An Investigation of the Neurotoxic Mechanisms of Benzo[a]pyrene in Alzheimer's Disease Using an Integrated Approach of Network Toxicology and Machine Learning.

INTRODUCTION: Benzo[a]pyrene (BaP) exposure is increasingly associated with the progression of Alzheimer's Disease (AD), yet the specific molecular links remain poorly understood. This study utilizes an integrated computational framework, combining network toxicology, machine learning, and molecular dynamics simulations, to identify core biomarkers and elucidate the potential pathological interplay between BaP and AD. METHODS: We began our analysis by identifying the intersection of targets and then created a Protein-Protein Interaction (PPI) Network to identify hub genes. To ensure accuracy, we selected final core molecular targets from the intersection of three distinct types of machine learning algorithms. To validate diagnostic value, immune cell infiltration data analysis was performed using the GSE138260 dataset. Finally, we used molecular docking and 100 ns dynamics to assess how BaP interacts with the core molecular target. RESULTS: We identified four proteins associated with BaP and AD: CASP3 (Caspase 3), HTT (Huntingtin), TH (Tyrosine Hydroxylase), and PARK7 (DJ-1). These proteins signal neuronal apoptosis and neuro-immune dysregulation due to their involvement in pathways associated with these processes. The Receiver Operating Characteristic (ROC) analysis demonstrated strong diagnostic properties for these targets. Molecular docking data also showed BaP as the main target, with TH binding with a value of -10.02 kcal/mol. The stability of this BaP-TH complex was further confirmed by 100 ns molecular dynamics simulations. DISCUSSION: The research reveals TH's critical effect on BaP-induced neurotoxicity. We also identify the potential molecular mechanisms contributing to Alzheimer's disease pathology via environmental exposure. CONCLUSION: This research identifies several significant molecular interactions between BaP and AD. One major molecular target for BaP interaction with AD is tyrosine hydroxylase (TH). Our findings here create an opportunity for the development of therapeutics for the treatment of AD cases caused by exposure to environmental toxins.