Environmental Chemistry and Ecotoxicology
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2026
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IF 12.3
Cong Zhang,Xulei Zuo,Xiaoyu Hou,Yuxi Zhang,Rongli Sun,Yuepu Pu,Juan Zhang
As concern over tire-derived environmental contaminants continues to grow, the antioxidant N-(1,3-dimethylbutyl)- N ′-phenyl- p -phenylenediamine (6PPD) and its oxidative transformation product, 6PPD-quinone (6PPDQ), have attracted increasing attention for their hepatotoxic potential. Despite accumulating evidence of 6PPDQ-induced liver injury, the molecular mechanisms linking this contaminant to non-alcoholic steatohepatitis (NASH) remain undefined. In this study, an integrated framework combining network toxicology, machine learning, and multi-omics analysis was employed to investigate the association between 6PPDQ exposure and NASH. Intersection of 1451 predicted 6PPDQ targets with NASH-related transcriptomic signatures yielded 52 overlapping candidate mediators enriched in oxidative stress, metabolic regulation, and inflammatory signaling pathways including ErbB, Notch, Hedgehog, Hippo, and TNF. Machine learning analysis across six algorithms identified five hub genes, EPHX2, ESD, FAS, SSB, and ZNF436, with individual AUC values ranging from 0.711 to 0.825. ESD was prioritized for focused analysis, and functional network analysis, eQTL-GWAS colocalization, immune infiltration profiling, single-cell RNA sequencing, and molecular docking together placed ESD within the lipid metabolic, apoptotic, and immunoregulatory circuits central to NASH pathogenesis. In vivo, male BALB/c mice ( n = 6 per group) exposed intraperitoneally to 0.4 or 4 mg/kg 6PPDQ for 28 days developed histological liver injury, hepatic lipid accumulation, and α-SMA-positive profibrotic activation, accompanied by significantly increased hepatic inflammatory and profibrotic gene expression. Serum ALT and AST rose dose-dependently, and hepatic Esd was upregulated at both the mRNA and protein levels. These findings support a proposed ESD-centered adverse outcome pathway framework linking 6PPDQ exposure to NASH-related hepatic injury.
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高影响因子
WATER RESEARCH
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2024
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IF 11.4
Wenyan Yu,Shaoyu Tang,Jonathan W.C. Wong,Zhujun Luo,Zongrui Li,Phong K. Thai,Minghan Zhu,Hua Yin,Junfeng Niu
N-(1,3-dimethylbutyl)-N′-phenyl-p-phenylenediamine quinone (6PPD-Q) has been identified to induce acute toxicity to multifarious aquatic organisms at exceptionally low concentrations. The ubiquity and harmful effects of 6PPD-Q emphasize the critical need for its degradation from water ecosystems. Herein, we explored the transformation of 6PPD-Q by an ultraviolet-activated peroxymonosulfate (UV/PMS) system, focusing on mechanism, products and toxicity variation. Results showed that complete degradation of 6PPD-Q was achieved when the initial ratio of PMS and 6PPD-Q was 60:1. The quenching experiments and EPR tests indicated that SO 4 •− and •OH radicals were primarily responsible for 6PPD-Q removal. Twenty-one degradation products were determined through high-resolution orbitrap mass spectrometry, and it was postulated that hydroxylation, oxidative cleavage, quinone decomposition, ring oxidation, as well as rearrangement and deamination were the major transformation pathways of 6PPD-Q. Toxicity prediction revealed that all identified products exhibited lower acute and chronic toxicities to fish, daphnid and green algae compared to 6PPD-Q. Exposure experiments also uncovered that 6PPD-Q considerably reduced the community diversity and altered the community assembly and functional traits of the sediment microbiome. However, we discovered that the toxicity of 6PPD-Q degradation solutions was effectively decreased, suggesting the superior detoxifying capability of the UV/PMS system for 6PPD-Q. These findings highlight the underlying detrimental impacts of 6PPD-Q on aquatic ecosystems and enrich our understanding of the photochemical oxidation behavior of 6PPD-Q.
