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Developmental and Reproductive Toxicity of Progestagens in the Xenopus (Silurana) tropicalis Test System
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Progestagenic compounds are emerging contaminants found in surface and ground water around the world. Information on the effects and potency of progestagens is needed in order to understand the environmental risks posed by these compounds. Using the Xenopus (Silurana) tropicalis test system, developmental and reproductive toxicity after exposure to selected progestagens were determined. Larval exposure to levonorgestrel (LNG) severely impaired oviduct and ovary development causing sterility. No effects on testicular development, spermcount or male fertility were observed. Hepatic mRNA expression of the androgen receptor was increased in the females indicating that the receptor is involved in LNG-induced developmental reproductive toxicity. Exposure of adult females to LNG, norethindrone (NET) or progesterone (P) increased the proportions of previtellogenic oocytes and reduced the proportions of vitellogenic oocytes compared with the controls, indicating an inhibited vitellogenesis. The effects on oocyte development were ascertained at environmentally relevant concentrations of LNG, NET and P (1.3, 1 and 10 ng/L respectively). Since unintentional co-exposure of progestagens and ethinylestradiol (EE2) occurs in wildlife and also in human infants, data on mixture effects of combined exposures to these hormones during development are needed. Co-exposure during development showed antagonistic effects of EE2 and LNG. EE2 caused a female biased sex ratio which showed a tendency to be antagonized by LNG. Moreover, the hepatic AR induction by LNG was counteracted by co-exposure to EE2. In conclusion, the results show that female amphibians are susceptible to reproductive toxicity of progestagens after developmental exposure as well as after adult exposure during the breeding period. The differentiating Müllerianduct and ovary, and the egg development are sensitive targets for progestagens. Finally, the findings reported in this thesis show that environmental progestagens impairs reproductive function in amphibians and may present a threat to reproduction in wild populations.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. , 51 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1099
Keyword [en]
Xenopus tropicalis, sex organ differentiation, oogenesis, fertility, ovary, oviduct, progestagens
National Category
Natural Sciences
Research subject
Biology with specialization in Environmental Toxicology
Identifiers
URN: urn:nbn:se:uu:diva-210990ISBN: 978-91-554-8812-3 (print)OAI: oai:DiVA.org:uu-210990DiVA: diva2:665042
Public defence
2014-02-14, Auditorium Minus, Museum Gustavianum, Akademigatan 3, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2014-01-23 Created: 2013-11-18 Last updated: 2014-02-10Bibliographically approved
List of papers
1. Early life progestin exposure causes arrested oocyte development, oviductal agenesis and sterility in adult Xenopus tropicalis frogs
Open this publication in new window or tab >>Early life progestin exposure causes arrested oocyte development, oviductal agenesis and sterility in adult Xenopus tropicalis frogs
2011 (English)In: Aquatic Toxicology, ISSN 0166-445X, E-ISSN 1879-1514, Vol. 103, no 1-2, 18-24 p.Article in journal (Refereed) Published
Abstract [en]

Levonorgestrel (LNG) is a commonly used pharmaceutical progestin found in the environment. Information on the long-term toxicity of progestins following early life exposure is scant. We investigated the effects of developmental LNG exposure on sex differentiation, reproductive organ development and fertility in the model frog Xenopus tropicalis. Tadpoles were exposed to 0, 0.06 or 0.5 nM LNG via the water from hatching until metamorphosis. At metamorphosis effects on gonadal differentiation were evaluated using a subsample of frogs. Remaining animals were held unexposed for nine months, at which time reproductive organ structure, function and fertility were determined. LNG exposure severely impaired oviduct and ovary development and fertility. All adult females in the 0.5 nM group (n = 10) completely lacked oviducts. They also displayed a significantly larger fraction of immature oocytes, arrested in meiotic prophase, than control females. Upon mating with unexposed males, only one of 11 LNG-exposed females laid eggs, whereas all control females did. No effects on testicular development, sperm count or male fertility were observed. At metamorphosis, no effects on sex ratio or gonadal histology were evident. The effects on ovarian and oviductal development were detected at adult age but not at metamorphosis, emphasising the importance of investigating the long-term consequences of developmental exposure. This is the first developmental reproductive toxicity study of a progestin in an aquatic vertebrate. Considering that several progestins are present in contaminated surface waters, further investigation into the sensitivity of frogs to progestins is warranted to understand the risk such compounds may pose to wild frog populations.

