The in vitro interference of synthetic progestogens with carp steroidogenic enzymes

Synthetic progestogens represent a class of pharmaceuticals widely used in oral contraceptives and in hormone replacement therapies. They reach the aquatic environment through wastewater effluents; however, environmental concentrations and effects on non-target organisms are poorly known. Given the important role of progestogens regulating fish spawning processes, this study aimed at assessing the in vitro interference of four currently used progestogens-drospirenone (DRO), levonorgestrel (LNG), norethindrone (NOR) and cyproterone acetate (CPA) - with key enzymatic activities involved in the synthesis of active steroids in carp (Cyprinus carpio). The enzymatic pathways investigated were (a) CYP17 (C17,20-lyase) and CYP11β involved in the synthesis of androgens, (b) CYP19 that catalyses the aromatization of androgens to estrogens, and (c) 20β-hydroxysteroid dehydrogenase (20β-HSD) responsible for the synthesis of maturation-inducing hormones. All tested progestogens significantly inhibited the synthesis of androgens: DRO (IC50: 3.8 μM) was the strongest inhibitor of CYP17 followed by CPA (IC50s: 183 μM). Moreover, NOR (IC50: 0.4 μM), DRO (IC50: 1.8 μM) and CPA (IC50s: 87 μM) inhibited CYP11β. An inhibition by NOR of ovarian CYP19 activity, and by DRO and CPA of 20β-HSD was also observed, but at rather high concentrations (500 μM). Overall, this study highlights the potential of synthetic progestogens, and particularly DRO and NOR, to interfere with the biosynthesis of androgens in carp gonads.