COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY C-TOXICOLOGY & PHARMACOLOGY
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2024
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IF 3.9
Fang Chanlin,Di Shanshan,Wang Caihong,Hu Qinglian,Jin Yuanxiang
The increasing release of tire-derived particles, particularly those containing N-(1,3-dimethylbutyl)- N ′-phenyl- p -phenylenediamine (6PPD), into the environment has raised concerns regarding their ecological impact. This study aims to elucidate the toxicological effects of 6PPD on the metabolism in early developmental stage of zebrafish. Larval zebrafish were exposed to 10 and 100 μg/L 6PPD, and some endpoints in biochemical parameters, gene expression, and metabolism were analyzed. The results showed that 6PPD exposure disrupted glucolipid metabolism in zebrafish larvae, evidenced by increased triglyceride (TG) levels and decreased glucose content. Nile red staining indicated significant lipid accumulation in the liver and intestines. Additionally, RT-qPCR analysis revealed the upregulation of genes involved in lipid synthesis and metabolism, such as ppar-γ and fas , and downregulation of glycolysis-related genes like pk and gk . Furthermore, the untargeted metabolomics technique was used to identify a total of 220 differentially expressed metabolites (DEMs) with changes in amino acid metabolism, lipid metabolism, and the TCA cycle. KEGG pathway enrichment analysis highlighted disruptions mainly in Taurine and hypotaurine metabolism, Arginine and proline metabolism, and Histidine metabolism, which played very important roles on energy metabolism in zebrafish. The results provided some critical insights into the ecological risks associated with 6PPD.
研究领域:
环境科学
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毒理学
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生物化学
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产品关联
DOI
PubMed
高影响因子
COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY C-TOXICOLOGY & PHARMACOLOGY
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2025
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IF 4.3
Yuexing Zhao,Weitao Liu,Jianfeng Feng,Ning Gao,Jinzheng Liu,Ruiying Shi,Aurang Zeb,Jianling Wang,Qi Wang,Chuan Yin,Xinwei Shi,Xiang Li,Yichen Ge
Tire wear particles (TWPs) are a significant source of microplastics (MPs) and N -(1,3-dimethylbutyl)- N ′-phenyl- p -phenylenediamine (6PPD) in aquatic environments. However, the combined toxicity of MPs and 6PPD to aquatic organisms remains unclear. Here, we investigated the bioaccumulation of 6PPD, developmental toxicity, oxidative stress, and metabolic alterations in zebrafish larvae following single and combined exposure to polystyrene MPs (PSMPs) and 6PPD. Our results indicated that co-exposure to PSMPs and 6PPD induced synergistic toxicity in zebrafish larvae, significantly elevating levels of reactive oxygen species (ROS) and malondialdehyde (MDA), along with enhancing antioxidant enzyme activities. PSMPs did not influence the bioaccumulation of 6PPD, but increased the concentration of 6PPD quinone (6PPD-Q) in zebrafish larvae. PSMPs and 6PPD altered the metabolomic profiles of zebrafish larvae, affecting organic acids and their derivatives, amino acids and carbohydrates. The primary distinctions between single and combined exposures were observed in organic acids (citric acid and 9-Octadecenoic acid), sugars (D-Allose, D-Arabinose, and d-Mannose), and cholesterol. These findings imply PSMPs alter the toxicity of 6PPD to zebrafish larvae, providing valuable data for assessing the potential risks of single and combined pollution of MPs and 6PPD to aquatic creatures.
