REFERENCES
1. Li, X.; Chen, X.; Chen, B.; Zhang, W.; Zhu, Z.; Zhang, B. Tire additives: evaluation of joint toxicity, design of new derivatives and mechanism analysis of free radical oxidation. J. Hazard. Mater. 2024, 465, 133220.
2. Hua, X.; Wang, D. Tire-rubber related pollutant 6-PPD quinone: A review of its transformation, environmental distribution, bioavailability, and toxicity. J. Hazard. Mater. 2023, 459, 132265.
3. Kazmi, S. S. U. H.; Xu, Q.; Tayyab, M.; et al. Navigating the environmental dynamics, toxicity to aquatic organisms and human associated risks of an emerging tire wear contaminant 6PPD-quinone. Environ. Pollut. 2024, 356, 124313.
4. Li, Y.; Zeng, J.; Liang, Y.; et al. A review of N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine (6PPD) and its derivative 6PPD-quinone in the environment. Toxics 2024, 12, 394.
5. Chen, X.; He, T.; Yang, X.; et al. Analysis, environmental occurrence, fate and potential toxicity of tire wear compounds 6PPD and 6PPD-quinone. J. Hazard. Mater. 2023, 452, 131245.
6. Yi, J.; Ruan, J.; Yu, H.; et al. Environmental fate, toxicity, and mitigation of 6PPD and 6PPD-Quinone: Current understanding and future directions. Environ. Pollut. 2025, 375, 126352.
7. Yin, T.; Liang, Y.; Liu, Y.; Liu, J.; Wang, X. Environmental occurrence, influencing factors, and toxic effects of 6PPD-Q. Toxics 2025, 13, 906.
8. Xu, F.; Su, M.; Tang, S. Spatiotemporal distribution of 6PPD-Q in China revealed by a national-scale quantification framework. Environ. Sci. Technol. 2026, 60, 1253-62.
9. Zhang, Y.; Yan, L.; Wang, L.; Zhang, H.; Chen, J.; Geng, N. A nation-wide study for the occurrence of PPD antioxidants and 6PPD-quinone in road dusts of China. Sci. Total. Environ. 2024, 922, 171393.
10. Zhang, H.; Li, L.; Jiang, J.; Zhou, Z.; Chen, Q.; Long, T. Developing water quality criteria and assessing ecological risks for 6PPD and 6PPD-Q in freshwater ecosystems. Environ. Pollut. 2025, 387, 127303.
11. Cao, G.; Wang, W.; Zhang, J.; et al. New evidence of rubber-derived quinones in water, air, and soil. Environ. Sci. Technol. 2022, 56, 4142-50.
12. Zhu, J.; Guo, R.; Ren, F.; Jiang, S.; Jin, H. Occurrence and partitioning of p-phenylenediamine antioxidants and their quinone derivatives in water and sediment. Sci. Total. Environ. 2024, 914, 170046.
13. Tian, Z.; Zhao, H.; Peter, K. T.; et al. A ubiquitous tire rubber-derived chemical induces acute mortality in coho salmon. Science 2021, 371, 185-9.
14. Ackerly, K. L.; Roark, K. J.; Lu, K.; Esbaugh, A. J.; Liu, Z.; Nielsen, K. M. Acute toxicity testing of 6PPD-quinone on the estuarine-dependent sport fish, Sciaenops ocellatus. Ecotoxicology 2024, 33, 582-9.
15. Jin, R.; Venier, M.; Chen, Q.; Yang, J.; Liu, M.; Wu, Y. Amino antioxidants: a review of their environmental behavior, human exposure, and aquatic toxicity. Chemosphere 2023, 317, 137913.
16. Roberts, C.; Kohlman, E.; Jain, N.; et al. Subchronic and acute toxicity of 6PPD-quinone to early life stage rainbow trout (oncorhynchus mykiss). Environ. Sci. Technol. 2025, 59, 6771-7.
17. Baker, J. A.; Cronshaw, I.; Monaghan, J.; Jaeger, A.; Bailey, H. C.; Krogh, E. T. Toxicity identification evaluation techniques isolate zinc and 6PPD-Q as causes of acute lethality to rainbow trout in road runoff. Environ. Toxicol. Chem. 2026, 45, 184-94.
18. Jiang, Y.; Wang, C.; Ma, L.; Gao, T.; Wāng, Y. Environmental profiles, hazard identification, and toxicological hallmarks of emerging tire rubber-related contaminants 6PPD and 6PPD-quinone. Environ. Int. 2024, 187, 108677.
19. Liang, Y.; Zhu, F.; Li, J.; et al. P-phenylenediamine antioxidants and their quinone derivatives: A review of their environmental occurrence, accessibility, potential toxicity, and human exposure. Sci. Total. Environ. 2024, 948, 174449.
