Disruption of dopamine metabolism by exposure to 6-PPD quinone in Caenorhabditis elegans

Abstract

Caenorhabditis elegans is a useful model for examining metabolic processes and related mechanisms. We here examined the effect of exposure to N-(1,3-dimethylbutyl)-N′-phenyl-p-phenylenediamine quinone (6-PPDQ) on dopamine metabolism and underling molecular basis in nematodes. The dopamine content was reduced by 6-PPDQ (1 and 10 μg/L). Meanwhile, dopamine related behaviors (basal slowing response and area restricted searching) were changed by 6-PPDQ (1 and 10 μg/L). Exposure to 6-PPDQ (1 and 10 μg/L) decreased expressions of genes (cat-2 and bas-1) encoding enzymes governing dopamine synthesis and cat-1 encoding dopamine transporter. Development of dopaminergic neurons was also affected by 10 μg/L 6-PPDQ as reflected by decrease in fluorescence intensity, neuronal loss, and defect in dendrite development. Exposure to 6-PPDQ (1 and 10 μg/L) altered expressions of ast-1 and rcat-1 encoding upregulators of cat-2 and bas-1. The dopamine content and expressions of cat-2 and bas-1 were inhibited by RNAi of ast-1 and increased by RNAi of rcat-1 in 6-PPDQ exposed nematodes. Using endpoints of locomotion behavior and brood size, in 6-PPDQ exposed nematodes, the susceptibility to toxicity was caused by RNAi of ast-1, cat-2, bas-1, and cat-1, and the resistance to toxicity was induced by RNAi of rcat-1. Therefore, 6-PPDQ exposure disrupted dopamine metabolism and the altered molecular basis for dopamine metabolism was associated with 6-PPDQ toxicity induction. Moreover, the defects in dopamine related behaviors and toxicity on locomotion and reproduction could be rescued by treatment with 0.1 mM dopamine.