Long-term exposure to 6-PPD quinone at environmentally relevant concentrations causes neurotoxicity by affecting dopaminergic, serotonergic, glutamatergic, and GABAergic neuronal systems in Caenorhabditis elegans.

ABSTRACT

6-PPD quinone (6-PPDQ), an emerging environmental pollutant, is converted based on 6-PPD via ozonation. However, a systematic evaluation on possible neurotoxicity of long-term and low-dose 6-PPDQ exposure and the underlying mechanism remain unknown. In the present work, 0.1-10 µg/L 6-PPDQ was added to treat Caenorhabditis elegans for 4.5 days, with locomotion behavior, neuronal development, sensory perception behavior, neurotransmitter content, and levels of neurotransmission-related genes being the endpoints. 6-PPDQ exposure at 0.1-10 µg/L significantly reduced locomotion behavior, and that at 1-10 µg/L decreased sensory perception behavior in nematodes. Moreover, 6-PPDQ exposure at 10 µg/L notably induced damage to the development of dopaminergic, glutamatergic, serotonergic, and GABAergic neurons. Importantly, nematodes with chronic 6-PPDQ exposure at 10 µg/L were confirmed to suffer obviously decreased dopamine, serotonin, glutamate, dopamine, and GABA contents and altered neurotransmission-related gene expression. Meanwhile, the potential binding sites of 6-PPDQ and neurotransmitter synthesis-related proteins were further shown by molecular docking method. Lastly, Pearson's correlation analysis showed that locomotion behavior and sensory perception behavior were positively correlated with the dopaminergic, serotonergic, glutamatergic, and GABAergic neurotransmission. Consequently, 6-PPDQ exposure disturbed neurotransmitter transmission, while such changed molecular foundation for neurotransmitter transmission was related to 6-PPDQ toxicity induction. The present work sheds new lights on the mechanisms of 6-PPDQ and its possible neurotoxicity to organisms at environmentally relevant concentrations.