研究领域:
环境毒理学
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水生生物学
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分子生态毒理学
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代谢组学
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污染物相互作用
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产品关联
DOI
PubMed
高影响因子
ENVIRONMENTAL SCIENCE & TECHNOLOGY
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2024
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IF 10.8
Zehua Song,Xiaomei Yu,Minghua Zhu,Zimeng Wu,Zhiqiang Fu,Jingwen Chen
The tire rubber antioxidant N-(1,3-dimethylbutyl)-N′-phenyl-p-phenylenediamine (6PPD) and its quinone product (6PPDQ) are prevalent emerging contaminants, yet their biotransformation profiles remain poorly understood, hampering the assessment of environmental and health risks. This study investigated the phase-I metabolism of 6PPD and 6PPDQ across aquatic and mammalian species through in vitro liver microsome (LM) incubations and in silico simulations. A total of 40 metabolites from seven pathways were identified using the highly sensitive nano-electrospray ionization mass spectrometry. Notably, 6PPDQ was consistently detected as a 6PPD metabolite with an approximate 2% yield, highlighting biotransformation as a neglected indirect exposure pathway for 6PPDQ in organisms. 6PPDQ was calculated to form through a facile two-step phenyl hydroxylation of 6PPD, catalyzed by cytochrome P450 enzymes. Distinct species-specific metabolic kinetics were observed, with fish LM demonstrating retarded biotransformation rates for 6PPD and 6PPDQ compared to mammalian LM, suggesting the vulnerability of aquatic vertebrates to these contaminants. Intriguingly, two novel coupled metabolites were identified for 6PPD, which were predicted to exhibit elevated toxicity compared to 6PPDQ and result from C–N oxidative coupling by P450s. These unveiled metabolic profiles offer valuable insights for the risk assessment of 6PPD and 6PPDQ, which may inform future studies and regulatory actions.
研究领域:
环境科学
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毒理学
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生物化学
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药理学
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产品关联
DOI
PubMed
高影响因子
Journal of Water Process Engineering
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2025
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IF 6.7
Yiyang Lin,Tao Lin,Han Chen,Junding Yin
The effect of N , N -bis(carboxymethyl)glutamic acid (GLDA) on the removal of organic pollutants by Fe(II)-mediated periodate (PI) advanced oxidation process at neutral pH was investigated, in which N-(1,3-dimethylbutyl)- N ′-phenyl- p -phenylenediamine quinone (6PPD-Q) was used as the model pollutant. The results showed that the Fe(II)-GLDA complex formed by mixing GLDA with Fe(II) in a 1:1 ratio reacted with PI can degrade 6PPD-Q effectively. The presence of GLDA alters the redox potential of Fe(II)/Fe(III), which allows for a better utilization of Fe(II) under the synergistic effect of ultraviolet (UV) irradiation. Based on quenching experiments, sulfoxide probe transformation and electron spin resonance (ESR) signals, the reactive species that play a major role in this process are Fe IV O and IO 3 . The degradation products of 6PPD-Q were detected by Ultra Performance Liquid Chromatography-Tandem Mass Spectrometry (UPLC-MS/MS) and two possible degradation pathways were proposed based on density functional theory (DFT) calculations. The toxicity of 6PPD-Q was found to be effectively reduced after degradation by Ecological Structure Activity Relationships (ECOSAR) software analysis and zebrafish experiments. This study provides some fundamental insights for the removal of organic pollutants by GLDA-enhanced Fe(II)/PI system under neutral conditions.
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DOI
高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
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2024
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IF 8.2
Chanlin Fang,Yundong Yu,Shanshan Di,Xinquan Wang,Yuanxiang Jin
The tire antioxidant 6PPD has garnered extensive attention due to its widespread presence in the environment and the harmful effects of its transformation products on aquatic organisms. 6PPD has been detected in airborne dust, and it can enter mammals through inhalation exposure. While the toxic effects of 6PPD exposure have been reported in mammals, its effects on hepatic metabolism still remain poorly understood. Here, we collected the serum and liver samples at 1, 6, and 72 h following a single oral exposure of 100 mg/kg body weight (bw) 6PPD, respectively. We also investigated changes in serum and hepatic physiological indicators and metabolites, correspondingly. Results indicated that single time oral exposure a high dose of 6PPD did not significantly affect the physiological indexes of rats within a short time frame. However, untargeted metabolomics analysis of the metabolites in the liver at 1, 6, and 72 h revealed that the number of differential expression metabolites gradually increased over time and the most affected substances were lipids and lipid-like molecules. Interestingly, the KEGG pathway enrichment analysis indicated that 6PPD disrupted the riboflavin metabolism, leading to a significant decrease in FMN levels at all time points. In addition, the hepatic glucose metabolism was significantly affected at 6 and 72 h after oral administration. Taken together, short-term exposure to 6PPD disturbed lipid and riboflavin metabolism and gradually affected glucose metabolism in the liver of rats. These findings revealed the impacts of 6PPD on the hepatic metabolism in animals, and also offered some important insights into its toxicology and health risk.
