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Ferredoxin 1B Deficiency Leads to Testis Disorganization, Impaired Spermatogenesis and Feminization in Zebrafish

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Ferredoxin 1B Deficiency Leads to Testis Disorganization, Impaired Spermatogenesis and Feminization in Zebrafish This is a repository copy of Ferredoxin 1b deficiency leads to testis disorganization, impaired spermatogenesis and feminization in zebrafish. White Rose Research Online URL for this paper: http://eprints.whiterose.ac.uk/148928/ Version: Accepted Version Article: Oakes, J.A., Li, N., Wistow, B.R.C. et al. (5 more authors) (2019) Ferredoxin 1b deficiency leads to testis disorganization, impaired spermatogenesis and feminization in zebrafish. Endocrinology. ISSN 0013-7227 https://doi.org/10.1210/en.2019-00068 This is a pre-copyedited, author-produced version of an article accepted for publication in Endocrinology following peer review. The version of record Oakes, J. et al, Ferredoxin 1b deficiency leads to testis disorganization, impaired spermatogenesis and feminization in zebrafish, Endocrinology, is available online at: https://doi.org/10.1210/en.2019-00068. Reuse Items deposited in White Rose Research Online are protected by copyright, with all rights reserved unless indicated otherwise. They may be downloaded and/or printed for private study, or other acts as permitted by national copyright laws. The publisher or other rights holders may allow further reproduction and re-use of the full text version. This is indicated by the licence information on the White Rose Research Online record for the item. Takedown If you consider content in White Rose Research Online to be in breach of UK law, please notify us by emailing [email protected] including the URL of the record and the reason for the withdrawal request. [email protected] https://eprints.whiterose.ac.uk/ Revised Manuscript - Clean Click here to access/download;Revised Manuscript - Clean;en.2019-00068 revised manuscript clean.docx 1 Ferredoxin 1b deficiency leads to testis disorganization, impaired 2 spermatogenesis and feminization in zebrafish 3 4 James A Oakes1,2, Nan Li1,2, Belinda RC Wistow1,2, Aliesha Griffin3, Lise Barnard4, Karl-Heinz Storbeck4, 5 Vincent T Cunliffe2, Nils P Krone1,2,5. 6 7 1Department of Oncology & Metabolism, School of Medicine, University of Sheffield, Sheffield, S10 8 2TH, United Kingdom 9 2The Bateson Centre, Department of Biomedical Science, Firth Court, University of Sheffield, 10 Western Bank, Sheffield, S10 2TN, United Kingdom 11 3Epilepsy Research Laboratory and Weill Institute for Neuroscience, Department of Neurological 12 Surgery, University of California, San Francisco, 513 Parnassus Ave., San Francisco, CA 94143, United 13 States 14 4Department of Biochemistry, Stellenbosch University, Stellenbosch, 7602, Matieland, South Africa 15 5Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, 16 Fetscherstrasse 74, 01307 Dresden, Germany 17 18 19 Short title for page headings: Fdx1b deficiency and testis function in zebrafish. 20 Key words: Ferredoxin, fdx1b, zebrafish, testes, sperm, androgen. 21 Corresponding author / reprint requests: 22 Nils P Krone MD FRCPCH 23 Academic Unit of Child Health 24 Department of Oncology & Metabolism 25 University of Sheffield 26 Sheffi C H 27 Western Bank 28 SHEFFIELD S10 2TH 29 UNITED KINGDOM 30 31 Tel (+44) 0114 271 7508 32 Fax (+44) 0114 275 5364 33 Email: [email protected] 34 35 Grants and fellowships: This work was supported by the International Fund Congenital Adrenal 36 Hyperplasia 2017 research grant (to N.K. and V.T.C) and the Deutsche Forschungsgemeinschaft 37 (KR3363/3-1). 38 Disclosure Summary: Nothing to disclose. 1 39 Abstract 40 The roles of steroids in zebrafish sex differentiation, gonadal development and function of the adult 41 gonad are poorly understood. Herein, we have employed a ferredoxin 1b (fdx1b) mutant zebrafish to 42 explore such processes. Fdx1b is an essential electron-providing cofactor to mitochondrial 43 steroidogenic enzymes, which are crucial for glucocorticoid and androgen production in vertebrates. 44 Fdx1b-/- zebrafish mutants develop into viable adults, in which concentrations of androgens and the 45 glucocorticoid, cortisol, are significantly reduced. Adult fdx1b-/- mutant zebrafish display 46 predominantly female secondary sex characteristics but may possess either ovaries or testes, 47 confirming that androgen signaling is dispensable for testicular differentiation in this species, as 48 previously demonstrated in androgen receptor mutant zebrafish. Adult male fdx1b-/- mutant 49 zebrafish do not exhibit characteristic breeding behaviors, and sperm production is reduced, 50 resulting in infertility in standard breeding scenarios. However, eggs collected from wild-type 51 females can be fertilized by the sperm of fdx1b-/- mutant males by IVF. The testes of fdx1b-/- mutant 