Inhibition in β-hydroxybutyrate synthesis by 6-PPD quinone at environmentally relevant concentrations is associated...

After exposure in organisms, 6-PPD quinone (6-PPDQ) can disrupt some biochemical metabolisms. β-Hydroxybutyrate is an important ketone body molecule; however, the relationship between disruption in its synthesis and 6-PPDQ toxicity induction remains unclear. In Caenorhabditis elegans, β-hydroxybutyrate content was reduced by 0.1-10 μg/L 6-PPDQ, accompanied with inhibition in expressions of hmgs-1 and Y71G12B.10 governing β-hydroxybutyrate synthesis. RNA interference (RNAi) of hmgs-1 and Y71G12B.10 resulted in susceptibility to 6-PPDQ caused intestinal immunosuppression. DAF-1, SMA-6, and DOP-1 were identified to show the response to 6-PPDQ, and their expressions were decreased by RNAi of hmgs-1 and Y71G12B.10 in 6-PPDQ exposed nematodes. HMGS-1, Y71G12B.10, and receptors of DAF-1, SMA-6, and DOP-1 further regulated 6-PPDQ caused suppression in mitochondrial unfolded protein response (mt UPR), which were linked to further induction of immunosuppression. Moreover, treatment with β-hydroxybutyrate relieved 6-PPDQ caused immunosuppression, suppression in mt UPR, and mitochondrial dysfunction. Therefore, our results suggested the contribution of inhibition in β-hydroxybutyrate synthesis to 6-PPDQ at environmentally relevant concentrations caused immunosuppression by modulating certain receptors controlled mt UPR.