研究领域:
毒理学
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环境科学
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代谢组学
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产品关联
DOI
PubMed
高影响因子
Journal of Advanced Research
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2025
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IF 13
Qu-Nan Wang,Chunzhi Wang,Yán Wāng
Introduction The extensive use of 6PPD in tire rubber has led to its increase in atmospheric tire wear particles. 6PPD reacts with ozone to form 6PPD-quinone (6PPD-Q), a respiratory toxicant enriched in tire and road wear particles. Objectives The aim of this study is to decipher the potential sensitive target organs and toxic actions by inhalation exposure to atmospheric 6PPD-Q. Methods This study employed a mouse inhalation exposure model to simulate environmental levels of 6PPD-Q at three concentrations of 0, 0.14, and 14 mg/m 3 . Using a 28-day exposure period followed by an equivalent recovery phase, we systematically evaluated the toxicological targets and effects of subacute exposure. Results The findings revealed that, compared to pulmonary, cardiovascular, and metabolic organ damage, 6PPD-Q-induced neurotoxicity was more persistent and irreversible, particularly characterized by prolonged anxiety-like behaviors. Histopathological analyses of the basolateral amygdala, using Nissl staining and markers of neuronal aging, indicated substantial neuronal degeneration linked to elevated oxidative stress, identifying this region as a critical target of 6PPD-Q neurotoxicity. Transcriptomic analysis uncovered that the expression of Egr1 , a transcription factor crucial for neuronal plasticity, was markedly dysregulated. Findings of significant downregulation at the gene level and an upward trend in protein expression suggest that Egr1 expression is influenced by translational efficiency, epigenetic modifications, and post-translational regulatory mechanisms. Egr1 dysregulation disrupted downstream networks involving solute carrier proteins and calcium-binding proteins, contributing to aberrant neurobehavioral outcomes. Notably, the elevation of Egr1 protein levels in the basolateral amygdala but not in the cerebral cortex highlights the region-specific nature of 6PPD-Q’s neurotoxic effects. Conclusion This study provides the first insights into the neurotoxicity and irreversibility of inhaled 6PPD-Q exposure, paving the way for future research into the long-term neurological consequences and regulatory mechanisms of 6PPD-Q.
研究领域:
毒理学
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神经科学
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环境健康
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产品关联
DOI
PubMed
高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
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2024
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IF 8.2
Yuying Zhang,Lei Yan,Longxing Wang,Haijun Zhang,Jiping Chen,Ningbo Geng
N , N ′-substituted p -phenylenediamines (PPDs) are widely used antioxidants in rubber tires, which could be released and accumulated in road dusts with rubber tires wear. As ozonation product of N -(1,3-dimethylbutyl)- N′ -phenyl- p -phenylenediamine (6PPD), 6PPD-quinone (6PPD-Q) exhibited higher toxicity to coho salmon. However, studies on their environmental behaviors are still limited. Road dust is the major medium PPDs exist, which significantly affects the levels of PPDs in other mediums, especially surface water and particulate matter. In this study, road dust samples were collected in 55 major cities of China to explore the distribution characteristics of PPDs and 6PPD-Q. The concentrations of total PPDs (ΣPPDs) and 6PPD-Q in urban trunk road dust samples were in the ranges of 7.90–727 and 3.00–349 ng/g, with median concentrations of 68 and 49 ng/g, respectively. 6PPD and 6PPD-Q are the dominant components in most road dusts. The functional region-dependent pollution characteristics of PPDs and 6PPD-Q give the first finding that urban tunnel road was the highly polluted region, followed by urban trunk roads. Suburban road dusts had a lower pollution level. Moreover, the estimated daily intake (EDI) of PPDs and 6PPD-Q for children was much higher than adults.
