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EFFECTS of FLAVONOIDS and OTHER PHYTOCHEMICALS on FISH Cypla MONOOXYGENASES, EMBRYONIC and REPRODUCTIVE DEVELOPMENT

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EFFECTS OF FLAVONOIDS AND OTHER PHYTOCHEMICALS ON FISH CYPlA MONOOXYGENASES, EMBRYONIC AND REPRODUCTIVE DEVELOPMENT A Thesis Submitted to the Committee of Graduate Studies in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in the Faculty of Arts and Science Trent University Peterborough. Ontario. Canada 0 Y iannis Kiparissis 200 1 Watershed Ecosystems Ph.D. Program June 2001 National Library Bibliothbque nationale du Canada Acquisitions and Acquisitions et Bibliographic Sewices services bibliographiques 395 Wellington Street 395, rue WeUington Ottawa ON KIA ON4 Ottawa ON KIAON4 Canada Canada The author has granted a non- L'auteur a accorde une Licence non exclusive licence allowing the exclusive pernettant a la National Library of Canada to Bibliotheque nationale du Canada de reproduce, loan, distr!iiute or sell reproduire, preter, distniuer ou copies of this thesis in microform, vendre des copies de cette these sous paper or electronic formats. la forme de microfiche/film, de reproduction sur papier ou sur format electronique. The author retains ownership of the L'auteur conserve la propriete du copyright in this thesis. Neither the droit d'auteur qui protege cette these. thesis nor substantial extracts &om it Ni la these ni des extraits substantiels may be printed or othenvise de celfe-ci ne doivent &re imprimes reproduced without the author's ou autrement reproduits sans son permission. autorisation. ABSTRACT Effects of Flavonoids and Other Phytochemicals on Fish CYPIA Monooxygenases, Embryonic and Reproductive Development The purpose of this study was to demonstrate that biological responses in fish such as induction of CYP1 A-dependent monooxygenases. embryonic defects. and reproductive failure that are observed in feral fish exposed to bleached kraft mill effluents (BKME) may be attributed to exposure to phytochemicals. Aqueous leachates from wood pulp and selected phytochemicals induced etboxyresorufin-0-deethylase (EROD)in rainbow trout (Oncorhynchzu mykiss). The same phytochemicals caused a multitude of developmental abnormalities in exposed embryos of Japanese medaka (Oryzias Zutipes). Further work with flavonoids. which are a specific class of phytochemicals. indicated that molecuiar structure and position of hydroxy-substitution are variables that affect EROD induction potency and embryotoxicity. The flavonoid compounds. flavone. flavonol. flavanone. chrysin. apigenin. naringenin. galangin, genistein, catechin. kaernpferol and quercetin all altered gonadal development in Japanese medaka. Intersex gonads. delayed maturation. reduced numbers of germ cells. ovarian atresia and alterations to secondary sex characteristics were evident in medaka from most treatments. Results from in vitro studies showed that flavonoids may affect reproductive development in fish by binding to either the estrogen or androgen receptor. or by binding to the sex steroid carrier proteins. Analysis of BKME by liquid chromatography mass spectrometry indicated that the isoflavonoid, genistein was present in wood pulp and in mill effluent at ppb concentrations. Thus. flavonoids may be responsible for the biological effects observed in fish downstream of pulp mills. To my wife Barb. daughter Lucy and parents ABav&aroand AopoBCa ACKNOWLEDGEMENTS First of all, I thank my supervisor Dr. Chris Metcalfe for his continued support throughout this study, for his editing skills and for his patience and faith in me. For their advice and useful comments on this dissertation. I thank the members of my committee. Dr. Art Niimi. Dr. Alicia Zobel and Dr. Brendan Hickie. I would like to acknowledge my good Friend Dr. Dave Janz who encouraged me (under the influence of plentiful ouzo and retsina) to convert this project From a Master's to a Ph.D. thesis. Special thanks to Dr. Richard Hughes for analyzing the effluent samples with the LC-MS and LC-MS-MS techniques. I was fortunate to work with some special people during this study: thanks to my labrnates. Tracy Metcalfe. Dr. Brenda Koenig. Dr. Gord Balch and Erin Bennett for helping me with various aspects of this study. I also thank Jason Allen and Mike Sanbom for taking good care of the medaka in the genistein experiment and Colin Khan for rnicrotoming ail the samples in the same experiment. This research was financially supported. in part. by an operating grant from the Natural Sciences and Engineering Research Council (NSERC), a grant from the Canadian Network of Toxicology Centres (CNTC). a grant from the international ofice of the Ministry of Education and Research (BMBF) in Germany. contracts from the Department of Fisheries and Oceans (DFO) and NSERC Graduate Scholarships. TABLE OF CONTENTS Abstract ............................................................... i . Acknowledgments ...................................................... 