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  • 1.
    Svensson, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Androgenic Effects of the Progestin Levonorgestrel in Three-spined Stickleback (Gasterosteus aculatus)2014Licentiate 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.

    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, p. 2043-2051Article 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, p. 84-91Article 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.

    Keywords
    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
  • 2.
    Svensson, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Progestagenic Aquatic Contaminants Act as Potent Androgens in Fish: Experimental Studies in Three-spined Stickleback and Zebrafish2016Doctoral 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.

    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, p. 2043-2051Article 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. Androgenic and anti-estrogenic potencies of progestins and other environmental androgens in female three-spined stickleback (Gasterosteus aculeatus)
    Open this publication in new window or tab >>Androgenic and anti-estrogenic potencies of progestins and other environmental androgens in female three-spined stickleback (Gasterosteus aculeatus)
    (English)Manuscript (preprint) (Other academic)
    Abstract
    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-286502 (URN)
    Available from: 2016-04-20 Created: 2016-04-20 Last updated: 2018-07-04
    3. 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, p. 84-91Article 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.

    Keywords
    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
    4. Developmental exposure to progestins causes male bias and precocious puberty in zebrafish (Danio rerio)
    Open this publication in new window or tab >>Developmental exposure to progestins causes male bias and precocious puberty in zebrafish (Danio rerio)
    Show others...
    2016 (English)In: Aquatic Toxicology, ISSN 0166-445X, E-ISSN 1879-1514, Vol. 177, p. 316-323Article 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.

    Keywords
    Progestins, Levonorgestrel, Progesterone, Zebrafish, Sex differentiation, Puberty
    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-284921 (URN)10.1016/j.aquatox.2016.06.010 (DOI)000381529700031 ()27348263 (PubMedID)
    Available from: 2016-04-19 Created: 2016-04-19 Last updated: 2018-12-14Bibliographically approved
  • 3.
    Svensson, Johan
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Brunström, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Androgenic activity of levonorgestrel in three-spined stickleback (Gasterosteus aculeatus)2012In: Abstracts book Part 4, 2012, p. 309-309Conference paper (Other academic)
  • 4.
    Svensson, Johan
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Brunström, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    The progestin levonorgestrel is a potent androgen in the three-spined stickleback (Gasterosteus aculeatus)2013Conference paper (Other academic)
  • 5.
    Svensson, Johan
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Brunström, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    The progestin levonorgestrel is a potent androgen in the three-spined stickleback (Gasterosteus aculeatus)2013Conference paper (Other academic)
  • 6.
    Svensson, Johan
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Fick, Jerker
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Brunström, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Environmental concentrations of an androgenic progestin disrupts the seasonal breeding cycle in male three-spined stickleback (Gasterosteus aculeatus)2014In: Aquatic Toxicology, ISSN 0166-445X, E-ISSN 1879-1514, Vol. 147, p. 84-91Article in journal (Refereed)
    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.

  • 7.
    Svensson, Johan
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Fick, Jerker
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Brunström, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    The Synthetic Progestin Levonorgestrel Is a Potent Androgen in the Three-Spined Stickleback (Gasterosteus aculeatus)2013In: Environmental Science and Technology, ISSN 0013-936X, E-ISSN 1520-5851, Vol. 47, no 4, p. 2043-2051Article in journal (Refereed)
    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.

1 - 7 of 7
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