6-PPD quinone at environmentally relevant concentrations disrupts citric acid cycle in Caenorhabditis elegans: Role of reduction in acetyl CoA and pyruvate contents

The 6-PPD quinone (6-PPDQ) is derived from 6-PPD, an antioxidant added in tires. Citric acid cycle plays a pivotal role in biochemical metabolisms. In Caenorhabditis elegans , we examined effect of 6-PPDQ exposure on citric acid cycle and the role of alteration in acetyl CoA and pyruvate contents during this process. In citric acid cycle, contents of intermediates were reduced by 0.1–10 μg/L 6-PPDQ. Meanwhile, expression of key enzyme genes ( cts-1 , idh-2 , dlst-1 , and dld-1 ) for citric acid cycle was decreased by 0.1–10 μg/L 6-PPDQ. After 6-PPDQ exposure, citric acid content was reduced by cts-1 RNAi, and NADH content was reduced by idh-2 , dlst-1 , and dld-1 RNAi. Exposure to 6-PPDQ (0.1–10 μg/L) further decreased acetyl CoA and pyruvate contents, and inhibited expression of enzyme genes ( dlat-1 and dld-1 ) governing acetyl CoA synthesis and enzyme genes ( pyk-1 and pyk-2 ) governing pyruvate synthesis. After 6-PPDQ exposure, dlat-1 and dld-1 RNAi reduced contents of acetyl CoA, citric acid, and NADH, and pyk-1 and pyk-2 RNAi reduced contents of pyruvate, citric acid, and NADH. In 6-PPDQ exposed nematodes, cts-1 , idh-2 , dlst-1 , dld-1 , dlat-1 , pyk-1 , and pyk-2 RNAi further caused susceptibility to 6-PPDQ toxicity. Our results suggested 6-PPDQ exposure risk in resulting in damage on citric acid cycle, which was linked to its toxicity induction. • 6-PPDQ reduced contents of intermediate metabolites in citric acid cycle. • 6-PPDQ inhibited expression of related enzyme genes governing citric acid cycle . • 6-PPDQ reduced pyruvate and acetyl-CoA contents and expression of related enzyme genes. • RNAi of citric acid cycle related genes affected 6-PPDQ toxicity induction. • Sodium pyruvate treatment inhibited the induction of 6-PPDQ toxicity.