Effects of parabens on human and rat placental 3β-hydroxysteroid dehydrogenase isoforms: Structure activity relationship and docking analysis

Abstract

Parabens are widely used as preservatives in personal care products and are linked to potential disruptions in placental steroidogenesis. However, their exact impact remains unclear. This study aimed to explore the inhibition, mechanisms, structure-activity relationships (SAR) of parabens on human placental 3β-hydroxysteroid dehydrogenase type 1 (h3β-HSD1) and its rat counterpart, r3β-HSD4.3β-HSD activity was assayed in placental microsomes using pregnenolone as substrate and HPLC-MS/MS to measure progesterone and the effects of parabens on 3β-HSD was evaluated and SAR was performed. The research identified their inhibition against h3β-HSD1, with nonylparaben showing the highest potency (IC₅₀, 4.17 µM), followed by phenylparaben, heptylparaben, hexylparaben, benzylparaben, butylparaben, propylparaben, and ethylparaben. The inhibition was characterized as mixed/noncompetitive. Additionally, these parabens inhibited progesterone secretion in human JAr cells at ≤100 µM. Similar trends were observed for r3β-HSD4. Docking simulations indicated that parabens interact with NAD⁺ and steroid-binding sites of both enzymes. A negative correlation between LogP, molecular weight, volume, and alcohol chain carbon with IC₅₀ values highlighted the role of carbon chain length in determining inhibitory efficacy. The inhibitory potency of parabens on 3β-HSD is significantly influenced by their structural attributes, particularly the length of their carbon chains and LogP values.