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The Synthetic Progestin Levonorgestrel Is a Potent Androgen in the Three-Spined Stickleback (Gasterosteus aculeatus)
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, Environmental toxicology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
2013 (English)In: Environmental Science and Technology, ISSN 0013-936X, E-ISSN 1520-5851, Vol. 47, no 4, 2043-2051 p.Article in journal (Refereed) Published
Abstract [en]

The use of progestins has resulted in contamination of aquatic environments and some progestins have in experimental studies been shown to impair reproduction in fish and amphibians at low ng L-1 concentrations. The mechanisms underlying their reproductive toxicity are largely unknown. Some progestins, such as levonorgestrel (LNG), exert androgenic effects in mammals by activating the androgen receptor (AR). Male three-spined stickleback (Gasterosteus aculeatus) kidneys produce spiggin, a gluelike glycoprotein used in nest building, and its production is directly governed by androgens. Spiggin is normally absent in females but its production in female kidneys can be induced by AR agonists. Spiggin serves as the best known biomarker for androgens in fish. We exposed adult female sticklebacks to LNG at 5.5, 40, and 358 ng L-1 for 21 days. Androgenic effects were found at LNG concentrations >= 40 ng L-1 including induction of spiggin transcription, kidney hypertrophy, and suppressed liver vitellogenin transcription. These are the first in vivo quantitative data showing that LNG is a potent androgen in fish supporting the contention that androgenic effects of certain progestins contribute to their reproductive toxicity.

Place, publisher, year, edition, pages
2013. Vol. 47, no 4, 2043-2051 p.
National Category
Natural Sciences
Identifiers
URN: urn:nbn:se:uu:diva-197658DOI: 10.1021/es304305kISI: 000315326700033OAI: oai:DiVA.org:uu-197658DiVA: diva2:613894
Available from: 2013-04-02 Created: 2013-04-02 Last updated: 2017-12-06Bibliographically approved
In thesis
1. Androgenic Effects of the Progestin Levonorgestrel in Three-spined Stickleback (Gasterosteus aculatus)
Open this publication in new window or tab >>Androgenic Effects of the Progestin Levonorgestrel in Three-spined Stickleback (Gasterosteus aculatus)
2014 (English)Licentiate 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, 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, like levonorgestrel (LNG), have androgenic properties and are several orders of magnitude more potent in terms of reproductive impairment in fish than non-androgenic progestins. We exposed three-spined stickleback (Gasterosteus aculeatus) to LNG to investigate its androgenic effects in fish. Male stickleback kidneys produce spiggin, a glue-like glycoprotein used in nest building. Spiggin production is directly and specifically governed by androgens and its induction in females serves as the best known biomarker for androgen exposure in fish. In the present project females were exposed to LNG for 21 days after which effects on spiggin biomarkers and vitellogenesis were evaluated. Male sticklebacks that were in the final stage of a breeding period were exposed to various concentrations of LNG for six weeks under winter conditions, after which reproductive status was evaluated from gross morphology, histology and key gene transcript levels. In female sticklebacks, LNG induced spiggin production in the kidneys and suppressed vitellogenesis in the liver. In males, LNG inhibited the post-breeding regression of secondary sex characters and spiggin production, as well as the resumption of spermatogenesis; thus LNG functionally inhibits the natural transition from breeding into non-breeding condition. Suppression of vitellogenesis in females and disruption of the male reproductive cycle as shown in this thesis could entail severe fitness costs and severely affect natural stickleback populations. Some of the present effects occurred at 6.5 ng L-1, well within the range of environmental LNG levels, and may therefore occur in progestin-contaminated waters. In conclusion, the present results establish LNG as a highly potent androgenic pollutant of environmental concern, and support the contention that the reproductive impairment in fish caused by progestins could to a significant degree be mediated by their androgenic properties.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. 36 p.
National Category
Biological Sciences
Research subject
Biology with specialization in Environmental Toxicology
Identifiers
urn:nbn:se:uu:diva-240608 (URN)
Presentation
2014-02-07, Evolutionsbiologiskt centrum, Norbyvägen 18A, 75236, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2015-01-22 Created: 2015-01-08 Last updated: 2015-01-22Bibliographically approved
2. 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.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1379
Keyword
Pharmaceuticals as contaminants, Progestins, Androgenic properties, Fish
National Category
Other Biological Topics
Research subject
Biology with specialization in Environmental Toxicology
Identifiers
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)
Opponent
Supervisors
Available from: 2016-05-18 Created: 2016-04-20 Last updated: 2016-06-01

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Svensson, JohanBrandt, IngvarBrunström, Björn

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