Integrating network toxicology and molecular dynamics simulations to compare the neuroendocrine disruption mechanisms...

Phthalate esters (PAEs) are environmental pollutants with potential neuroendocrine effects, yet systematic comparisons across congeners remain scarce. We employed electrostatic potential analysis (ESP), network toxicology, molecular docking, and molecular dynamics with MM-PBSA (Molecular Mechanics Poisson-Boltzmann Surface Area) binding free energy calculations to evaluate six PAEs. Target prediction from public databases and neuroendocrine-related gene compilation yielded 176 common genes, identifying five hubs AKT1, ESR1, MAPK3, PPARG, and TNF-α. MM-PBSA binding energies ranged from -40.23 to -8.25 kcal/mol, with DINP binding strongest to ESR1 and DEHP exhibiting the highest affinities to PPARG and TNF-α. ESP revealed congener-specific surface properties, with DEP and DIBP exhibiting strong negative potentials on carbonyl oxygens, whereas DEHP and DINP were predominantly hydrophobic. We propose a tentative in silico hierarchy with DEHP > BBP ≈ DBP > DINP > DIBP > DEP. This work provides a theoretical basis for congener specific risk assessment of PAEs.