Synergistic in silico models uncover endocrine and reproductive toxicity of organophosphates

Organophosphates (OPs) are ubiquitous environmental contaminants used in applications ranging from agriculture to home electronics. Their endocrine-disrupting properties have primarily been investigated for a limited number of legacy compounds. Here, we developed an in silico model integrating spherical harmonics, QSAR, and molecular docking, with 97% sensitivity for estrogen receptor (ER) disruptors, validated against in vitro assays targeting ERα and androgen receptor (AR), to assess endocrine activity across 42 OPs and commercial mixtures. A large proportion (88%) disrupted ERα and/or AR at sub-toxic levels, with aryl and triaryl phosphates showing the strongest effects and frequent dual receptor activity. Docking analyses indicate that many OPs interact within the ERα ligand-binding domain through predominantly hydrophobic contacts, showing ∼60% overlap with estradiol-binding residues, while reduced polar interactions may explain their antagonistic behavior. Endocrine activity was consistent with reproductive toxicity evidence. A distinct OP sub-cluster exhibited inactivity driven by steric constraints and limited flexibility.