Dayu Hu, Yuxing Wang, Guocheng Hu, Qing Li, Dayong Wang
Due to its widespread occurrence in environments, the exposure risk to 6-PPD quinone (6-PPDQ) is receiving increasing attention. Considering the crucial role of retinoic acid in regulating physiological state, we investigated the effects of 6-PPDQ on retinoic acid synthesis and the underlying mechanisms in nematodes. Retinoic acid content was reduced by 6-PPDQ (0.1-10 μg/L). Expression of enzyme genes alh-3 governing retinoic acid synthesis and dhs-19 governing retinal synthesis was decreased by 6-PPDQ. Retinoic acid content was reduced by alh-3 and dhs-19 RNA interference (RNAi). Additionally, alh-3 and dhs-19 RNAi conferred susceptibility to 6-PPDQ toxicity, and these two genes functioned in intestine to modulate 6-PPDQ toxicity. In the intestine, alh-3 and dhs-19 expressions were decreased by intestinal pmk-1, bar-1, and daf-16 RNAi, and pmk-1, bar-1, and daf-16 RNAi reduced retinoic acid content and induced susceptibility to 6-PPDQ toxicity. Additionally, 6-PPDQ decreased expression of sex-1 encoding retinoic acid receptor. After 6-PPDQ exposure, sex-1 expression was decreased by alh-3 and dhs-19 RNAi, and sex-1 RNAi further inhibited pmk-1, bar-1, and daf-16 expressions. sex-1 RNAi caused susceptibility to 6-PPDQ toxicity. Moreover, 6-PPDQ-induced toxicity and decrease in sex-1 expression were suppressed by retinoic acid treatment. Therefore, 6-PPDQ disrupted retinoic acid synthesis, which was linked to toxicity induction through the formation of a feedback loop between the alh-3/dhs-19-sex-1 axis and intestinal signals.