52 males are disorganized and lack defined seminiferous tubule structure. Expression of several pro- 53 male and spermatogenic genes is decreased in the testes of fdx1b-/- mutant males, including pro- 54 male transcription factor SRY-box 9a (sox9a) and spermatogenic genes insulin-like growth factor 3 55 (igf3) and insulin-like 3 (insl3). This study establishes an androgen- and cortisol-deficient fdx1b 56 zebrafish mutant as a model for understanding the impacts of steroid deficiency on sex development 57 and reproductive function. This model will be particularly useful for further investigation of the roles 58 of steroids in spermatogenesis, gonadal development and regulation of reproductive behavior, thus 59 enabling further elucidation of the physiological consequences of endocrine disruption in 60 vertebrates. 61 2 62 Introduction 63 The development of the gonads and secondary sexual characteristics in zebrafish are highly plastic 64 processes that are sensitive to a range of environmental and physiological signals. These sensitivities 65 make zebrafish an experimentally tractable subject in which to elucidate how abnormalities of 66 steroid metabolism and signaling contribute to the endocrine disruption of reproductive physiology 67 and other sex-specific characteristics1. 68 Mitochondrial cytochrome P450 enzymes are crucial for steroidogenesis, and their activity requires 69 electron transfer from cofactors including Ferredoxin 1 (FDX1) (Figure 1)2. The pathways to 70 mineralocorticoid and glucocorticoid biosynthesis are well conserved between humans and zebrafish 71 (Figure 1), however some distinctions exist. Zebrafish possess two CYP11A1 homologs: cyp11a1 and 72 cyp11a2. Cyp11a2 is thought to be the principal side chain cleavage enzyme in larval and adult 73 steroidogenesis, whereas Cyp11a1 is thought to have important roles in very early development3. 74 Cyp11c1 is the zebrafish homolog for CYP11B1, which encodes 11-hydroxylase in humans. A 75 homolog for the human gene CYP11B2, encoding aldosterone synthase, has not been identified in 76 zebrafish; nor has aldosterone been detected, suggesting that zebrafish are unable to produce this 77 steroid hormone4. 78 The pathway to estrogen production is also highly alike in zebrafish and humans, with estradiol 79 acting as the principal estrogen4. In contrast, the pathway to androgen production is somewhat 80 different in zebrafish compared to humans (Figure 1). The principal active androgen in zebrafish is 81 11-ketotestosterone (11KT) and this may be produced via multiple pathways. Unlike the situation in 82 humans, dihydrotestosterone is not thought to be a major androgen in teleost fish, although 83 production may be possible5. The major pathway for androgen production in zebrafish begins with 84 -hydroxyandrostenedione by Cyp11c1, which is subsequently 85 converted to 11-ketoandrostenedione by Hsd11b26. Finally, 11-ketoandrostenedione is converted to 86 11KT by Hsd17b36,7. 3 87 In an alternative pathway androstenedione may be converted to testosterone by Hsd17b37, which is 88 -hydroxytestosterone6 C -hydroxytestosterone is finally 89 converted to 11KT by Hsd11b24. The contribution of this pathway to 11KT production is thought to 90 -hydroxytestosterone appear to be produced at extremely low 91 levels6 T KT - 92 hydro -hydroxytestosterone by Hsd17b3. This reaction has been 93 demonstrated in cells expressing hsd17b37, but is unlikely to occur in vivo6,8. 94 In humans, FDX1 is an important co-factor to the steroidogenic cytochrome P450 side-chain cleavage 95 CYPA CYPB -hydroxylase (CYP11B1)2. FDX1, and the 96 associated ferredoxin reductase, act as sequential electron donors, facilitating transfer of electrons 97 from NADPH to cytochrome P450 enzymes2. This process is crucial for processing of target 98 substrates. The zebrafish ortholog of FDX1, Fdx1b, appears to be the electron-providing cofactor to 99 the steroidogenic cytochrome P450 side-chain cleavage enzymes (Cyp11a1, Cyp11a2) and 100 P -hydroxylase (Cyp11c1), however, these functions have not been definitively 101 proven. Cyp11a1 and Cyp11a2, homologs of CYP11A1, catalyze the conversion of cholesterol to 102 pregnenolone, while Cyp11c1, the zebrafish homolog of CYP11B1, catalyses the 11-hydroxylation of 103 11-deoxycortisol to produce cortisol9. Cyp11c1 may also facilitate conversion of the 104 mineralocorticoid 11-deoxycorticosterone to corticosterone in teleost fish10. Unlike in mammals, 105 -hydroxylase is postulated to play a crucial role in androgen synthesis in zebrafish, namely the 106 11-hydroxylation of androgen precursors (Figure 1). Zebrafish possess two ferredoxin 1 paralogs: 107 fdx1 and fdx1b. We have previously shown that fdx1b-/- mutant larvae are profoundly glucocorticoid 108 deficient whereas fdx1 morphants displayed a severe early developmental phenotype9. Fdx1b 109
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