Neurotoxicity mechanism of polychlorinated biphenyl mediated by dopaminergic system

Polychlorinated Biphenyls (PCBs) are persistent organic pollutants in the environment. With high lipophilicity, PCBs are easily accumulated in the brain, finally leading to neurotoxicity. The underlying neurotoxicity mechanism of PCBs remains poorly understood and requires urgent investigation. The neurotransmitter system has been identified as a potential target of PCB-involved neurotoxicity. Current research on the neurotoxicity mechanism of PCBs predominantly focuses on single target. Due to the high complexity of the brain, the disorder of synaptic transmission triggered by environmental pollutants is highly complicated, and the corresponding mechanisms are likely to involve multi-targets. Here, we focused on two highly correlated components of the dopaminergic system-the dopamine transporter (DAT) and dopamine receptor (DR), to investigate whether there is a synergetic effect between them. By combining multiple computational methods and experimental assays, this study elucidated that DAT was a potential target of neurotoxicity for PCBs in the dopaminergic system, whereas it was highly unlikely for DR to bind PCBs. The computational results indicated that the affinity of the pentachloro biphenyl was higher than the tetrachloro biphenyl. The Van der Waals and π-π interactions were the main driving forces for PCBs binding to DAT. The decomposition energy confirmed that the key residues involved in the ligand binding were converged to Val120, Tyr124, and Phe325 for most of the tested PCBs. Our findings not only provide a detailed and plausible molecular mechanism of PCBs' neurotoxicity, but also are useful for the rational drug design to fight diverse CNS disorders and other diseases involving DAT.