JOURNAL OF HAZARDOUS MATERIALS
·
2026
·
IF 10.6
Xia-Wen Qiu,Jiajun Chen,Jiayan Wang,Yujie Li,Xiaoyan Qi,Xianchang Zeng,Huajun Feng,Xianghui Kong
Respiratory viral infections contribute substantially to global disease burden and mortality. N -(1,3-dimethylbutyl)- N ′-phenyl- p -phenylenediamine quinone (6PPD-Q) has garnered significant attention due to its marked ecotoxicity. However, it remains unclear how this prevalent environmental pollutant impacts host immune defense against respiratory viral infections. This study established a murine model involving 14-day consecutive intranasal administration of environmentally relevant doses of 6PPD-Q coupled with intranasal instillation of influenza A virus (IAV) or tail vein injection of vesicular stomatitis virus (VSV). Our findings revealed that mice pre-exposed to 6PPD-Q exhibited higher mortality during viral infection. Notably, 6PPD-Q exposure resulted in extensive viral dissemination, severe pulmonary pathology, and markedly dysregulated inflammation, characterized by excessive increases in IL-6, TNF-α, IL-1β, and IL-10. Immune profiling demonstrated that 6PPD-Q exposure induced the selective accumulation of neutrophils, monocytes, and monocyte-derived macrophages (MDMs) in the lungs during IAV infection. Interestingly, macrophage depletion unequivocally abolished the differences of survival, viral loads, and cytokine levels between the vehicle- and 6PPD-Q-treated mice. Mechanistically, 6PPD-Q activated NF-κB signaling in pulmonary MDMs, driving excessive inflammatory responses. Our findings confirm that 6PPD-Q significantly increases host susceptibility to viral pneumonia. This underscores the critical significance of environmental health management in the prevention and control of respiratory infectious diseases.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
·
2026
·
IF 10.6
Hanghai Zhou,Zhendong Li,Zhou Wu,Lihua Zou,Hong Sun,Hua Li,Xin Wang,Yuan Wang,Junwei Jin,Thilo Hofmann,Jiangwu Tang
Tire and road wear particles introduce complex mixtures of metals and organic additives into soils, yet the primary drivers of their combined toxicity remain poorly resolved. Here, we investigated the individual and combined effects of zinc oxide (ZnO), a major inorganic tire additive, and 6PPD-quinone (6PPD-Q), a toxic transformation product of the tire antioxidant 6PPD, using a soil invertebrate exposure model. A gradient of ZnO concentrations was tested alone and in combination with an environmentally relevant level of 6PPD-Q to simulate co-contaminated soils. While single exposures induced oxidative stress, metabolic perturbation, and gut microbiome alteration, co-exposure under high Zn conditions resulted in increased mortality and growth inhibition relative to single treatments. Chemical analysis revealed enhanced Zn accumulation in organisms under co-exposure, whereas 6PPD-Q bioaccumulation declined at elevated Zn levels, indicating that internal Zn burden was more consistently associated with organism-level impairment than measured internal 6PPD-Q concentration under the tested conditions. Integrated biochemical, histological, and multi-omics analyses showed that co-exposure was associated with enhanced oxidative stress, altered energy metabolism, impaired neuroimmune function, and destabilized gut microbial structure and predicted metabolic potential. Complementary multi-omics analyses revealed coordinated alterations in antioxidant defense, detoxification capacity, and mitochondrial metabolism under high-Zn co-exposure, consistent with a reduced physiological tolerance to chemical stress. Together, these findings support the interpretation that zinc accumulation likely represents a primary contributor to co-exposure toxicity, while 6PPD-quinone may amplify adverse outcomes by constraining organismal stress-buffering capacity. These results highlight the need to consider metal–organic interactions and differential toxic contributions in mixture-based environmental risk assessment of tire-derived contaminants.
