Synthetic progestins medroxyprogesterone acetate and dydrogesterone and their binary mixtures adversely affect reproduction and lead to histological and transcriptional alterations in zebrafish (Danio rerio).

Medroxyprogesterone acetate (MPA) and dydrogesterone (DDG) are synthetic progestins widely used in human and veterinary medicine. Although aquatic organisms are exposed to them through wastewater and animal farm runoff, very little is known about their effects in the environment. Here we provide a comprehensive analysis of the responses of zebrafish (Danio rerio) to MPA, DDG, and their binary mixtures at measured concentrations between 4.5 and 1663 ng/L. DDG and both mixtures impaired reproductive capacities (egg production) of breeding pairs and led to histological alterations of ovaries and testes and increased gonadosomatic index. Transcriptional analysis of up to 28 genes belonging to different pathways demonstrated alterations in steroid hormone receptors, steroidogenesis enzymes, and specifically, the circadian rhythm genes, in different organs of adult zebrafish and eleuthero-embryos. Alterations occurred even at environmentally relevant concentrations of 4.5-4.8 ng/L MPA, DDG and the mixture in eleuthero-embryos and at 43-89 ng/L in adult zebrafish. Additionally, the mixtures displayed additive effects in most but not all parameters in adults and eleuthero-embryos, suggesting concentration addition. Our data suggest that MPA and DDG and their mixtures induce multiple transcriptional responses at environmentally relevant concentrations and adverse effects on reproduction and gonad histology at higher levels.

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