研究领域:
环境科学
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毒理学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
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2024
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IF 12.2
Xianjie Li,Caixia Wu,Ping Yang,Yanxi Li,Shuai Wang,Dan Cai,Ran Wei,Jinfeng Gao,Xuemei Wen,Jieping Luo,Rui Wang,Xueyuan Bai,Shen Chen,Ping Guo
The burden of N-(1,3-dimethylbutyl)-N′-phenyl-p-phenylenediamine (6PPD) and its oxidized products on human health can no longer be ignored due to the detection types and concentrations in the environment continue to increase. Environmental ozone (O 3 ) and ultraviolet A (UVA) may induce ozonation and photoaging of 6PPD to produce toxic products. However, the impact of specific environmental conditions on the aging and toxic effects of 6PPD is unclear. This study investigated the aging effects of O 3 and UVA on 6PPD, and compared the repeated inhalation toxicity of differently aging 6PPDs in C57BL/6 male mice. The result showed that UVA and O 3 accelerated 6PPD aging, and the aging products varied depending on the O 3 and irradiation conditions. After 10 weeks of inhalation intoxication at human comparable level, mice exhibited significant neurobehavior alterations, respiratory dysfunction, and DNA damage in the blood, showing significant heterogeneity among groups. Notably, 6PPD treated with perozonation and UVA aging may be the most toxic. The study suggests inhalation health risks of transportation derived tire pollutants under the influence of ground-level ozone and ultraviolet light need more attention, and provides new insights into risk assessment and pollution control of 6PPD and other pollutants from the perspective of environmental factors.
研究领域:
环境科学
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毒理学
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医学
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产品关联
DOI
PubMed
高影响因子
ECOTOXICOLOGY
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2024
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IF 2.4
Yang Liu,Liu Kexin,Shi Lina,Chen Ming,Liu Junyan,Dai Shiniu,Xi Yilong,Wen Xinli
N-(1,3-dimethylbutyl)-N’-phenyl-p-phenylenediamine (6PPD) and Zn 2+ , extensively used in the tire manufacturing process, are frequently detected in freshwater environments. However, the intergenerational effects of isolated 6PPD exposure and joint 6PPD and Zn 2+ exposure at concentrations approximating environmental levels remain unknown. This study assessed the chronic toxicity and intergenerational effects of 6PPD (0.02–20 μg/L) and a mixture of 6PPD and Zn 2+ (5 μg/L) over three generations in Daphnia magna bioassays. In the F0 generation, a dose-dependent decline in total offspring number was observed with 6PPD exposure alone, while co-exposure with Zn 2+ exacerbated the reproductive toxicity of 6PPD. Across three generations, low-dose (0.02 µg/L) 6PPD alone and combined with Zn 2+ induced a cumulative degenerative maternal effect. Conversely, high-dose (20 µg/L) 6PPD, both independently and in combination with Zn 2+ , exhibited an adaptive maternal effect. Notably, the grandmaternal effect emerged exclusively in the co-exposure group treated with 20 μg/L 6PPD and 5 μg/L Zn 2+ , with no such effect in the group exposed to 20 μg/L 6PPD alone, suggesting that Zn 2+ may enhance the potential toxicity of 6PPD. Overall, this study provides novel insight into the intergenerational impacts of environmentally relevant levels of 6PPD alone and in combination with a heavy metal, elucidating the environmental risks posed by tire-derived chemicals through their synergistic effects on transgenerational toxicity.
研究领域:
环境科学
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毒理学
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产品关联
DOI
PubMed
高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
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2023
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IF 9.8
Chanlin Fang,Liya Fang,Shanshan Di,Yundong Yu,Xinquan Wang,Caihong Wang,Yuanxiang Jin
N-(1,3-dimethylbutyl)- N ′-phenyl- p -phenylenediamine (6PPD) is a type of p -phenylenediamine (PPD), which is widely used in the manufacture of rubber tires owing to its excellent antiozonant properties. In this study, the developmental cardiotoxicity of 6PPD was evaluated in zebrafish larvae, and the LC50 was approximately 737 μg/L for the larvae at 96 h post fertilization (hpf). In the 6PPD treatment of 100 μg/L, the accumulation concentrations of 6PPD were up to 2658 ng/g in zebrafish larvae, and 6PPD induced significant oxidative stress and cell apoptosis in the early developmental stages of zebrafish. Transcriptome analysis showed that 6PPD exposure could potentially cause cardiotoxicity in larval zebrafish by affecting the transcription of the genes related to the calcium signal pathway and cardiac muscle contraction. The genes related to calcium signaling pathway ( slc8a2b , cacna1ab , cacna1da , and pln ) were verified by qRT-PCR, which were significantly downregulated in larval zebrafish after exposing to 100 μg/L of 6PPD. Simultaneously, the mRNA levels of the genes related to cardiac functions ( myl7 , sox9 , bmp10 , and myh71 ) also respond accordingly. H&E staining and heart morphology investigation indicated that cardiac malformation occurred in zebrafish larvae exposed to 100 μg/L of 6PPD. Furthermore, the phenotypic observation of transgenic Tg (myl7: EGFP) zebrafish also confirmed that 100 μg/L of 6PPD exposure could change the distance of atria and ventricles of the heart and inhibit some key genes ( cacnb3a , ATP2a1l , ryr1b ) related to cardiac function in larval zebrafish. These results revealed the toxic effects of 6PPD on the cardiac system of zebrafish larvae.
