Aryl Organophosphate Esters and Hemostatic Disruption: Identifying Risk through Machine Learning and Experimental Validation

Organophosphate esters (OPEs) have emerged as a significant environmental concern due to their widespread occurrence and potential human health risks. The presence of OPEs in human blood suggests direct interactions with hematological components, which may compromise hemostatic balance and lead to adverse health outcomes. Despite the critical role of hemostatic balance in maintaining blood stability, the effects of OPEs on this system remain poorly understood. This investigation was undertaken to delineate the effects and potential mechanisms of OPEs that modulate hemostasis, utilizing in silico approach and high-throughput in vitro investigation. We analyzed 85 environmentally prevalent OPEs for their structural descriptors and affinity for proteins essential to hemostatic function. The multiple linear regression implicated aryl-OPEs, distinguished by their benzene ring scaffold, as potent disruptors of hemostatic balance. This analysis result was rigorously validated through the in vitro hemostatic balance assays. Further investigation through network toxicology, artificial intelligence (α-Fold) algorithms, and an agonist cotreatment assay revealed proliferator-activated receptor γ (PPARγ) as a key mediator of aryl-OPEs induced hemostatic disruption. By integrating in vitro experimental insights with in vivo exposure data, we concluded that specific aryl-OPEs, such as bisphenol a bis (diphenyl phosphate) (BDP) and cresyl diphenyl phosphate (CDP), pose a moderate risk to the hemostatic balance of the general population. Our findings not only contribute to the prioritization of OPEs risk management but also establish a methodology for assessing the hematological toxicity of emerging pollutants.