Significant enhancement of inhibitory strength of bisphenol A analogs against human and rat 5α-reductase 1 upon halogenation of the benzene ring: Potentially disrupting neurosteroid biosynthesis

Bisphenol A (BPA) halogenation derivatives, formed via radical or electrophilic substitution, constitute a class of emerging contaminants, with brominated variants dominating the flame-retardant market. Their effect on steroid 5α-reductase 1 (SRD5A1) activity in neural and testicular cells remains unclear. This study examined inhibitory effects of seven BPA analogs on SRD5A1, focusing on dihydrotestosterone synthesis. Using SRD5A1 in human brain SF126 cell and rat testicular microsomes, we found an inhibitory potency gradient. For human SRD5A1: tetrabromobisphenol A (12.71 μM) > tetrachlorobisphenol A (16.01 μM) > trichlorobisphenol A (18.95 μM) > 3-chlorobisphenol A (45.37 μM) > BPA = bisphenol S (BPS) = tetrabromobisphenol S (no effect at 100 μM). For rat enzyme: tetrabromobisphenol A (3.60 μM) > tetrachlorobisphenol A (9.27 μM) > trichlorobisphenol A (12.43 μM) > 3-chlorobisphenol A (26.37 μM) > BPA (over 100 μM) = BPS (over 100 μM) > tetrabromobisphenol S (no effect at 100 μM). The inhibition was mixed/competitive. Structure-activity relationship (SAR) analysis showed negative correlations between IC₅₀ values and logarithm of the partition coefficient (LogP), heavy atoms, and hetero atoms of these chemicals for both enzymes. 3D-QSAR pharmacophore analysis showed key binding features to human SRD5A1. Tetrabromobisphenol A has all, while 3-chlorobisphenol A only has hydrophobic sites. Computational docking explained molecular interactions with SRD5A1 binding sites, linking to physicochemical properties. These findings demonstrate SRD5A1 inhibition nuances by halogenated BPA analogs with direct relevance to potential implications. Our data establish the inhibitory potential of halogenated BPA analogs on human brain SRD5A1, revealing distinct SAR and molecular interactions. The inclusion of the rat model provided comparative insight into species-specific responses, underscoring the importance of considering both human relevance and interspecies variability in evaluating endocrine-disrupting risks.