. Secondly, I would like to thank my supervisors Michel Fournier and Sylvain De Guise. Thank you, Michel, for giving me the freedom to develop my own project, and follow my personal research interest. I was able to grow and develop my independence as a researcher in your laboratory. Thank you also for financing my attendance in nine national and international conferences. The exchange with other researchers in the field was an invaluable asset. Thank you, Sylvain, for your help in shaping my articles to their current form. I highly valued and appreciated your input and am grateful that you pushed me to be a better writer. Furthermore, I would like to thank the members of the jury Cathy Vaillancourt, François Gagné, Daniel Martineau and André Lajeunesse to have accepted to correct and evaluate my thesis. Some of you have accompanied me through more than this last exam and helped shape my project to what it is today. Thank you for your continued interest in my research and guidance. Thank you to Mike Hammill and the Marine Mammal group of the Institut Maurice-Lamontagne for the grey seal muscle samples and for letting me hitchhike during your field work. A special thanks to the field team of 2014 including Pierre Carter, Joanie Van De Walle and Caroline Sauvé for making 13 h work days fun and relaxing. I would like to take this moment to apologize to the harbor seals of the Bic National Park and Métis. But thank you for providing me with your blood cells. I highly appreciate it. I would like to thank Stéphane Masson from the Aquarium du Québec and Stéphane Lair for their help in obtaining blood samples from the four harbor seal residents of the aquarium. And thanks to Dalia, Cléo, Daphnée and Nikki for some of your blood. Sorry that my research was an inconvenience for you. Moreover, I would like to thank Sébastien Sauvé for his interest in collaborating with me to determine if seals do accumulate APIs. It is bittersweet that we were not able to finish the v 0 project, but I am happy that it might be finalized with one of your interns. Thank you also to Sung Vo Duy for help with technical questions and for your time. Furthermore, I’d like to thank David Chatenet for letting me utilize the freeze-dry system of your lab and to Myriam Létourneau for technical assistance. I’m sorry for the smelly samples! Thanks to Patrick Labonté and his team for letting me use some of their space and material every once in a while. A big thank you to Marlène Fortier, the fairy godmother of our lab, for teaching me everything I know about the FACS, your technical assistance and personal support in times of need. Thanks also to Pauline Brousseau for our discussions and for your help in correcting especially my earlier pieces of writing for exams. Thank you for welcoming me in your home during the field work period. I really enjoyed our table conversations. The past four years would not have been the same without my fellow labmates Dr. Émilie Lacaze, Dr. Lauris Evariste, Dr. Julie Pédelucq, Dr. Marc Fraser, Dr. Messika Revel, Zohra Omori, Philippine Granger, Alexandre Beaudry et Pierre-Luc Cloutier. You will be in my heart forever and I hope we will see each other again in future congresses. A special thanks to my two interns Méryl Mounier and João Victor Alvaia and my Apprentis Bruno Fernandez Anaya, Kimberly Gale and Yoan Patry-Menard. Teaching hands-on science for the first time was a very gratifying experience with you. Not a thanks, but a heartfelt sorry, to my friends from Germany for not having written more in the past couple of years. I am confident this will change now. And a huge thanks to my family for being there for me, and for your sacrifices that allowed me to be where I am today. Lastly, I’d like to thank my Canadian family Matthieu Blanchet and Pamela H. D. Kleinert. Matthieu, not a thousand words can describe how grateful I am for your existence. You fought and suffered through this project just as hard as I did. When results were coming in you were just as happy and relieved as I was. We rode the emotional rollercoaster of scientific research together. And Pamela, even though you have no idea what was happening in the past 2 ½ years, thank you for