# Association Between Organophosphate Flame Retardant Exposure and Trouble Sleeping: Integrating Epidemiological Evidence with Mechanistic Insights

## TL;DR

This study finds a link between exposure to a common flame retardant and trouble sleeping, suggesting a possible environmental health risk.

## Contribution

The study integrates epidemiological data with molecular mechanisms to propose a novel pathway linking OPFRs to sleep disturbances.

## Key findings

- DBuP, a metabolite of TnBP, shows a non-linear, J-shaped relationship with trouble sleeping.
- Network analysis identified five core genes (PPARG, MMP9, PTGS2, APP, EGFR) interacting with DBuP and TnBP.
- Molecular docking and simulations suggest TnBP and DBuP bind to these genes, potentially driving inflammatory responses.

## Abstract

Trouble sleeping has become a global public health challenge. However, the relationship between organophosphate flame retardant (OPFR) exposure and trouble sleeping remains unclear. This study integrated epidemiological analysis, network toxicology, molecular docking, molecular dynamics simulations, and adverse outcome pathway (AOP) construction to identify OPFRs linked to trouble sleeping and attempted to elucidate underlying molecular mechanisms. We analyzed cross-sectional data from the U.S. National Health and Nutrition Examination Survey (NHANES 2013–2018) involving 4585 eligible adults. Logistic regression confirmed dibutyl phosphate (DBuP) as significantly correlated with trouble sleeping. Restricted cubic splines (RCSs) revealed a significant non-linear, J-shaped relationship between dibutyl phosphate (DBuP) levels and trouble sleeping. Weighted quantile sum (WQS) analysis determined that DBuP accounted for the majority contribution (58.23%) to the observed effects within exposure mixtures. These findings indicated that DBuP, a metabolite of tributyl phosphate (TnBP), was closely related to trouble sleeping, suggesting that the environmental health risks of TnBP may be jointly contributed to by itself and DBuP. We used network analysis to identify five core target genes (PPARG, MMP9, PTGS2, APP, EGFR) that interact with DBuP and its parent compound TnBP. Molecular docking predicted binding poses of TnBP and DBuP toward these five core targets; all showed moderate binding affinity (ΔG ≤ −5.0 kcal/mol) except MMP9, which exhibited weak binding. Molecular dynamics simulations further supported this putative binding. Enrichment analysis highlighted inflammatory response pathways. Ultimately, we elucidated the process from molecular exposure to trouble sleeping by constructing an AOP framework. In conclusion, we proposed that TnBP and DBuP may contribute to trouble sleeping through multi-target interactions, primarily through PPARG-driven inflammatory dysregulation. These findings suggest a potential link between OPFR exposure and trouble sleeping, providing insights that warrant further mechanistic investigation.