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Developmental exposure to progestins causes male bias and precocious puberty in zebrafish (Danio rerio)
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Comparative Physiology.
Department of Chemistry, Umeå University, Linnaeus väg 6, Umeå, SE-90 187, Sweden.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Comparative Physiology.
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2016 (English)In: Aquatic Toxicology, ISSN 0166-445X, E-ISSN 1879-1514, Vol. 177, 316-323 p.Article in journal (Other academic) Published
Abstract [en]

Progestins are aquatic contaminants that in low concentrations can impair fish reproduction. The mechanisms are likely multiple since different progestins interact with other steroid receptors in addition to progesterone receptors. Puberty is the process when animals first acquire the capability to reproduce and it comprises maturation of sperm and eggs. In zebrafish, puberty is initiated around 45 days post fertilization (dpf) in females and around 53-55 dpf in males, and is marked by increased production of pituitary gonadotropins. We exposed juvenile zebrafish from 20 to 80 dpf to the androgenic progestin levonorgestrel at concentrations of 5.5, 79 and 834 ng L-1 and to the non-androgenic progestin progesterone at concentrations of 3.7, 77 and 1122 ng L-1, during sexual differentiation and puberty. Levonorgestrel exposure caused 100% males even at the lowest concentration tested whereas progesterone did not affect the sex ratio. Transcript levels of the gonadal genes amh, CYP11B and CYP19a1a indicated that the masculinizing effect of levonorgestrel occurred very rapidly. Transcript concentrations of gonadotropins in pituitaries were low in control fish at 44 dpf, but high at 55 dpf and onward. In fish exposed to levonorgestrel or progesterone gonadotropin transcript concentrations were high already at 44 dpf, indicating that both progestins caused precocious puberty. Gonad histology at 50 dpf confirmed a well advanced sexual maturation, but only in males. Our results show that progestins can affect sexual development in fish and that the androgenic progestin levonorgestrel induces a male phenotype at concentrations similar to those detected in aquatic environments.

Place, publisher, year, edition, pages
2016. Vol. 177, 316-323 p.
Keyword [en]
Progestins, Levonorgestrel, Progesterone, Zebrafish, Sex differentiation, Puberty
National Category
Natural Sciences
URN: urn:nbn:se:uu:diva-284921DOI: 10.1016/j.aquatox.2016.06.010ISI: 000381529700031PubMedID: 27348263OAI: oai:DiVA.org:uu-284921DiVA: diva2:920976
Available from: 2016-04-19 Created: 2016-04-19 Last updated: 2016-10-05Bibliographically approved
In thesis
1. Progestagenic Aquatic Contaminants Act as Potent Androgens in Fish: Experimental Studies in Three-spined Stickleback and Zebrafish
Open this publication in new window or tab >>Progestagenic Aquatic Contaminants Act as Potent Androgens in Fish: Experimental Studies in Three-spined Stickleback and Zebrafish
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The extensive use of pharmaceuticals and their poor removal by wastewater treatment plants has led to the emergence of pharmaceutical compounds as global aquatic contaminants. Progestins, the synthetic analogues to progesterone (P4), are receiving increasing attention as contaminants and have been shown to impair reproduction in fish and amphibians at low ng L-1 concentrations. Certain progestins have androgenic properties and are several orders of magnitude more potent in terms of reproductive impairment in fish than non-androgenic progestins. To characterize the androgenic effects of progestins in fish, adult three-spined sticklebacks (Gasterosteus aculeatus) and zebrafish (Danio rerio) larvae were exposed to progestins via the ambient water. In female sticklebacks, the androgenic progestins levonorgestrel (LNG) and norethindrone (NET) induced production of the androgenic biomarker protein spiggin and reduced production of the egg yolk protein vitellogenin. Comparison with well-known environmental androgens showed that LNG and NET, with regard to spiggin induction and vitellogenin induction, are among the most potent environmental androgens known. In male sticklebacks, LNG inhibited the post-breeding regression of secondary sex characters and spiggin production, as well as the resumption of spermatogenesis, functionally inhibiting the natural transition from breeding into non-breeding condition. Exposure of zebrafish larvae to LNG caused all fish to develop into males, whose sexual development was also significantly accelerated. P4 had no effect on the sex ratio, while slightly accelerating sexual development at high concentrations. Suppression of vitellogenesis in females, disruption of the male reproductive cycle, male-biased sex ratios and precious male puberty could all entail severe fitness costs and severely affect fish populations. Most of the effects of androgenic progestins in this thesis occurred at levels within the range of reported environmental levels, and may therefore occur in progestin-contaminated waters. In conclusion, the present results establish LNG and NET as highly potent androgenic pollutants of environmental concern, and provide strong support to the contention that the reproductive impairment in fish caused by progestins is chiefly mediated by their androgenic properties.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. 45 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1379
Pharmaceuticals as contaminants, Progestins, Androgenic properties, Fish
National Category
Other Biological Topics
Research subject
Biology with specialization in Environmental Toxicology
urn:nbn:se:uu:diva-286535 (URN)978-91-554-9587-9 (ISBN)
Public defence
2016-06-10, Lindahlsalen, Evolutionsbiologiskt Centrum, Norbyvägen 18 A, Uppsala, 10:00 (English)
Available from: 2016-05-18 Created: 2016-04-20 Last updated: 2016-06-01

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Svensson, JohanMustafa, ArshiSchmitz, MonikaBrunström, Björn
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