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
·
2026
·
IF 10.6
Lu Zhang,Huizhen Li,Zhong Zheng,Ruomiao Yang,Qian Hu,Xiaolei Zhang,Jing You
2-((4-Methylpentan-2-yl)amino)-5-(phenylamino)cyclohexa-2,5-diene-1,4-dione (6PPD-Q), a ubiquitous transformation product of tire rubber antioxidants, has emerged as an aquatic pollutant of high ecotoxicological concern due to its extremely high acute toxicity to sensitive salmonid species. While recent toxicological studies have identified several pathways associated with acute toxicity, systemic lipid dysregulation in sensitive salmonids remains poorly characterized. Semi-quantitative untargeted lipidomics was employed to characterize lipidomic perturbations in surviving rainbow trout ( Oncorhynchus mykiss ), a species highly sensitive to 6PPD-Q, following acute exposure and to explore how these perturbations may contribute to adverse effects. Following a 24 h acute exposure to 6PPD-Q at environmentally relevant concentrations (0.45, 0.9, and 1.8 μg/L), significant oxidative stress was observed, evidenced by elevated reactive oxygen species, malondialdehyde levels, and increased antioxidant enzyme activities. Lipidomic analysis revealed extensive dysregulation of the lipid profile. This disruption was characterized by the accumulation of triglycerides (TG) and oxidized triglycerides (OxTG), alongside a selective decrease in diacylglycerols (DG) and phospholipids (PL) containing polyunsaturated fatty acids. Docosahexaenoic acid (DHA) and arachidonic acid (AA) were identified as the most affected species (DHA-PL and AA-PL). Furthermore, a significant reduction in mitochondria-associated lipids, specifically cardiolipin (CL) and coenzyme Q10 (CoQ10), was noted, which was consistent with previously reported mitochondrial impairment. These perturbations suggested that 6PPD-Q may be associated with suppressed fatty acid β-oxidation, resulting in TG accumulation. This study provides new insights into lipidomic perturbations associated with acute 6PPD-Q exposure and identifies specific OxTG species as candidate biomarkers for environmental monitoring and ecological risk assessment.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY C-TOXICOLOGY & PHARMACOLOGY
·
2026
·
IF 4.4
Huan Ru,Chanlin Fang,Yuanxiang Jin
N-(1,3-Dimethylbutyl)- N ′-phenyl- p -phenylenediamine (6PPD) is a rubber antioxidant commonly used to manufacture automobile tires. The tire-road wear particles (TRWP) generated during the driving of automobiles, carried by rainwater and surface runoff, will bring the 6PPD and polyethylene microplastics contained in TRWP into the water body, posing a threat to the health and safety of aquatic life. However, the cardiotoxic effects and underlying mechanisms of their combined exposure remain unclear. In this study, zebrafish were exposed to PE-NPs (50 nm in diameter), 6PPD, and their mixtures to investigate cardiac developmental toxicity and molecular mechanisms. The results showed that 6PPD alone caused cardiac phenotypic abnormalities, including shortened SV-BA distance, reduced stroke volume, and decreased heart rate. Co-exposure with PE-NPs further aggravated these toxic phenotypes and significantly disrupted the expression of genes related to myocardial contraction, cardiac development, and heart failure. Mechanistically, PE-NPs enhanced the pericardial accumulation of nanoplastics, triggered more severe ROS overproduction, and induced oxidative stress by upregulating transcription of gpx , cat , and CuZn-SOD while reducing SOD, CAT, and GSH activities. Meanwhile, co-exposure activated the p53 -mediated apoptotic pathway, increased the bax / bcl2 ratio, stimulated caspase8 expression, and ultimately aggravated pericardial cell apoptosis in zebrafish larvae. Collectively, PE-NPs exacerbate 6PPD-induced cardiotoxicity in zebrafish early life stages by enhancing pericardial accumulation, amplifying oxidative damage, and promoting apoptosis. This study provides novel mechanistic insights for ecological risk assessment of combined pollution caused by tire-wear-derived 6PPD and nanoplastics in aquatic environments.
✓ 已验证
DOI
PubMed
高影响因子
Environmental Chemistry and Ecotoxicology
·
2026
·
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.