研究领域:
环境毒理学
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发育生物学
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分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
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2025
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IF 11.3
Chenyang Rao,Yanxia Zuo,Dongfang Xiang,Bo Xian,Fuhao Chu,Fang Fang,Xiaowei Xiang,Wei Tang,Shaopan Bao,Tao Fang
In recent years, N -(1,3-dimethylbutyl)- N′ -phenyl- p -phenylenediamine (6PPD) has attracted significant attention in environmental science, yet its behavior in biological systems remains poorly understood. This study involved a 28-day zebrafish exposure experiment at three concentrations (2, 20, and 200 μg/L), to investigate its physiologically based toxicokinetic (PBTK) properties, the formation of biotransformation products, and the metabolic characteristics of liver tissue. The results indicated that the liver and intestines are key organs for 6PPD accumulation, with tissue-specific distribution patterns. The biotransformation of 6PPD in the liver involves various phase I and phase II metabolic reactions, including hydroxylation, N -dealkylation, and sulfation processes. Furthermore, Metabolomics analysis revealed substantial changes in both the diversity and abundance of liver metabolites with increasing 6PPD concentrations, particularly in key biological processes such as lipid metabolism, amino acid metabolism, and redox balance. Notably, significant disruptions in sphingolipid and glycerophospholipid pathways suggest 6PPD may impair membrane fluidity and stability, potentially leading to membrane damage and dysfunction. Overall, this study provides crucial insights into the biological behavior of 6PPD in zebrafish, contributing essential knowledge for its ecotoxicological evaluation.
研究领域:
环境科学
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毒理学
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代谢组学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
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2022
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IF 10.753
Jiawen Ji,Jinze Huang,Niannian Cao,Xianghong Hao,Yanhua Wu,Yongqiang Ma,Dong An,Sen Pang,Xuefeng Li
The typical tire manufacturing additive 6PPD, its metabolites 6PPDQ and 4-Hydroxy should be monitored because of their ubiquitous presence in the environment and the high toxicity of 6PPDQ to coho salmon. The toxic effect of 6PPD and its metabolites have been revealed superficially, especially on behavioral characteristics. However, the behavioral indicators explored so far are relatively simple and the toxic causes are poorly understood. With this in mind, our work investigated the toxic effects of 6PPD, 6PPDQ and 4-Hydroxy on adult zebrafish penetratingly through machine vision, and the meandering, body angle, top time and 3D trajectory are used for the first time to show the abnormal behaviors induced by 6PPD and its metabolites. Moreover, neurotransmitter changes in the zebrafish brain were measured to explore the causes of abnormal behavior. The results showed that high-dose treatment of 6PPD reduced the velocity by 42.4% and decreased the time at the top of the tank by 91.0%, suggesting significant activity inhibition and anxiety. In addition, γ-aminobutyric acid and acetylcholine were significantly impacted by 6PPD, while dopamine exhibited a slight variation, which can explain the bradykinesia, unbalance and anxiety of zebrafish and presented similar symptoms as Huntingdon's disease. Our study explored new abnormal behaviors of zebrafish induced by 6PPD and its metabolites in detail, and the toxic causes were revealed for the first time by studying the changes of neurotransmitters, thus providing an important reference for further studies of the biological toxicity of 6PPD and its metabolites.
研究领域:
环境毒理学
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神经科学
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水生生物学
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行为科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）