Effects of Fungicides on Rat's Neurosteroid Synthetic Enzymes

Exposure to environmental endocrine disruptors may interfere with nervous system's activity. Fungicides such as tebuconazole, triadimefon, and vinclozolin have antifungal activities and are used to prevent fungal infections in agricultural plants. In the present study, we studied effects of tebuconazole, triadimefon, and vinclozolin on rat's neurosteroidogenic 5α-reductase 1 (5α-Red1), 3α-hydroxysteroid dehydrogenase (3α-HSD), and retinol dehydrogenase 2 (RDH2). Rat's 5α-Red1, 3α-HSD, and RDH2 were cloned and expressed in COS-1 cells, and effects of these fungicides on them were measured. Tebuconazole and triadimefon competitively inhibited 5α-Red1, with IC₅₀ values of 8.670 ± 0.771 × 10^-6 M and 17.390 ± 0.079 × 10^-6 M, respectively, while vinclozolin did not inhibit the enzyme at 100 × 10^-6 M. Triadimefon competitively inhibited 3α-HSD, with IC₅₀ value of 26.493 ± 0.076 × 10^-6 M. Tebuconazole and vinclozolin weakly inhibited 3α-HSD, with IC₅₀ values about 100 × 10^-6 M, while vinclozolin did not inhibit the enzyme even at 100 × 10^-6 M. Tebuconazole and triadimefon weakly inhibited RDH2 with IC₅₀ values over 100 × 10^-6 M and vinclozolin did not inhibit this enzyme at 100 × 10^-6 M. Docking study showed that tebuconazole, triadimefon, and vinclozolin bound to the steroid-binding pocket of 3α-HSD. In conclusion, triadimefon potently inhibited rat's neurosteroidogenic enzymes, 5α-Red1 and 3α-HSD.