✓ 已验证
DOI
高影响因子
JOURNAL OF ENVIRONMENTAL MANAGEMENT
·
2025
·
IF 8.4
Chenyang Rao,Yanxia Zuo,Tianyu Gao,Dongfang Xiang,Fuhao Chu,Xiaowei Xiang,Xingkang Deng,Wei Tang,Shaopan Bao,Tao Fang
N -(1,3-dimethylbutyl)- N′ -phenyl- p -phenylenediamine (6PPD), a widely used tire rubber antioxidant has emerged as a concerning environmental contaminant. While its toxicity to aquatic organisms is well established, the molecular mechanisms remain unclear. This work systematically investigated the molecular mechanisms of 6PPD-induced hepatotoxicity in zebrafish through an integrated approach combining histological analysis, multi-omics profiling, biochemical assays, and computational modeling. Hematoxylin and eosin (H&E) staining revealed significant liver damage after 28 d of exposure. Transcriptomic and proteomic profiling of the high-concentration group (200 μg/L) demonstrated disruptions in Phase I/II detoxification, redox homeostasis, and energy metabolism, notably involving the mitochondrial electron transport chain and TCA cycle. Biochemical assays further confirmed increased malondialdehyde (MDA) levels and impaired antioxidant capacity. Additionally, molecular docking and dynamics simulations revealed strong binding affinities between 6PPD and key hepatic proteins (CYP2K6, CAT and GSTM2), suggesting potential direct interference with metabolic and antioxidant defense pathways. Based on these findings, we hypothesize a positive feedback mechanism whereby excessive reactive oxygen species (ROS) generation exacerbates metabolic dysfunction. This hypothesis is supported by gene expression changes, elevated MDA levels, and abnormal lipid accumulation observed via Oil Red O staining. Overall, our results provide mechanistic insight into 6PPD-induced liver injury, highlighting the interplay between oxidative stress and disrupted energy metabolism.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2025
·
IF 6.1
Leisheng Wang,Yifei Fu,Shiwei Xu,Enhong Chen,Shuo Zhang,Dongjie Yang,Youzhao He,Yuanlong Gu,Yong Mao,Fenglai Yuan,Hao Hu
6PPD-quinone (6PPDQ), a derivative of the antioxidant 6PPD used in the rubber industry, has been implicated in environmental and public health risks. To explore its impact on metabolic and cognitive functions, we orally administered 6PPDQ to mice and assessed its effects. Our results show that 6PPDQ induces a dose-dependent increase in body weight, elevated fasting blood glucose, insulin resistance, and other hallmarks of metabolic syndrome. Furthermore, cognitive tests revealed significant impairments in learning and memory in 6PPDQ-treated mice. Transcriptomic and Western blot analyses suggest that 6PPDQ disrupts insulin signaling through inhibition of the PI3K-AKT pathway, leading to metabolic and cognitive dysfunction. Notably, treatment with the PI3K-AKT agonist SC79 partially alleviated these effects. These findings highlight the health risks of 6PPDQ exposure and suggest potential avenues for preventive and therapeutic strategies.
研究领域:
环境毒理学
·
神经科学
·
代谢性疾病
·
信号转导
·
药理学
·
公共卫生
✓ 已验证
产品关联
DOI
PubMed
高影响因子
COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY C-TOXICOLOGY & PHARMACOLOGY
·
2025
·
IF 4.3
Yuanhua Wang,Jie Ren,Siling Zhang,Hao Xu
The tire-derived antioxidant 6PPD (N-(1,3-dimethylbutyl)- N ′-phenyl- p -phenylenediamine), a ubiquitous environmental contaminant, poses significant risks to aquatic ecosystems, yet its sex-specific physiological impacts remain underexplored. This study investigated the effects of environmentally relevant 6PPD concentrations (20 μg/L) on feeding, digestion, absorption, and reproduction in adult zebrafish over 28 days. Results revealed pronounced male-specific impairments: 6PPD-exposed males exhibited reduced feeding speed and maximum food intake, alongside suppressed locomotor responses to food stimuli. Mechanistically, upregulation of intestinal cholecystokinin b ( cckb ) and delayed intestinal content emptying were identified as potential drivers of feeding inhibition in males. Concurrently, 6PPD induced intestinal oxidative stress in males, manifested through decreased activities of catalase (CAT) and superoxide dismutase (SOD), alongside elevated malondialdehyde (MDA) levels, and activated ferroptosis via dysregulation of critical genes ( gpx4a , cybb , slc7a11 , hmox1a , tfr1b and trf2 ). These disruptions correlated with shortened intestinal villi, goblet cell loss, and impaired nutrient absorption, leading to increased fecal output and diminished growth performance in males. In contrast, females displayed no significant structural damage to intestinal epithelium or declines in digestive and absorptive capacities. Notably, 6PPD caused no gonadal histopathological changes, hormonal dysregulation, reduced fertilization and hatching rates, nor transgenerational effects such as developmental abnormalities or locomotor deficits in offspring. This study provides the first evidence of male-selective feeding suppression and intestinal toxicity induced by 6PPD, highlighting sex-dependent vulnerability in aquatic species and underscoring the need for gender-specific risk assessments of tire-derived pollutants.
