Exploring the toxicological impact of BDE-209 on neurodegenerative diseases through network toxicology, molecular docking, molecular dynamics simulation and in-vitro study.
TL;DR
Findings implicate mTOR dysregulation in BDE-209 cellular responses, but direct binding, chronic exposure, and in vivo disease relevance require further validation.
Abstract
Decabromodiphenyl ether (BDE-209) is a persistent flame retardant associated with neurotoxicity, but its potential links to neurodegenerative diseases remain unclear. We integrated network toxicology, molecular docking, molecular dynamics (MD) simulations, and in vitro experiments to investigate BDE-209 in Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS). Network analysis identified 90 shared targets, enriched in lipid metabolism, oxidative stress, and inflammatory pathways, including IL-17 and TNF signaling. Docking prioritized the FKBP12-mTOR complex as a candidate binding system, with a score of -8.6 kcal/mol. MD simulations supported the stability of the predicted pose, which was dominated by van der Waals and hydrophobic interactions involving PHE-128 and TRP-190. In differentiated PC12 cells, BDE-209 increased p-mTOR at 10 μM and IL-1β at 20 μM without overt cytotoxicity. Rapamycin attenuated the p-mTOR response, supporting mTOR involvement, although mTOR dependence of IL-1β induction was not established. At 40 μM, BDE-209 reduced viability, potentially confounded by precipitation or aggregation. These findings implicate mTOR dysregulation in BDE-209 cellular responses, but direct binding, chronic exposure, and in vivo disease relevance require further validation.