20. Li, X.; Zhou, S.; Zhang, T.; et al. Occurrence and environmental fate/behaviors of tire wear particles and their human and ecological health: an emerging global issue. Arch. Toxicol. 2025, 99, 4353-66.
21. Zhang, J.; Cao, G.; Wang, W.; et al. Stable isotope-assisted mass spectrometry reveals in vivo distribution, metabolism, and excretion of tire rubber-derived 6PPD-quinone in mice. Sci. Total. Environ. 2024, 912, 169291.
22. Fang, L.; Fang, C.; Di, S.; et al. Oral exposure to tire rubber-derived contaminant 6PPD and 6PPD-quinone induce hepatotoxicity in mice. Sci. Total. Environ. 2023, 869, 161836.
23. Li, X.; Wu, C.; Yang, P.; et al. Environmental factors ultraviolet a and ozone exacerbate the repeated inhalation toxicity of 6PPD in mice via accelerating the aging reaction. J. Hazard. Mater. 2025, 486, 137000.
24. Wang, L.; Tang, W.; Sun, N.; et al. Low-dose tire wear chemical 6PPD-Q exposure elicit fatty liver via promoting fatty acid biosynthesis in ICR mice. J. Hazard. Mater. 2025, 489, 137574.
25. Shi, R.; Zhang, Z.; Zeb, A.; et al. Environmental occurrence, fate, human exposure, and human health risks of p-phenylenediamines and their quinones. Sci. Total. Environ. 2024, 957, 177742.
26. Zhao, H. N.; Thomas, S. P.; Zylka, M. J.; Dorrestein, P. C.; Hu, W. Urine excretion, organ distribution, and placental transfer of 6PPD and 6PPD-quinone in mice and potential developmental toxicity through nuclear receptor pathways. Environ. Sci. Technol. 2023, 57, 13429-38.
27. Chen, H.; Jin, H.; Ren, F.; Guo, R.; Zhu, J.; Huang, K. Enantioselectivity in human urinary excretion of N-(1,3-dimethylbutyl)-N'-phenyl-1,4-benzenediamine (6PPD) and 6PPD-quinone. Environ. Pollut. 2025, 378, 126489.
28. Jia, K.; Sun, J.; Du, Q.; et al. Mass Spectrometry imaging unveils the metabolic effect of 6PPD-quinone in exposed mice. Environ. Sci. Technol. 2025, 59, 4282-91.
29. Qin, Z.; Li, Y.; Qin, Y.; et al. Correlation between 6PPD-Q and immune along with metabolic dysregulation induced liver lesions in outdoor workers. Environ. Int. 2025, 199, 109455.
30. Fang, J.; Wang, X.; Cao, G.; et al. 6PPD-quinone exposure induces neuronal mitochondrial dysfunction to exacerbate Lewy neurites formation induced by α-synuclein preformed fibrils seeding. J. Hazard. Mater. 2024, 465, 133312.
31. Chen, H.; Wang, C.; Li, H.; et al. A review of toxicity induced by persistent organic pollutants (POPs) and endocrine-disrupting chemicals (EDCs) in the nematode Caenorhabditis elegans. J. Environ. Manage. 2019, 237, 519-25.
32. Tao, R.; Sun, M.; Ma, J.; et al. Advancing the understanding of PFAS-induced reproductive toxicity in key model species. Environ. Sci. Process. Impacts. 2025, 27, 3050-75.
33. Yang, B.; Aschner, M.; Lu, R. Toxicological insights into hydrogen sulfide biology in Caenorhabditis elegans: detection, metabolism, and functional outcomes. Crit. Rev. Toxicol. 2025, 55, 735-50.
34. Wang D-Y. Exposure toxicology in Caenorhabditis elegans. Springer Nature Singapore Pte Ltd, 2020.
35. Wu, J.; Shao, Y.; Hua, X.; Li, Y.; Wang, D. Photo-aged polylactic acid microplastics causes severe transgenerational decline in reproductive capacity in C. elegans: insight into activation of DNA damage checkpoints affected by multiple germline histone methyltransferases. Environ. Pollut. 2025, 382, 126697.
36. Wang D-Y. Toxicology at environmentally relevant concentrations in Caenorhabditis elegans. Springer Nature Singapore Pte Ltd, 2022.
37. Wang, W.; Hu, G.; Li, Y.; Wang, D. 6-PPD quinone inhibits ammonia excretion to cause multiple aspects of toxicity in Caenorhabditis elegans by activating dual oxidase complex-SKN-1 axis. Environ. Pollut. 2026, 390, 127528.
38. Song, M.; Ruan, Q.; Wang, D. Paeoniflorin alleviates toxicity and accumulation of 6-PPD quinone by activating ACS-22 in Caenorhabditis elegans. Ecotoxicol. Environ. Saf. 2024, 286, 117226.
