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Androgenic Effects of the Progestin Levonorgestrel in Three-spined Stickleback (Gasterosteus aculatus)
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
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: urn:nbn:se:uu:diva-240608OAI: oai:DiVA.org:uu-240608DiVA: diva2:776828
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
List of papers
1. The Synthetic Progestin Levonorgestrel Is a Potent Androgen in the Three-Spined Stickleback (Gasterosteus aculeatus)
Open this publication in new window or tab >>The Synthetic Progestin Levonorgestrel Is a Potent Androgen in the Three-Spined Stickleback (Gasterosteus aculeatus)
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.

National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-197658 (URN)10.1021/es304305k (DOI)000315326700033 ()
Available from: 2013-04-02 Created: 2013-04-02 Last updated: 2017-12-06Bibliographically approved
2. Environmental concentrations of an androgenic progestin disrupts the seasonal breeding cycle in male three-spined stickleback (Gasterosteus aculeatus)
Open this publication in new window or tab >>Environmental concentrations of an androgenic progestin disrupts the seasonal breeding cycle in male three-spined stickleback (Gasterosteus aculeatus)
2014 (English)In: Aquatic Toxicology, ISSN 0166-445X, E-ISSN 1879-1514, Vol. 147, 84-91 p.Article in journal (Refereed) Published
Abstract [en]

Synthetic steroid hormones from contraceptive pharmaceuticals have become global aquatic contaminants. Progestins, the synthetic analogs 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, such as levonorgestrel have androgenic properties and seem to be several orders of magnitude more potent in terms of reproductive impairment in fish than non-androgenic progestins and progestagens. We recently reported that levonorgestrel has strong androgenic effects in female three-spined sticklebacks (Gasterosteus aculeatus), including induction of the normally male-specific glue protein spiggin and suppression of vitellogenesis. In light of this we investigated if exposure to levonorgestrel could disrupt the highly androgen-dependent seasonal reproductive cycle in male sticklebacks. Male sticklebacks that were in the final stage of a breeding period were exposed to various concentrations of levonorgestrel for six weeks in winter conditions in terms of light and temperature, after which reproductive status was evaluated from gross morphology, histology and key gene transcript levels. During the experimental period the controls had transitioned from full breeding condition into the non-breeding state, including regression of secondary sex characteristics, cessation of spiggin production in the kidney, and resumption of spermatogenesis in the testes. This is ascribed to the natural drop in plasma androgen levels after breeding. However, in the groups concurrently exposed to levonorgestrel, transition to the non-breeding condition was dose-dependently inhibited. Our results show that levonorgestrel can disrupt the seasonal breeding cycle in male sticklebacks. The fitness costs of such an effect could be detrimental to natural stickleback populations. Some effects occurred at a levonorgestrel concentration of 6.5 ng L-1, well within the range of levonorgestrel levels in surface waters and may therefore occur in progestin-contaminated waters. Furthermore, the effects by levonorgestrel in the present study were likely mediated mainly by its androgenic activity, and the low concentration at which they occurred makes levonorgestrel one of the most potent androgenic contaminants known.

Keyword
Levonorgestrel, Progestins, Three-spined stickleback, Androgen, Reproductive cycle
National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-221976 (URN)10.1016/j.aquatox.2013.12.013 (DOI)000331856600011 ()
Available from: 2014-04-08 Created: 2014-04-07 Last updated: 2017-12-05Bibliographically approved

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