bringing a light and many laughs into our lives. But please, in the future, let us sleep past 4 a.m., if it’s possible. Thanks. vi 0 Der Panther Sein Blick ist vom Vorübergehn der Stäbe so müd geworden, daß er nichts mehr hält. Ihm ist, als ob es tausend Stäbe gäbe und hinter tausend Stäben keine Welt. Der weiche Gang geschmeidig starker Schritte, der sich im allerkleinsten Kreise dreht, ist wie ein Tanz von Kraft um eine Mitte, in der betäubt ein großer Wille steht. Nur manchmal schiebt der Vorhang der Pupille sich lautlos auf –. Dann geht ein Bild hinein, geht durch der Glieder angespannte Stille – und hört im Herzen auf zu sein. - Rainer Maria Rilke (1903) vii 0 viii 0 RÉSUMÉ La contamination anthropogénique des régions côtières et estuaires a des conséquences pour la santé de l’écosystème. L'exposition des organismes de niveau trophique aux contaminants historiques a été corrélé à des défauts de reproduction, à l’apparition de cancer, et à la favorisation de maladies infectieuses qui peuvent conduire parfois à des évènements de mortalité de masse. Les principes actifs pharmaceutiques représentent une catégorie de contaminants d’intérêt croissant du fait de leur petite taille, de leur habileté à traverser les membranes, et de leur capacité à interagir avec les systèmes biologiques. L’étude de l’effet potentiel de leur combinaison entre eux ou à d’autres familles de composés en milieu aquatique en n'est qu'à ses premiers balbutiements. Mon travail de thèse se décompose en trois études ayant pour but l’évaluation de l’effet que des composés pharmaceutiques, seuls ou en combinaison, peuvent avoir sur le système immunitaire adaptatif des phoques communs (Phoca vitulina). Un ensemble de biomarqueurs a été utilisé pour évaluer la toxicité aigüe des principes actifs pharmaceutiques au niveau cellulaire ainsi que plus finement au niveau de l’expression de certains gènes. L’objectif principal était d’établir des courbes dose-réponse, ainsi que de déterminer la toxicité (IC50) pour les composés sélectionnés. La première étude consistait à évaluer de l’immunotoxicité de composés pharmaceutiques sur une lignée cellulaire dérivée d’un lymphome à cellules B de phoque commun. Des biomarqueurs comme la prolifération lymphoblastique, le cycle cellulaire et l’apoptose, ainsi que la viabilité ont été utilisés pour mesurer le niveau de toxicité de composés pharmaceutiques, seuls ou en combinaison. La prolifération lymphoblastique ainsi que le cycle cellulaire ont été affectés lors de l’utilisation de certains composés. Par ailleurs, les tests (à l'exception de celui de viabilité) ont révélé des effets synergiques lors du traitement avec des combinaisons de composés. La deuxième étude consistait à évaluer de l’immunotoxicité de composés pharmaceutiques sur des cultures primaires de lymphocytes T de chiots de phoques communs en liberté. Dans cette étude, la prolifération lymphocytaire a été inhibée alors que la viabilité est demeurée globalement inchangée lors de traitements avec les composés, seuls ou en combinaison. Les effets des combinaisons de composés n'ont pas été additifs. Les lymphocytes T étaient plus ix 0 sensibles aux composés individuels que la lignée cellulaire dérivée d’un lymphome à cellules B, mais moins sensibles aux combinaisons. Lors de la troisième étude, nous voulu vérifier si le composé pharmaceutique le plus toxique lors des études précédentes (17α-ethinyl estradiol, EE2), à des concentrations inférieures, était capable d’interférer avec l’expression de certains gènes, dans le but d’identifier plus précisément les mécanismes de toxicité. Nous avons observé une toxicité sur la lignée cellulaire dérivée d’un lymphome à cellules B associée a une augmentation importante de l’expression de l’ARNm de la protéine de choc thermique de 70 kDa uniquement pour les concentrations entrainant des effets sur la prolifération et le cycle cellulaire. Dans son ensemble, ce travail a suggéré que le système immunitaire du phoque commun pouvait être affecté par l’exposition à des composés pharmaceutiques présents dans l’environnement, cependant à des concentrations supérieures à celles mesurées actuellement.
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