研究领域:
环境科学
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生态毒理学
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分析化学
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PubMed
高影响因子
AQUATIC TOXICOLOGY
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2026
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IF 4.6
Lipeng Liang,Hao Wang,Luning Cai,Jiaxin Liang,Xiaojun Niu,Xiaofei Song
The ubiquitous presence of the tire rubber antioxidant 6PPD and its toxic transformation product, 6PPD-quinone (6PPDQ), poses emerging risks to aquatic ecosystems. This study evaluated the comparative hepatotoxicity and enterotoxicity of environmentally relevant concentrations of 6PPD and 6PPDQ in adult zebrafish ( Danio rerio ), with a specific focus on the gut-liver axis. Histopathological analysis revealed that both compounds induced dose-dependent liver damage, characterized by hepatocyte vacuolation and nuclear degeneration; notably, 6PPDQ elicited distinct, and in some aspects comparable, tissue injury relative to the parent compound. Biochemical assays confirmed that oxidative stress is a key mechanism of toxicity, evidenced by elevated malondialdehyde (MDA) levels (increased by up to 62.2%) and glutathione peroxidase (GSH-Px) activity (increased by up to 257.1%), alongside inhibited superoxide dismutase (SOD) and catalase (CAT) activities (reduced by up to 15.2% and 25.3%, respectively). In the intestine, exposure compromised barrier integrity and triggered inflammation, indicated by villus structural damage and the upregulation of NF-κB p65 expression. 16S rRNA sequencing unveiled distinct dysbiosis patterns: 6PPD exposure reduced the abundance of Firmicutes and enriched Proteobacteria, whereas 6PPDQ significantly altered the abundances of Bacteroidetes and Proteobacteria. Functional prediction analysis indicated hypothetical functional shifts, suggesting that 6PPDQ may specifically impair immune-related pathways while enhancing energy metabolism. Collectively, these findings demonstrate that 6PPD and 6PPDQ induce concurrent multi-organ toxicity via the gut-liver axis, with the transformation product 6PPDQ presenting a distinct ecological risk profile. This study highlights the critical need to incorporate transformation products into the risk assessment of tire-derived contaminants.
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高影响因子
TALANTA
·
2025
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IF 6.1
Mingyi Du,Zhiyuan Xu,Dongying Zhang,Yingxi Shi,Mengyu Zhang,Renli Yin,Adela Jing Li,Rongliang Qiu
N -(1,3-Dimethylbutyl)- N′ -phenyl-p-phenylenediamine (6PPD), a widely used rubber antioxidant, and its ozonolysis derivative, 6PPD-quinone (6PPD-Q), have recently attracted significant attention due to their toxic effect in urban runoff mortality syndrome and widespread occurrence in aquatic environments. In this study, a magnetic covalent organic framework (Fe 3 O 4 @TpPa-NO 2 ) was synthesized and applied as a magnetic solid-phase extraction (MSPE) adsorbent for the selective extraction of environmentally relevant levels of 6PPD and 6PPD-Q from road runoff, Pearl River water, tap water and human urine samples. The nanocomposite exhibited a uniform spherical morphology, high surface area, well-defined mesoporous structure and strong magnetic responsiveness, enabling rapid efficient analyte capture via synergistic hydrogen bonding and π-π stacking interactions. Critical adsorption parameters were systematically optimized to enhance the overall performance. Combined with ultra-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS), the developed method demonstrated good sensitivity (limit of detection: 0.004–0.005 μg L −1 ), high linearity (R 2 ≥ 0.9942) and qualified recoveries (70.2−112.0%) in real samples. The concentrations of 6PPD and 6PPD-Q ranged from 0.013 to 0.15 μg L −1 , further highlighting the widespread occurrence in aquatic environments. Compared to traditional pretreatment methods, the Fe 3 O 4 @TpPa-NO 2 -based MSPE method offers a sensitive and reliable approach for monitoring rubber-derived pollutants in environmental and biological samples.
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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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PubMed
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JOURNAL OF HAZARDOUS MATERIALS
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2024
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IF 12.2
Chunyu Liu,Xingchen Zhao,Liqiong Guo,Qilin Yu,Weifei Zhang,Zijuan Peng,Yan Gao,Xiaoyun Gong,Penghui Li,Hui Jiao,Tao Zhou,Qinghe Zhang,Shanjun Song,Guibin Jiang
With increasing concerns about N-(1,3-Dimethylbutyl)-N′-phenyl-p-phenylenediamine (6PPD) and 6PPD-quinone (6PPD-Q), relevant environmental investigations and toxicological research have sprung up in recent years. However, limited information could be found for human body burden assessment. This work collected and analyzed 200 samples consisting of paired urine and plasma samples from participants (50 male and 50 female) in Tianjin, China. Low detection frequencies (DF, <15 %) were found except for urinary 6PPD-Q (86 %), which suggested the poor residue tendency of 6PPD and 6PPD-Q in blood. The low DFs also lead to no substantial association between two chemicals. Data analysis based on urinary 6PPD-Q showed a significant difference between males and females ( p < 0.05). No significant correlation was found for other demographic factors (Body Mass Index (BMI), age, drinking, and smoking). The mean values of daily excretion (ng/kg bw/day) calculated using urinary 6PPD-Q for females and males were 7.381 ng/kg bw/day (female) and 3.360 ng/kg bw/day (male), and apparently female suffered higher daily exposure. Further analysis with daily excretion and ALT (alanine aminotransferase)/TSH (thyroid stimulating hormone)/ blood cell analysis indicators found a potential correlation with 6PPD-Q daily excretion and liver/immune functions. Considering this preliminary assessment, systematic research targeting the potential organs at relevant concentrations is required.
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
危险品化学品经营许可证（带存储）