Activity of binary mixtures of drospirenone with progesterone and 17?-ethinylestradiol in vitro and in vivo
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Authors
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Publication date
22.02.2016
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Type
01A - Journal article
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Parent work
Aquatic Toxicology
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Volume
174
Issue / Number
Pages / Duration
109-22
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Publisher / Publishing institution
Elsevier
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Abstract
Despite potential exposure of aquatic organisms to mixtures of steroid hormones, very little is known on their joint activity in fish. Drospirenone (DRS) is a new synthetic progestin used in contraceptive pills in combination with 17α-ethinylestradiol (EE2). Here we systematically analyzed effects of DRS in binary mixtures with progesterone (P4) and EE2. First, we determined the in vitro activity of single compounds in recombinant yeast assays that express the human progesterone, androgen, or estrogen receptor, followed by determination of mixture activities of DRS and P4, DRS and EE2, as well as medroxyprogesterone acetate (MPA) and dydrogesterone (DDG). Mixtures of DRS and P4, as well as of DRS and EE2 showed additive progestogenic and androgenic activities. However, DDG and MPA showed non-additive progestogenic and androgenic activities. We then analyzed the in vivo activity of single compounds and mixtures of DRS and P4, as well as DRS and EE2, by assessing transcriptional changes of up to 14 selected target genes in zebrafish embryos at 48h post fertilization (hpf), and in eleuthero-embryos at 96hpf and 144hpf. DRS, P4, and EE2 led to significant transcriptional alteration of genes, including those encoding hormone receptors (pgr, esr1), a steroidogenic enzyme (hsd17b3), and estrogenic markers (vtg1, cyp19b), in particular at 144 hpf. In general, DRS showed stronger transcriptional changes than P4. In mixtures of DRS and P4, they were mainly non-additive (antagonistic interaction). In mixtures of DRS and EE2, transcriptional responses of esr1, vtg1 and cyp19b were dominated by EE2, suggesting an antagonistic interaction or independent action. Equi-effective mixtures of DRS and EE2, based on progesterone receptor transcripts, showed antagonistic interactions. Our data suggest that interactions in mixtures assessed in vitro in recombinant yeast cannot be translated to the in vivo situation. The receptor-based responses did not correspond well to the transcriptional responses in embryos which are much more complex due to the interplay between hormonal pathways, receptor crosstalk, and hormonal feedback loops.
Keywords
Zebrafish embryos, Transcriptional effects, Steroid mixtures, Recombinant yeast assays, Progestins, Mixture activity, Ethinylestradiol
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ISBN
ISSN
0166-445X
1879-1514
1879-1514
Language
English
Created during FHNW affiliation
Yes
Strategic action fields FHNW
Publication status
Published
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Peer review of the complete publication
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Citation
Rossier, N. M., Chew, G., Zhang, K., Riva, F., & Fent, K. (2016). Activity of binary mixtures of drospirenone with progesterone and 17?-ethinylestradiol in vitro and in vivo. Aquatic Toxicology, 174, 109–122. https://doi.org/10.1016/j.aquatox.2016.02.005