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Noelia Díaz Blanco Effects of environmental factors on the gonadal transcriptome of European sea bass (Dicentrarchus labrax), juvenile growth and sex ratios Noelia Díaz Blanco Ph.D. thesis 2014 Submitted in partial fulfillment of the requirements for the Ph.D. degree from the Universitat Pompeu Fabra (UPF). This work has been carried out at the Group of Biology of Reproduction (GBR), at the Department of Renewable Marine Resources of the Institute of Marine Sciences (ICM-CSIC). Thesis supervisor: Dr. Francesc Piferrer Professor d’Investigació Institut de Ciències del Mar (ICM-CSIC) i ii A mis padres A Xavi iii iv Acknowledgements This thesis has been made possible by the support of many people who in one way or another, many times unknowingly, gave me the strength to overcome this "long and winding road". First of all, I would like to thank my supervisor, Dr. Francesc Piferrer, for his patience, guidance and wise advice throughout all this Ph.D. experience. But above all, for the trust he placed on me almost seven years ago when he offered me the opportunity to be part of his team. Thanks also for teaching me how to question always everything, for sharing with me your enthusiasm for science and for giving me the opportunity of learning from you by participating in many projects, collaborations and scientific meetings. I am also thankful to my colleagues (former and present Group of Biology of Reproduction members) for your support and encouragement throughout this journey. To the “exGBRs”, thanks for helping me with my first steps into this world. Working as an undergrad with you Dr. Laia Navarro, Dr. Mercedes Blázquez, Dr. Jordi Viñas, Dr. Alejandro Mechaly and Dr. Natalia Ospina, sowed the spark of this thesis. But I also would like to thank my officemates during these years, Sílvia Joly, David Otero, Laia, Mecha and Dafni Anastasiadi; it has been a pleasure to share with you this journey through its highs and lows. Thanks are also due to Dr. Laia Ribas; I won’t forget our long hours dissecting Zebrafish!! and your help on the final sprint of this thesis. Thanks also to Elvira Martínez, Gemma Fuster and Dr. Maxi Delgado for their help with fish maintenance, and to the undergrads I had the chance to teach and interact with: Kostantinos, Sergi, Rosa, David, Toni, Susana, Alejandro, Pablo…I have learned a lot from you. During my thesis I also had the chance to be part of other research teams during short stages and collaborations. From them I treasure not only the knowledge received but the persons I have met that have broaden my visions of science and the world we are living in. I would like to express my gratitude to Prof. Francisco Pelegrí (University of Wisconsin-Madison) and his team, Dr. Sreelaja Nair and Dr. Robyn Lindeman for all the efforts they put on my project v and for being always willing to listen and advice. Thanks are also due to Prof. Lázló Orbán and Dr. Woei Chang (Temasek Life Sciences Laboratory, Singapur) who during a short but fruitful collaboration taught me a lot and made me feel part of their team. I further extend my gratitude to the many people I had the chance to meet with at the Department of Renewable Marine Resources at the Institute of Marine Sciences (ICM-CSIC). For our coffee breaks conversations: Isabel, Jacopo, Balbina, Batis, Siscu, Laura, Toni, Amalia. To my Ph.D. colleagues at the ICM, past and present, that I will remember as friends: Vanessa, Cristina, Cinta, Àngel, Andrés, Samuele, Ainhoa, Sam, Giuliano, Valeria, Federico, Fernando, Marta, Anabel, Vanesa, Jose Antonio, Eva, Jordi, Raquel, Daniela, Paula, Giulia, Silvia, Dani, Carol, Marc, Alba, Sonia, and many more. Specially to Gorka, Elvira, David, Ari, Ulla and Dafni, for your unconditional friendship, for keeping my feet on the ground and cheer up my days. Thanks are also due to my family and friends. Gracias a mis amigos, los que os habéis mantenido a mi lado durante todos estos años, por entender mis ausencias, mis retrasos… simplemente por estar ahí aun cuando no entendierais muy bien el “per què de tot plegat”. A mis “Nenis”, Silvia, Lourdes, Laura y Ricard, por la felicidad de crecer juntos. A Marga y Robert por ser como de la familia. A Gema, que tuvo la osadía de seguir sus sueños hasta la Estación Biológica de Doñana y con quien he podido compartir aventuras y conversaciones de cómo salvar la ciencia, desde el ya lejano curso de aves en el que nos conocimos. A Maria y Alfonso por nuestras aventuras badaloninas (y las que nos quedan!), pero en especial a ti Maria, per estimar-me tant com per dir-me “jo! no vull que te'n vagis, però ves-te’n” i pels nostres “això ho podem fer nosaltres”. Pero este viaje empezó mucho antes. Gracias a mi familia por darme la mejor de las infancias, siempre rodeada de campo y playa. A todos ellos, a los que están y a los que nos han dejado, mil gracias, porque me habéis hecho la persona que soy hoy en día. A mis abuelos, por hacerme partícipe