Impact of mycotoxins on placental function: Focus on cyclopiazonic acid, deoxynivalenol, patulin, and zearalenone's metabolites

Mycotoxins are secondary metabolites produced by fungi and pose significant risks to human and animal health. This study aimed to determine inhibitory potency of 7 mycotoxins and metabolites (cyclopiazonic acid, deoxynivalenol, patulin, zearalenone, α-zearalenol, β-zearalenol, and β-zearalanol) against human placental 3β-hydroxysteroid dehydrogenase 1 (h3β-HSD1) and rat homolog r3β-HSD4, as well as their effects on progesterone output in human JAr cells and perform mechanism and structure-activity relationship analysis. In placentas, h3β-HSD1 is responsible for pregnenolone-to-progesterone conversion. Cyclopiazonic acid, deoxynivalenol, patulin, α-zearalenol, β-zearalenol, and β-zearalanol significantly inhibited h3β-HSD1 activity at 100 μM, while zearalenone did not. Their IC₅₀ values ranged from 8.25 μM to 30.50 μM (patulin), and Ki values from 9.04 μM to 31.18 μM, acting as mixed inhibitors. These mycotoxins also inhibited progesterone output by JAr cells at ≥10 μM. For r3β-HSD4, similar inhibitions were observed. IC₅₀ values ranged from 10.55 μM to 42.83 μM. Docking analysis of mycotoxins with h3β-HSD1 and r3β-HSD4 showed interactions like cyclopiazonic acid binding to NAD⁺-binding site. Structure-activity relation analysis revealed correlations between molecular characteristics (hydrophilicity, density) and IC₅₀ values. 3D-QSAR analysis developed ten pharmacophore models, and Hypo1 was selected as the best model, which was validated by testing compounds like cyclopiazonic and patulin.