Volume 4, Issue 4 (2025) – 9 articles
Cover Picture: Due to its widespread environmental presence, the potential toxicity of 6-PPD quinone (6-PPDQ) has attracted increasing attention. Here, we show that 6-PPDQ disrupts retinoic acid synthesis in nematodes, leading to enhanced toxicity. Exposure to 6-PPDQ reduced retinoic acid levels by suppressing the expression of dhs-19 and alh-3, two key enzymes involved in retinal and retinoic acid synthesis. Knockdown of dhs-19 or alh-3 further decreased retinoic acid content and increased susceptibility to 6-PPDQ toxicity, with both genes acting in the intestine. Intestinal signaling pathways involving pmk-1, bar-1, and daf-16 regulated dhs-19 and alh-3 expression and retinoic acid homeostasis. Moreover, 6-PPDQ suppressed the retinoic acid receptor gene sex-1, which in turn modulated pmk-1, bar-1, and daf-16 signaling. Retinoic acid supplementation alleviated 6-PPDQ-induced toxicity and restored sex-1 expression. Collectively, our findings demonstrate that 6-PPDQ induces toxicity by impairing retinoic acid synthesis and signaling through an intestine-centered feedback loop.
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