11 List of Figures ......................................................... ix Chapter 1 Genera1 Introduction .................................................. 1 1.1 Identification of the ProbIem .................................. 1 1.2 Adverse Effects on Feral Fish .................................. 3 1.3 Phytochemicals ............................................ 6 1.4 Objectives ................................................ 9 Chapter 2 induction of Hepatic EROD in Fish Exposed to Leachates from Wood Pulp ...... 12 2.1 Abstract .................................................. 12 2.2 Introduction ................................................ 13 2.3 Material and Methods ....................................... 15 2.3.1WoodPulp ......................................... 15 2.3.2 Fish Exposure and Preparation of Hepatic Microsomes ...... 15 2.3.3 EROD Analysis ..................................... 17 2.3.4 Statistical Analyses .................................. 18 2.4 Results .................................................... 19 2.5 Discussion ................................................. --73 Chapter 3 Induction of Hepatic CYP 1A-dependent Monooxygenases in Rainbow Trout (Oncorhynchw mykiss) Dosed to Phytochemicals ........................... 26 3.1 Abstract ................................................... 26 3.2Introduction ................................................ 27 3.3 Material and Methods ........................................ 30 3.3.1 Chemicals .......................................... 30 3.3.2 CYPl A Induction Assays ............................. 30 33.3 Determination of OctanoVwater Partition Coefficients for Phytochemicds ............................................ 32 Chapter 4 Embryonic Potential of Phytochemicals to Japanese Medaka (Oryzias latipes) .... 42 4.1Abstract ................................................... 42 4.2 Introduction ................................................ 43 4.3 Material and Methods ........................................ 46 4.3.1 Chemicals and Solutions .............................. 46 4.3.2 Japanese Medaka Embryotoxicity Assay .................. 47 4.4Results .................................................... 48 4.5 Discussion ................................................. 54 Chapter 5 Effects of Various Flavonoids on Fish: EROD induction. Embryotoxicity and Reproductive Development ............................................ 62 5.1 Abstract ................................................... 62 5.2 Introduction ................................................ 64 5.3 Material and Methods ........................................ 70 5.3.1 Chemicals .......................................... 70 5.3.2 EROD Induction .................................... 71 5.3.3 Japanese Medaka Embryotoxicity Assay .................. 71 5.3.4 Japanese Medaka Reproductive Development Studies ....... 73 5.3.4.a Reproductive Development Experiment # 1 ........ 73 5.3.4. b Reproductive Development Experiment #2 ........ 75 5.3.4.c Reproductive Development Experiment #3 ........ 76 5.3.5 in vitro assays ....................................... 76 5 -35.a Yeast Estrogenicity Assay (YES Assay) ........... 76 5.3.5.b in vitro Binding Assays ....................... 77 5.4Results .................................................... 78 5.4. l EROD Bioassay ..................................... 78 5 A.2 Japanese Medaka Embryotoxicity Assay .................. 80 5.4.3 Japanese Medaka Reproductive Development Studies ....... 90 5.4.3.a Reproductive Development Experiment # 1 ........ 90 5.4.3.b Reproductive Development Experiment #2 ........ 96 5 .4.3 .c Reproductive Development Experiment #3 ....... 117 5.4.4 in vim Studies .................................... 124 5.4.4.a YES Estrogenicity Assay (YES Assay) ............ 124 5.4.J.b in vitro Binding Studies ....................... 124 5.5Discussion ................................................. 132 Chapter 6 Identification of the Isoflavonoid. Genistein in Bleached Kraft Mill Effluent ...... 158 6.1Abstract ................................................ I58 6.2Introduction ................................................ 159 6.3 Material and Methods ........................................ 160 6.3.1 Chemicals .......................................... 160 6.3.2 Sample Collection ................................... 161 6.3.3 Preparation of Extracts ................................ 161 6.3.4 Analysis ........................................... 163 6.4 Results and Discussion ....................................... 165 Chapter 7 Conchsions ......................................................... 175 References .........................................................
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