39. Liu, Z.; Bian, Q.; Wang, D. 6-PPD quinone induces response of nuclear hormone receptors in the germline associated with formation of reproductive toxicity in Caenorhabditis elegans. J. Hazard. Mater. 2025, 495, 138815.
40. Hu, D.; Wang, Y.; Hu, G.; Liu, R.; Wang, D. 6-PPD quinone-inhibited retinoic acid synthesis mediates toxicity through feedback loop between ALH-3/DHS-19-SEX-1 axis and intestinal signals in Caenorhabditis elegans. J. Environ. Expo. Assess. 2025, 4, 40.
41. Hua, X.; Wang, D. 6-PPD quinone causes alteration in ubiquinone-mediated complex III associated with toxicity on mitochondrial function and longevity in Caenorhabditis elegans. J. Environ. Chem. Eng. 2025, 13, 116571.
42. Wang, Y.; Hu, G.; Wang, D. 6-PPD quinone reduces lifespan by activating a feedback loop between cholesterol transformation related signal and insulin signaling in C. elegans. J. Environ. Sci. 2025, S1001074225006990.
43. Hua, X.; Wang, D. 6-PPD quinone at environmentally relevant concentrations induced damage on longevity in C. elegans: mechanistic insight from inhibition in mitochondrial UPR response. Sci. Total. Environ. 2024, 954, 176275.
44. Hua, X.; Wang, D. An environmentally relevant concentration of 6-PPD quinone inhibits two types of mitophagy to cause mitochondrial dysfunction and lifespan reduction in Caenorhabditis elegans. Environ. Sci. Process. Impacts. 2025, 27, 1928-40.
45. An, L.; Fu, X.; Chen, J.; Ma, J. Application of Caenorhabditis elegans in lipid metabolism research. Int. J. Mol. Sci. 2023, 24, 1173.
46. Wan, X.; Liang, G.; Wang, D. 6-PPD quinone at environmentally relevant concentrations disrupts citric acid cycle in Caenorhabditis elegans: role of reduction in acetyl CoA and pyruvate contents. Environ. Chem. Ecotoxicol. 2025, 7, 1119-29.
47. Wang, W.; Li, Y.; Wang, D. Long-term exposure to 6-PPD quinone inhibits glutamate synthesis and glutamate receptor function associated with its toxicity induction in Caenorhabditis elegans. Toxics 2025, 13, 434.
48. Wu, J.; Li, L.; Hu, D.; Liu, R.; Bian, Q.; Wang, D. Environmentally relevant concentrations of 6-PPDQ disrupt vitamin D3 adsorption and receptor function in Caenorhabditis elegans. Environ. Sci. Process. Impacts. 2025, 27, 2798-808.
49. Wang, Y.; Wu, J.; Wang, D. 6-PPD quinone causes lipid accumulation across multiple generations differentially affected by metabolic sensors and components of COMPASS complex in Caenorhabditis elegans. Environ. Pollut. 2025, 366, 125539.
50. Flynn NE, Meininger CJ, Haynes TE, Wu G. The metabolic basis of arginine nutrition and pharmacotherapy. Biomed. Pharmacother. 2002, 56, 427-38.
51. Khalaf, D.; Krüger, M.; Wehland, M.; Infanger, M.; Grimm, D. The effects of oral l-arginine and l-citrulline supplementation on blood pressure. Nutrients 2019, 11, 1679.
52. Santulli, G.; Trimarco, V.; Trimarco, B.; Izzo, R. Beneficial effects of Vitamin C and l-arginine in the treatment of post-acute sequelae of COVID-19. Pharmacol. Res. 2022, 185, 106479.
53. Rotoli, B. M.; Barilli, A.; Visigalli, R.; Ferrari, F.; Dall’Asta, V. y+LAT1 and y+LAT2 contribution to arginine uptake in different human cell models: implications in the pathophysiology of lysinuric protein intolerance. J. Cell. Mol. Med. 2020, 24, 921-9.
54. Díaz-Pérez, F.; Radojkovic, C.; Aguilera, V.; et al. L-arginine transport and nitric oxide synthesis in human endothelial progenitor cells. J. Cardiovasc. Pharmacol. 2012, 60, 439-49.
55. Tang, R.; Wang, X.; Zhou, J.; et al. Defective arginine metabolism impairs mitochondrial homeostasis in Caenorhabditis elegans. J. Genet. Genomics. 2020, 47, 145-56.
56. Fiordelisi, A.; Cerasuolo, F. A.; Avvisato, R.; et al. L-arginine supplementation as mitochondrial therapy in diabetic cardiomyopathy. Cardiovasc. Diabetol. 2024, 23, 450.
