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Jon P. Nash,^1,2,3 David E. Kime,¹ Leo T. M. Van der Ven,⁴ Piet W. Wester,⁴ François Brion,⁵ Gerd Maack,³ Petra Stahlschmidt-Allner,⁶ and Charles R. Tyler³

¹Animal and Plant Sciences, University of Sheffield, Sheffield ,United Kingdom; ²Laboratory of Aquatic Ecology, Katholieke Universiteit Leuven, Leuven, Belgium; ³School of Biological Sciences, University of Exeter, Exeter, United Kingdom; ⁴Rijksinstituut voor volksgezondheid en mileu (RIVM), Bilthoven, The Netherlands; ⁵L'Institut national de L'environnement et des risque (INERIS), Verneuil-en-Halatte, France; ⁶Hessisches Landesamt für umwelt und geologie (HLUG), Wiesbaden, Germany

Abstract
Heightened concern over endocrine-disrupting chemicals is driven by the hypothesis that they could reduce reproductive success and affect wildlife populations, but there is little evidence for this expectation. The pharmaceutical ethynylestradiol (EE₂) is a potent endocrine modulator and is present in the aquatic environment at biologically active concentrations. To investigate impacts on reproductive success and mechanisms of disruption, we exposed breeding populations (n = 12) of zebrafish (Danio rerio) over multiple generations to environmentally relevant concentrations of EE₂. Life-long exposure to 5 ng/L EE₂ in the F₁ generation caused a 56% reduction in fecundity and complete population failure with no fertilization. Conversely, the same level of exposure for up to 40 days in mature adults in the parental F₀ generation had no impact on reproductive success. Infertility in the F₁ generation after life-long exposure to 5 ng/L EE₂ was due to disturbed sexual differentiation, with males having no functional testes and either undifferentiated or intersex gonads. These F₁ males also showed a reduced vitellogenic response when compared with F₀ males, indicating an acclimation to EE₂ exposure. Depuration studies found only a partial recovery in reproductive capacity after 5 months. Significantly, even though the F₁ males lacked functional testes, they showed male-pattern reproductive behavior, inducing the spawning act and competing with healthy males to disrupt fertilization. Endocrine disruption is therefore likely to affect breeding dynamics and reproductive success in group-spawning fish. Our findings raise major concerns about the population-level impacts for wildlife of long-term exposure to low concentrations of estrogenic endocrine disruptors. Key words: ecotoxicology, endocrine disruption, ethynylestradiol, mating systems, population effects, reproductive success, zebrafish. Environ Health Perspect 112:1725-1733 (2004) . doi:10.1289/ehp.7209 available via http://dx.doi.org/ [Online 4 November 2004]

Address correspondence to J.P. Nash, Laboratory of Aquatic Ecology, Katholieke Universiteit Leuven, 3000 Leuven, Belgium. Telephone: 32-16-323966. Fax: 32-16-324575. E-mail: jon@fishyone.net

We thank C. Spary, E. Saunders, B. McAllister, M. Skidmore, K. Van Look, and S. Holden for help with data collection and C. Kelly (CEFAS, Burnham-on-Crouch, UK) for the analytical chemistry. We also thank the reviewers for their useful comments.

This study was supported by grant GR3/10840 from the British Natural Environmental Research Council (D.E.K.) , an EC Marie Curie fellowship (J.P.N.) , and Exeter University (C.R.T.) .

The authors declare they have no competing financial interests.

Received 27 April 2004 ; accepted 22 October 2004.