Keyword
Endocrine disruption, Developmental reproductive toxicity, Levonorgestrel, Oogenesis, Oviduct, Sex differentiation
National Category
Biological Sciences
Research subject
Ecotoxicology
Identifiers
urn:nbn:se:uu:diva-153282 (URN)10.1016/j.aquatox.2011.02.003 (DOI)000290502000003 ()21392492 (PubMedID)
Available from: 2011-05-10 Created: 2011-05-10 Last updated: 2017-12-11Bibliographically approved
2. Disrupted Oogenesis in the Frog Xenopus tropicalis after Exposure to Environmental Progestin Concentrations
Open this publication in new window or tab >>Disrupted Oogenesis in the Frog Xenopus tropicalis after Exposure to Environmental Progestin Concentrations
2012 (English)In: Biology of Reproduction, ISSN 0006-3363, E-ISSN 1529-7268, Vol. 86, no 4, 126- p.Article in journal (Refereed) Published
Abstract [en]

Levonorgestrel is a synthetic progesterone commonly used in pharmaceuticals (e. g., in contraceptives). It is found in sewage treatment plant effluents at concentrations up to 30 ng/L and was recently shown to pose a threat to egg laying in fish. Information on the susceptibility of adult amphibians to progestin toxicity is lacking. The present study aimed to 1) characterize progestogenic effects on the full cycle of oogenesis (egg development) in frogs and 2) determine female amphibians' susceptibility to reproductive impacts from progestogenic compounds in the environment. Sexually mature female Xenopus tropicalis were exposed to levonorgestrel via the surrounding water for 7 days (0, 51, or 307 ng/L) or 28 days (0, 1.3, 18, 160, or 1240 ng/L). Their ovaries were analyzed histologically with respect to frequencies of immature (in early meiotic prophase I), previtellogenic, vitellogenic, mature, and atretic oocytes. The 28-day exposure caused reduced proportions of oocytes at immature, vitellogenic, and mature stages, and increased proportions of previtellogenic oocytes compared with the control. The lowest tested concentration, 1.3 ng/L, increased the proportions of previtellogenic oocytes and reduced the proportions of vitellogenic oocytes, indicating inhibited vitellogenesis. The present study shows that progestin concentrations found in the aquatic environment impaired oogenesis in adult frogs. Our results indicate that progestogenic effects on oocyte development include interrupted germ cell progression into meiosis and inhibited vitellogenesis. Considering the crucial role of oogenesis in female fertility, our results indicate that progestogenic pollutants may pose a threat to reproduction in wild amphibian populations.

Keyword
amphibians, endocrine disruption, levonorgestrel, meiosis, oocyte development, pharmaceuticals, reproductive toxicology, vitellogenesis
National Category
Biological Sciences
Identifiers
urn:nbn:se:uu:diva-179588 (URN)10.1095/biolreprod.111.097378 (DOI)000306549500014 ()
Available from: 2012-08-20 Created: 2012-08-20 Last updated: 2017-12-07Bibliographically approved
3. Antagonistic Mixture Effects of Levonorgestrel and Ethinylestradiol on Androgen Receptor mRNA Expression during Sex Differentiation.
Open this publication in new window or tab >>Antagonistic Mixture Effects of Levonorgestrel and Ethinylestradiol on Androgen Receptor mRNA Expression during Sex Differentiation.
(English)Article in journal (Refereed) Submitted
National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-210988 (URN)
Available from: 2013-11-18 Created: 2013-11-18 Last updated: 2014-02-10
4. Disrupted oogenesis in Xenopus tropicalis exposed to environmental norethindrone and progesterone concentrations.
Open this publication in new window or tab >>Disrupted oogenesis in Xenopus tropicalis exposed to environmental norethindrone and progesterone concentrations.
(English)Manuscript (preprint) (Other academic)
National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-210989 (URN)
Available from: 2013-11-18 Created: 2013-11-18 Last updated: 2014-02-10

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