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Clotrimazole exposure modulates aromatase activity in gonads and brain during gonadal differentiation in Xenopus tropicalis frogs
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
Department of Chemistry, Umeå University.
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2009 (English)In: Aquatic Toxicology, ISSN 0166-445X, E-ISSN 1879-1514, Vol. 91, no 2, 102-109 p.Article in journal (Refereed) Published
Abstract [en]

Clotrimazole is a pharmaceutical used for treatment of fungal infections. It has been found in surface waters outside municipal wastewater treatment plants but data are scarce regarding its effects on aquatic organisms. It is known that clotrimazole and other imidazole fungicides are inhibitors of the enzyme aromatase (CYP 19). Aromatase converts androgens into estrogens and is suggested to be involved in the sex differentiation in amphibians. The aim of the present study was to evaluate effects of larval exposure to clotrimazole on aromatase activity in brain and gonads, and on gonadal differentiation in Xenopus tropicalis frogs. Another purpose was to determine if larval exposure to ethynylestradiol (EE(2)), at a concentration known to cause male-to-female sex reversal, affects aromatase activity in brain and gonads during gonadal differentiation. Tadpoles were exposed from shortly after hatching (Nieuwkoop and Faber developmental stages 47-48) until complete metamorphosis (NF stage 66) to 6, 41, and 375 nM clotrimazole or 100 nM (nominal) EE(2). Aromatase activity was measured in the brain and gonad/kidney complex of tadpoles during gonadal differentiation (NF stage 56) and, in the clotrimazole experiment, also at metamorphosis. In clotrimazole-exposed tadpoles gonadal aromatase activity increased over exposure time in the 41 and 375 nM groups but did not differ significantly from the control group. Gonadal aromatase activity was increased in both sexes exposed to 41 and 375 nM clotrimazole at metamorphosis. Brain aromatase activity was decreased in tadpoles (NF stage 56) exposed to 375 nM clotrimazole, but at metamorphosis no differences were seen between groups or between sexes. No effects of clotrimazole on sex ratio or gonadal histology were noted at completed metamorphosis. EE(2)-exposed tadpoles had a slightly decreased gonadal aromatase activity, though not significantly different from control group, and there was no effect of EE(2) on brain aromatase activity. All EE(2)-exposed tadpoles developed ovaries. These findings indicate that estrogen-induced ovarian differentiation is not paralleled by increased gonadal aromatase activity in X. tropicalis. Further studies are needed, especially on developmental reproductive toxicity, to assess the risk for endocrine disruption in wild amphibians posed by clotrimazole and other imidazole fungicides.

Place, publisher, year, edition, pages
2009. Vol. 91, no 2, 102-109 p.
Keyword [en]
Amphibians, Imidazole, Estrogen, Cytochrome p450, Sex differentiation, Endocrine disruption, Steroidogenesis
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:uu:diva-97449DOI: 10.1016/j.aquatox.2008.10.005ISI: 000263452500002PubMedID: 19036460OAI: oai:DiVA.org:uu-97449DiVA: diva2:172404
Available from: 2008-09-05 Created: 2008-09-05 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Endocrine Disruption in Amphibians: Developmental Effects of Ethynylestradiol and Clotrimazole on the Reproductive System
Open this publication in new window or tab >>Endocrine Disruption in Amphibians: Developmental Effects of Ethynylestradiol and Clotrimazole on the Reproductive System
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Amphibian populations are declining world-wide and one of the suggested reasons is environmental pollutants. Studies of long-term effects on the reproductive system in frogs following larval exposure to environmental pollutants are scarce. It is therefore important to develop methods to study developmental reproductive toxicity in amphibians. In this thesis the usefulness of Xenopus tropicalis (the West African clawed frog) as a model species for a test system was investigated. Effects on the reproductive system after larval exposure to the pharmaceuticals ethynylestradiol (EE2) and clotrimazole were evaluated. The susceptibility to EE2 exposure was compared between the model species and a wild species, the European common frog (Rana temporaria). Larval exposure to EE2 caused female-biased sex ratios in both examined frog species, indicating male-to-female sex-reversal. In adult Xenopus tropicalis, male frogs that were not sex-reversed had reduced fertility and decreased amount of mature spermatozoa in the seminiferous tubules. The proportion of frogs with ovaries but lacking oviducts increased with increasing EE2-concentrations. A female frog without oviducts is sterile. The development of ovaries in sex-reversed male frogs was implied to be similar to control females. The combination of a reduced number of males, due to sex-reversal, and impaired fertility could have severe effects on frog populations. Larval exposure to clotrimazole modulated aromatase activity in gonads and brain in Xenopus tropicalis. Brain aromatase activity was decreased at the time for gonadal differentiation and gonadal aromatase activity was increased at metamorphosis. The findings in this thesis indicate that reproduction in wild frogs might be impaired by estrogenic compounds in the environment. The results combined with the short generation time supports the use of Xenopus tropicalis as a model species when evaluating long term effects of endocrine disruptors on the reproductive system in amphibians.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2008. 57 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 545
Keyword
Test system, Xenopus tropicalis, Rana temporaria, sex ratio, sex differentiation, fertility, aromatase, ovary, testis, oviduct
National Category
Biological Sciences
Identifiers
urn:nbn:se:uu:diva-9209 (URN)978-91-554-7260-3 (ISBN)
Public defence
2008-09-26, Lindahlsalen, Evolutionsbiologisk centrum (EBC), Norbyvägen 18A, Uppsala, 09:15 (English)
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Available from: 2008-09-05 Created: 2008-09-05 Last updated: 2013-09-06Bibliographically approved

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