57. Wang, Z.; Yang, N.; Hou, Y.; et al. L-arginine-loaded gold nanocages ameliorate myocardial ischemia/reperfusion injury by promoting nitric oxide production and maintaining mitochondrial function. Adv. Sci. (Weinh). 2023, 10, e2302123.
59. Wang, Y.; Wang, D. Effect of disruption in the intestinal barrier function during the transgenerational process on nanoplastic toxicity induction in Caenorhabditis elegans. Environ. Sci.:. Nano. 2025, 12, 2741-9.
60. Wang, W.; Li, Y.; Wang, D. Exposure to 6-PPD quinone disrupts adsorption and catabolism of leucine and causes mitochondrial dysfunction in Caenorhabditis elegans. Toxics 2025, 13, 544.
61. Wu, T.; He, J.; Ye, Z.; et al. Aged biodegradable nanoplastics enhance body accumulation associated with worse neuronal damage in Caenorhabditis elegans. Environ. Sci. Technol. 2025, 59, 4352-63.
62. Hua, X.; Wang, D. Transgenerational response of germline histone acetyltransferases and deacetylases to nanoplastics at predicted environmental doses in Caenorhabditis elegans. Sci. Total. Environ. 2024, 952, 175903.
63. Wang, Y.; Hu, G.; Wang, D. Increased S-adenosyl methionine strengthens the suppression in mitochondrial unfolded protein response induced by 6-PPD quinone at environmentally relevant concentrations in Caenorhabditis elegans. Environ. Pollut. 2025, 386, 127231.
64. Hua, X.; Wang, D. 6-PPD quinone at environmentally relevant concentrations activates feedback response of electron transport chain to mediate damage on mitochondrial function and longevity in Caenorhabditis elegans. Environ. Chem. Ecotoxicol. 2025, 7, 2356-65.
65. Edwards, C.; Canfield, J.; Copes, N.; et al. Mechanisms of amino acid-mediated lifespan extension in Caenorhabditis elegans. BMC. Genet. 2015, 16, 8.
66. Wu, J.; Shen, S.; Wang, D. 6-PPD quinone at environmentally relevant concentrations induces immunosenescenece by causing immunosuppression during the aging process. Chemosphere 2024, 368, 143719.
67. Liu, Z.; Li, Y.; Wang, D. Transgenerational response of glucose metabolism in Caenorhabditis elegans exposed to 6-PPD quinone. Chemosphere 2024, 367, 143653.
68. Hua, X.; Liang, G.; Chao, J.; Wang, D. Exposure to 6-PPD quinone causes damage on mitochondrial complex I/II associated with lifespan reduction in Caenorhabditis elegans. J. Hazard. Mater. 2024, 472, 134598.
69. Wang D-Y. Molecular toxicology in Caenorhabditis elegans. In: Nematodes as Model Organisms, Springer Nature Singapore Pte Ltd, 2019; pp. 244-75.[DOI: 10.1079/9781789248814.0010].
70. Hua, X.; Wang, D. Exposure to 6-PPD quinone at environmentally relevant concentrations inhibits both lifespan and healthspan in C. elegans. Environ. Sci. Technol. 2023, 57, 19295-303.
71. Veljkovic, E.; Stasiuk, S.; Skelly, P. J.; Shoemaker, C. B.; Verrey, F. Functional characterization of Caenorhabditis elegans heteromeric amino acid transporters. J. Biol. Chem. 2004, 279, 7655-62.
72. Ishii, N.; Fujii, M.; Hartman, P. S.; et al. A mutation in succinate dehydrogenase cytochrome b causes oxidative stress and ageing in nematodes. Nature 1998, 394, 694-7.
73. Kayser, E. B.; Morgan, P. G.; Hoppel, C. L.; Sedensky, M. M. Mitochondrial expression and function of GAS-1 in Caenorhabditis elegans. J. Biol. Chem. 2001, 276, 20551-8.
74. Suthammarak, W.; Somerlot, B. H.; Opheim, E.; Sedensky, M.; Morgan, P. G. Novel interactions between mitochondrial superoxide dismutases and the electron transport chain. Aging. Cell. 2013, 12, 1132-40.
75. Anderson, N. S.; Haynes, C. M. Folding the Mitochondrial UPR into the Integrated Stress Response. Trends. Cell. Biol. 2020, 30, 428-39.
76. Rashid, J.; Kumar, S. S.; Job, K. M.; Liu, X.; Fike, C. D.; Sherwin, C. M. T. Therapeutic potential of citrulline as an arginine supplement: a clinical pharmacology review. Paediatr. Drugs. 2020, 22, 279-93.
77. Yin, J.; Liu, R.; Jian, Z.; et al. Di (2-ethylhexyl) phthalate-induced reproductive toxicity involved in dna damage-dependent oocyte apoptosis and oxidative stress in Caenorhabditis elegans. Ecotoxicol. Environ. Saf. 2018, 163, 298-306.
