Exposure to 6-PPD Quinone at Environmentally Relevant Concentrations Causes Abnormal Locomotion Behaviors and Neurodegeneration in Caenorhabditis elegans

Abstract

6-PPD quinone (6-PPDQ) can be transformed from 6-PPD through ozonation. Nevertheless, the potential neurotoxicity of 6-PPDQ after long-term exposure and the underlying mechanism are largely unclear. In Caenorhabditis elegans, we here observed that 0.1–10 μg/L of 6-PPDQ caused several forms of abnormal locomotion behaviors. Meanwhile, the neurodegeneration of D-type motor neurons was observed in 10 μg/L of 6-PPDQ-exposed nematodes. The observed neurodegeneration was associated with the activation of the Ca2+ channel DEG-3-mediated signaling cascade. In this signaling cascade, expressions of deg-3, unc-68, itr-1, crt-1, clp-1, and tra-3 were increased by 10 μg/L of 6-PPDQ. Moreover, among genes encoding neuronal signals required for the control of stress response, expressions of jnk-1 and dbl-1 were decreased by 0.1–10 μg/L of 6-PPDQ, and expressions of daf-7 and glb-10 were decreased by 10 μg/L of 6-PPDQ. RNAi of jnk-1, dbl-1, daf-7, and glb-10 resulted in the susceptibility to 6-PPDQ toxicity in decreasing locomotory ability and in inducing neurodegeneration, suggesting that JNK-1, DBL-1, DAF-7, and GLB-10 were also required for the induction of 6-PPDQ neurotoxicity. Molecular docking analysis further demonstrated the binding potential of 6-PPDQ to DEG-3, JNK-1, DBL-1, DAF-7, and GLB-10. Together, our data suggested the exposure risk of 6-PPDQ at environmentally relevant concentrations in causing neurotoxicity in organisms.

Exposure to 6-PPD Quinone at Environmentally Relevant Concentrations Inhibits Both Lifespan and Healthspan in C. elegans

“…The exposure concentrations of 6-PPDQ were 0.1, 1, and 10 μg/L, which were selected as described. , Currently, concentrations of 6-PPDQ in runoff water, river, wastewater, and drinking water vary from ng/L to μg/L . The highest concentration of 6-PPDQ was reported in roadway runoff (19 μg/L) .…”

Urine Excretion, Organ Distribution, and Placental Transfer of 6PPD and 6PPD-Quinone in Mice and Potential Developmental Toxicity through Nuclear Receptor Pathways

“…These results raise concerns about the potential health effects of 6PPD and 6PPDQ, especially during pregnancy. Studies have suggested that 6PPD and 6PPDQ can cause developmental and neurotoxicity in vitro and in zebrafish and elegan models. − For example, 6PPDQ can form DNA adducts in mammalian cells, indicating potential for teratogenic effects . Exposure to 6PPDQ caused abnormal locomotion behaviors in Caenorhabditis elegans at 0.1–10 μg/L and neurodegeneration at 10 μg/L .…”

“…26 Exposure to 6PPDQ caused abnormal locomotion behaviors in Caenorhabditis elegans at 0.1−10 μg/L and neurodegeneration at 10 μg/L. 27 postfertilization) caused morphological changes, behavioral toxicity, and cardiotoxicity in zebrafish larvae. 28 Exposure of zebrafish embryos to 6PPD (0.22 mg/L; 2−120 h postfertilization) caused developmental toxicity and altered hormone levels and gene expressions in embryos.…”

“…Studies have suggested that 6PPD and 6PPDQ can cause developmental and neurotoxicity in vitro and in zebrafish and elegan models. − For example, 6PPDQ can form DNA adducts in mammalian cells, indicating potential for teratogenic effects . Exposure to 6PPDQ caused abnormal locomotion behaviors in Caenorhabditis elegans at 0.1–10 μg/L and neurodegeneration at 10 μg/L . 6PPD and 6PPDQ exposure to zebrafish embryos (10 and 25 μg/L) during the developmental period (1–96 h postfertilization) caused morphological changes, behavioral toxicity, and cardiotoxicity in zebrafish larvae .…”

Automated, High-Throughput Analysis of Tire-Derived p-Phenylenediamine Quinones (PPDQs) in Water by Online Membrane Sampling Coupled to MS/MS

“…6-PPD reacts with ground-level ozone to produce 6-PPDQ and other oxidized byproducts . Since the discovery of 6-PPDQ, acute toxicity at environmentally relevant (ng to μg/L) concentrations has been established for several species including white-spotted char (Salvelinus leucomaenis), rainbow trout (Oncorhynchus mykiss), brook trout (Salvelinus fontinalus), and early-life stage Chinook (Oncorhynchus tshawytscha). − Further, several groups have identified sublethal effects of 6-PPDQ (intestinal, neural) , across multiple species including Caenorhabditis elegans, mice, and fathead minnow (Pimephales promelas) . While the mechanism of 6-PPDQ toxicity is still being uncovered, Mahoney et al recently reported in vitro evidence that 6-PPDQ toxicity may be mediated by disruption of mitochondrial respiration and Blair et al have observed disruption of the blood–brain barrier in coho salmon treated with roadway runoff …”