de su amor por los animales, la tierra y las viejas costumbres. A mis primas, por darme la mayor de las alegrías con esas criaturitas con las que se me cae la baba: Cesc, vi Eduard, Valeria. A mi también familia, Vicente, Isabel y Jorge, por vuestro amor y apoyo. A ti Lorena, esa “roomie” inesperada y con retraso, porque cuando miro atrás siempre has estado ahí, gracias por acompañarme en esta recta final y ser mi “Floreta de Gràcia”. A mis padres, por su amor y apoyo incondicional. Por inculcarme la importancia de la educación, el esfuerzo y la bondad. Por darme lo que no tuvieron, posibilidades. Y finalmente a ti, Xavi, por ser el mejor de los compañeros de viaje posible. Por estar siempre a mi lado animándome a ir “Tras la parte más pequeña”. Barcelona, 19 de mayo de 2014. vii viii Abstract In many gonochoristic fish, sex is plastic since it can be altered by the influence of environmental factors. In this thesis, using the European sea bass (Dicentrarchus labrax) model, a teleost fish with a polygenic sex determining system influenced by the environment, we have studied the effects of different environmental factors — including food supply, elevated temperatures and presence of estrogens— on growth, sex differentiation and gonadal development of juveniles. Global analysis of gene expression was carried out by a custom-made microarray. We found that, like in mammals, sex determines growth and that the first sex-related differences in growth are established before the appearance of the first molecular markers indicative of sex. Further, the juvenile testis transcriptome is influenced by poor growth during sex differentiation, while proper food supply during juvenile development is able to rescue the testis transcriptome of previously poor-growing individuals. We found that the previously observed masculinization as a result of elevated temperatures is caused by long-lasting effects at the transcriptomic level, by favoring the expression of male-related genes and decreasing that of female- related genes. In contrast, exposure to estrogen negatively affects both male- and female-related genes and pathways. Interestingly, the expression patterns of a suite of genes related to epigenetic regulatory mechanisms of gene expression showed different degrees of dependency to genetic background, developmental time and external influences according to their functional category. Resum A molts peixos gonocoristes, el sexe és plàstic donat que pot ésser alterat per la influència de factors ambientals. En aquesta tesi, utilitzant el llobarro (Dicentrarchus labrax) com a model, un peix teleosti amb un sistema poligènic de determinació del sexe influït per l'ambient, hem estudiat els efectes de diferents factors ambientals —incloent la disponibilitat d'aliment, temperatures elevades i presència d’estrògens— en el creixement, la diferenciació sexual i el desenvolupament gonadal dels juvenils. L'anàlisi global ix de l'expressió gènica s'ha realitzat mitjançant un xip d’ADN fet a mida. Hem trobat que, de la mateixa manera que ocorre en els mamífers, el sexe determina el creixement i que les primeres diferències en el creixement vinculades amb el sexe s'estableixen prèviament a l'aparició dels primers marcadors moleculars indicatius del sexe. A més, el transcriptoma de testicles juvenils està influït per un creixement pobre durant la diferenciació sexual, mentre que un subministrament adequat de menjar durant l’etapa juvenil és capaç de rescatar el transcriptoma testicular d’animals amb un pobre creixement previ. Hem trovat que la masculinització observada anteriorment com a resultat de les temperatures elevades està causada per efectes persistents a nivell transcriptòmic, afavorint l'expressió de gens relacionats amb el desenvolupament masculí i disminuint la dels gens relacionats amb el desenvolupament femení. Per contra, l'exposició a estrògens afecta negativament tant als gens relacionats amb el desenvolupament masculí com el femení. És destacable com els patrons d'expressió d'una sèrie de gens relacionats amb la regulació epigenètica de l’expressió gènica mostren graus diferents de dependència a factors genètics, període del desenvolupament i factors ambientals segons la seva categoria funcional. x Prologue This thesis has been carried out at the Group of Biology of Reproduction (GBR), lead by Dr. Francesc Piferrer, at the Department of Renewable Marine Resources of the Institute of Marine Sciences (ICM-CSIC), Barcelona, under the International Ph.D. Programme in Biomedicine at the Experimental and Health Sciences Department of the Universitat Pompeu Fabra (UPF), during the period 2007-2014. The aim of this thesis was to study the relationship between growth and sex differentiation in the European sea bass (Dicentrarchus labrax) model, as well as to study some environmental effects, such as temperature or hormones, on its sex differentiation at a whole gonadal transcriptomic level.
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