uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
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.
Show others and affiliations
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.

Place, publisher, year, edition, pages
2016. Vol. 177, p. 316-323
Keywords [en]
Progestins, Levonorgestrel, Progesterone, Zebrafish, Sex differentiation, Puberty
National Category
Natural Sciences
Identifiers
URN: urn:nbn:se:uu:diva-284921DOI: 10.1016/j.aquatox.2016.06.010ISI: 000381529700031PubMedID: 27348263OAI: oai:DiVA.org:uu-284921DiVA, id: diva2:920976
Available from: 2016-04-19 Created: 2016-04-19 Last updated: 2018-12-14Bibliographically 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. p. 45
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1379
Keywords
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
2. Neuromolecular and behavioural profile of teleosts: - effects of boldness, agonistic behaviour and reproductive status
Open this publication in new window or tab >>Neuromolecular and behavioural profile of teleosts: - effects of boldness, agonistic behaviour and reproductive status
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis investigates if boldness is reflected in the function of brain histaminergic system in zebrafish (Danio rerio). Moreover, behavioural differences in AB line, spiegeldanio (spd) line and wild caught strain of zebrafish have also been explored apart from the winner-loser effect in AB and spd fish. This thesis also includes studies on the effect of progestins on reproductive behaviour in zebrafish and regulation of leptinergic system on sexual maturation in male Atlantic salmon (Salmo salar L.).

Boldness is reflected in higher expression of histamine receptor 1 (hrh1) in the telencephalon and diencephalon of male zebrafish and dominance by an elevated expression of hrh1 in the optic tectum. In female zebrafish boldness is also associated with lower expression of histamine receptor 3 (hrh3) in the optic tectum and dominance by lower expression of hrh3 in the telencephalon. Comparison of behavioural traits of zebrafish of AB, spd and wild type shows that wild type strain is most shy and shows no gender difference. AB is bolder than spd in the open field test while spd is bolder AB in the novel tank dive test. Similarly results for aggression are also test dependent since the spd is more aggressive than AB in the mirror test, however no difference is measured during dyadic fight test. A typical loser effect and activation of serotonergic system is observed in both AB and spd fish. Further, both levonorgestrel (LNG) and progesterone (P4) cause an early puberty in male zebrafish. However only levonorgestrel causes males biased population at environmental concentrations. In male Atlantic salmon, during early spring, both leptin paralogues, lepa1 and lepa2 in the liver and leptin receptor (lepr) in the brain are downregulated in non-maturing control group. At final maturational stage both hepatic lepa1 and lepa2 are upregulated 7.7 times and 49 times respectively in maturing control males. A significant upregulation of lepr is also measured from mid to late spermatogenesis.  

This thesis elucidates that an elevated brain histaminergic tone is associated with boldness and dominance and in both sexes changes at gene level are orchestrated by different brain region. Boldness is a contextual trait as it depends on strain, line, sex and test. The loser effect after losing a fight is present in both AB and spd line, however it has been shown for the first time in spd line here. Only androgenic progestin causes male biased population but both androgenic and anti androgenic progestin cause early puberty in zebrafish. The expression of leptinergic system is significantly affected during early sexual maturation in parr stage of salmon. Moreover, depleted fat stores are associated with low leptin levels and feed restriction is association with an elevated leptinergic tone in liver and pituitary. This thesis not only emphasizes that strain vs line difference exists and should be an important criterion before designing any experiment, but it also indicates an important role histaminergic system, progestins and leptinergic system in divergent behaviour profiles, puberty and sexual maturation, respectively of teleosts and contributes to our understanding of it.

Place, publisher, year, edition, pages
Uppsala University: Acta Universitatis Upsaliensis, 2019. p. 97
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1757
Keywords
Histamine receptor 1 (hrh1), histamine receptor 2 (hrh2), histamine receptor 3 (hrh3), boldness, personality, aggression, Histaminergic activity, Serotonergic activty (5-HIAA/5-HT), Dopaminergic activty (DOPAC/DA), spiegeldanio (spd), wild caught zebrafish, AB zebrafish, behaviour, brain.
National Category
Physiology Behavioral Sciences Biology
Identifiers
urn:nbn:se:uu:diva-369582 (URN)978-91-513-0539-4 (ISBN)
Public defence
2019-02-15, B21, Biomedical Centrum (BMC), Husargatan 3, Uppsala, 10:00 (English)
Opponent
Supervisors
Available from: 2019-01-23 Created: 2018-12-14 Last updated: 2019-02-18Bibliographically approved

Open Access in DiVA

No full text in DiVA

Other links

Publisher's full textPubMed

Search in DiVA

By author/editor
Svensson, JohanMustafa, ArshiSchmitz, MonikaBrunström, Björn
By organisation
Environmental toxicologyComparative Physiology
In the same journal
Aquatic Toxicology
Natural Sciences

Search outside of DiVA

GoogleGoogle Scholar

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 339 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf