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AFSS) with Other Bioassays for Detecting Antiandrogens

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AFSS) with Other Bioassays for Detecting Antiandrogens Cefas contract report C5108 Comparison of the Androgenised Female Stickleback Screen (AFSS) with other bioassays for detecting antiandrogens Authors Ioanna Katsiadaki Marion Sebire Issue date: 01/04/2011 Comparison of the AFSS assay with other bioassays for detecting antiandrogens Authors: Ioanna Katsiadaki (Contract manager, Cefas Weymouth) Marion Sebire Issue date: 01/04/2011 Head office Centre for Environment, Fisheries and Aquaculture Science Pakefield Road, Lowestoft, Suffolk NR33 0HT, UK Tel +44 (0) 1502 56 2244 Fax +44 (0) 1502 51 3865 www.cefas.co.uk Cefas is an executive agency of Defra The AFSS and other bioassays for antiandrogens Executive Summary 1. The current OECD test guidelines for screening chemicals with potential endocrine disrupting activity (TG 229 and to a certain extend TG 230) cannot clearly identify androgen antagonists due to the lack of an androgen specific endpoint in the three validated species, the fathead minnow, the medaka and the zebrafish. 2. In mammalian toxicology there is a large literature body suggesting that chemicals with high affinity for the androgen receptor may be partly responsible for the increasing incidence of human reproductive disorders. An excellent mechanistic mammalian assay (the Hershberger assay) has played instrumental role in the characterisation of several chemicals as antiandrogenic. 3. The reported antiandrogenic activity in the aquatic environment is substantial. The evidence of high levels of antiandrogens in various water bodies emphasises the need for a suitable screening assay using fish. 4. Several fish species have secondary sexual characteristics whose development is controlled by androgens and therefore are promising as biomarkers for quantifying antiandrogen exposure. Of these, changes in anal fin morphology (gonopodium) in the mosquitofish and the guppy development of tubercles in fathead minnow, growth of papillary processes in the medaka, and induction of spiggin in the stickleback are discussed in detail. 5. Changes in the gonopodium in mosquitofish and guppy have not been exploited as a biomarker for antiandrogens to date (only as a marker for androgen exposure), the tubercle score in fathead minnow has produced variable responses in the literature whilst the studies on the effect of antiandrogens using as an endpoint the papillary processes in the medaka are limited. 6. In contrast, spiggin, the androgen biomarker, present in the kidney of the three-spined stickleback has been extensively used in this field, displaying an unprecedented sensitivity, specificity and resolution (dynamic range) for the detection of androgens and antiandrogens in the environment. 7. The in vivo test that was developed to specifically detect (anti)androgenic activity of chemicals using spiggin, the Androgenised Female Stickleback Screen (the AFSS, currently a draft guidance document) has undergone both validation and peer review and has proved its reproducibility and sensitivity, including lack of interferences from endocrine negative chemical(s). The AFSS and other bioassays for antiandrogens 8. Currently the only Test Guideline validated by the OECD as a screen for (anti)androgens is the castrated rat Hershberger bioassay. The principle of the AFSS is very similar to the Hershberger rat assay; in both assays the androgen sensitive tissues are stimulated by an androgen. Simultaneous administration of putative antiandrogenic chemicals can block this effect providing excellent mechanistic models for the evaluation of chemicals with affinity for the androgen receptor(s). 9. The main difference between the two assays is that in the male rat, the endogenous source of androgens (testes) is eliminated by surgical castration whilst in the stickleback intact female fish are used instead of male fish, bypassing the need for surgical intervention. 10. In the AFSS the only measured endpoint is the kidney levels of spiggin; this protein is measured by ELISA (just like the fish vitellogenin assays) providing an impressive dynamic range for detecting antiandrogens. The difference a stimulated and a non-stimulated female kidney is about 1000-fold whilst in the Hershberger the differences in the weight of the androgen-sensitive tissues between stimulated and non stimulated rats is only about 5-fold. 11. Comparing the sensitivities of a mammalian and a fish in vivo test is a challenge; due to the different modes of chemical exposure the bioavailability of chemicals is dramatically different; the chemicals in the Hershberger are administered by injections (androgen) or oral gavage (antiandrogens) whilst in the AFSS exposure to both chemicals is waterborne. 12. Qualitative comparison of the AFSS and Hershberger data on seven chemicals demonstrated not only that both assays detected successfully their antiandrogenic potential but also their ranking in terms of potency was very similar. The AFSS and other bioassays for antiandrogens Table of contents 1 Introduction ......................................................................................................................... 1 1.1 Background information ........................................................................................................ 1 1.2 The issue of environmental antiandrogens ........................................................................... 2 1.3 Scope of this report ................................................................................................................ 5 2 Androgen-dependent traits in fish ......................................................................................... 6 2.1 General androgen-regulated traits in fish .............................................................................. 6 2.1.1 Changes in phenotypic sex ratio ..................................................................................... 6 2.1.2 Reproductive behaviour .................................................................................................. 7 2.1.3 Fecundity ......................................................................................................................... 8 2.1.4 Vitellogenin ..................................................................................................................... 8 2.1.5 Gonadal histology ........................................................................................................... 9 2.1.6 Summary of generic effects as markers for antiandrogens .......................................... 10 2.2 Species-specific androgen-regulated traits in fish ............................................................... 11 2.2.1 Spiggin in the stickleback .............................................................................................. 11 2.2.2 Gonopodium in mosquitofish and guppy ..................................................................... 13 2.2.3 Tubercles in the fathead minnow ................................................................................. 14 2.2.4 Anal fin (papillary processes) in medaka ...................................................................... 17 3 The AFSS and other bioassays for antiandrogens. ................................................................ 18 3.1 The principle of the AFSS ..................................................................................................... 18 3.2 Alternative androgenised female fish for detecting antiandrogens .................................... 19 3.3 The principle of the Hershberger bioassay .......................................................................... 20 3.4 Antiandrogen testing in the AFFS and the Hershberger assays ........................................... 21 4 Overall discussion and conclusions ...................................................................................... 25 5 Tables ................................................................................................................................ 27 Table 1. Synopsis of in vivo fish exposures to well known antiandrogens. ..................................... 28 Table 2. Synopsis of in vivo fish exposures to well known antiandrogens where females are stimulated by exogenous androgens. ............................................................................................... 38 Table 3. Comparison of the Hershberger and AFSS assays in term of responses to antiandrogenic chemicals........................................................................................................................................... 40 6 References ......................................................................................................................... 42 The AFSS and other bioassays for antiandrogens List of abbreviations 11KT 11-ketotestosterone EE2 17 α-ethinyl-oestradiol E2 17β-oestradiol AR androgen receptor BPA bisphenol A COWS Cowper’s glands CA cyproterone acetate DDE dichloro-diphenyl-dichlorethylene DHT dihydrotestosterone ELISA enzyme linked immunosorbent assay FHM fathead minnow FN fenitrothion FSDT Fish Sexual Development Test FL flutamide GLANS glans penis KEH kidney secondary proximal epithelium height LABC levetor ani-bulbocavernosus muscle LN linuron LOEC Lowest Observed Effect Concentration MED medaka MT methyltestosterone NOEC No Observed Effect Concentration PCR polymerase chain reaction PRO procymidone SSC secondary sexual characteristics SV seminal vesicles plus coagulating glands T testosterone TP testosterone propionate SB three-spined stickleback TB trenbolone VP ventral
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