Effects of new generation progestins, including as mixtures and in combination with other classes of steroid hormones, on zebrafish early life stages.

Fish are exposed to progestins and steroid mixtures in contaminated waters but the ecotoxicological implications are not sufficiently known. Here we analyze effects of the new generation progestin dienogest (DNG) followed by investigating effects of mixtures of new generation progestins containing DNG, cyproterone acetate and drospirenone and the hormone progesterone. Furthermore, effects of this mixture were studied after adding 17β-estradiol (E2) and clobetasol propionate (CLO) in zebrafish embryos and larvae at concentrations between 0.01 and 10 μg/L. DNG showed only very minor transcriptional alterations among the 24 assessed genes with downregulation of the fshb transcript only. The progestin mixture caused weak induction of the lhb, cyp2k22 and sult2st3 transcripts. Addition of E2 to the mixture caused strong induction vtg1, cyp19b, esr1 and lhb, as well as downregulation of fshb from 0.01 μg/L onwards. Besides altering the same transcripts, addition of CLO altered glucocorticoid regulated genes mmp-9, mmp-13, g6pca, fkbp5 and irg1l. While each steroid class exhibited its specific activity independently in the mixture, sult2st3 and cyp2k22 were regulated by both E2 and CLO. Furthermore, CLO alone and in mixtures decreased spontaneous muscle contractions, increased heartrate and induced edema. Our study highlights the prominent effects of E2 and CLO in environmental steroid mixtures, while new generation progestins show relatively low activity.

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Declaration of competing interest The authors declare that they have no competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.