研究领域:
生态毒理学
·
环境科学
·
水生毒理学
·
分子生物学
·
生殖生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
·
2025
·
IF 11.3
Yu Feng,Hongyi Xian,Ruobing Bai,Zhiming Li,Hao Li,Long Zhang,Xiyun Huang,Yuji Huang,Boxuan Liang,Yanhong Deng,Xiaohong Yang,Xiaoqing Chen,Wenjie Yu,Li Yan,Da Chen,Xinguang Zhong,Zhenlie Huang
The pervasive environmental presence of N-(1,3-Dimethylbutyl)-N′-phenyl-p-phenylenediamine (6PPD) and its transformation product, 6PPD-quinone (6PPDQ), has raised concerns about their potential toxicity, yet their interactions with the gut microbiota at environmentally relevant concentrations remain poorly understood. Here, we investigated the effects of 6PPD and 6PPDQ on the gut-liver axis in zebrafish ( Danio rerio ). Zebrafish larvae exposed to 0.01, 1, and 100 μg/L of 6PPD or 6PPDQ for five days exhibited intestinal and hepatic developmental toxicity, including hepatic lipid accumulation and hepatomegaly. Adult zebrafish exposed for 21 days displayed compromised intestinal barrier integrity, gut dysbiosis, and lipidomic disturbances in the liver. Statistical analysis using the multi-response permutation procedure confirmed significant shifts in gut microbial community structure. Dysbiosis was characterized by reduced beneficial bacteria and an increase in pathogenic taxa, accompanied by elevated circulating lipopolysaccharide (LPS) and upregulated hepatic expression of lbp (LPS-binding receptor). Hepatic lipid accumulation resulted from increased triglyceride (TG) and total cholesterol synthesis, with lipidomics revealing distinct disruptions: 6PPD impaired phosphatidylinositol phosphate synthesis, while 6PPDQ affected TG homeostasis. Correlation analysis linked gut microbial shifts to hepatic lipid dysregulation. These findings suggest that 6PPD and 6PPDQ exposure disrupts gut-liver axis homeostasis, potentially driving non-alcoholic fatty liver disease development. This study underscores the need to integrate gut-liver-microbiota endpoints into environmental risk assessments for aquatic organisms.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
·
2025
·
IF 11.3
Chao Wang,Junhao Lin,Jiewei Deng,Xinyan Li,Junqiu Zhai,Yunyun Yang,Tiangang Luan
N-(1,3-Dimethylbutyl)-N’-phenyl-p-phenylenediamine (6PPD) is a widely used antioxidant in tire rubber. Exposure to 6PPD and its quinone derivative, 6PPDQ, has increasingly been linked to environmental pollution and potential health risks. Given the established association between environmental contaminants and the incidence of lung cancer—particularly the prevalence of non-small cell lung cancer (NSCLC) as a major malignancy—the specific effects of 6PPD and 6PPDQ on NSCLC progression remain unexplored. Here, we demonstrate that 6PPD and 6PPDQ significantly promote NSCLC cell proliferation and migration by targeting the PTEN-PI3K/AKT signaling axis and inducing ARG2-mediated metabolic reprogramming. Using single-cell metabolomics, we identified shared metabolic characteristics in NSCLC cells exposed to 6PPD/6PPDQ, including disruptions in amino acid metabolism, tricarboxylic acid (TCA) cycle, and nucleotide synthesis. Mechanistically, 6PPD and 6PPDQ interacted with key residues in the C2 domain of PTEN, reducing its catalytic activity and leading to sustained activation of the PI3K/AKT pathway. Activation of the PI3K/AKT pathway further enhanced ARG2 expression, thereby promoting metabolic reprogramming to support NSCLC cell proliferation and migration. These results confirmed the pivotal role of the PI3K/AKT pathway in 6PPD and 6PPDQ-induced NSCLC progression. Our findings revealed novel molecular mechanisms by which 6PPD and 6PPDQ drove NSCLC progression, and confirmed their carcinogenic potential and role in pollution-related lung cancer risk. Moreover, the study highlighted the urgent need for further investigation into their health impacts.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
FOOD CHEMISTRY
·
2026
·
IF 10.4
Wenhao Li,Jiaqi Zhao,Qian Sun,Manman Wang,Yu He
A novel ratiometric fluorescence molecularly imprinted probe was developed. • High-affinity imprinted sites granted the sensor superior specificity. • The aggregation-induced emission effect boosted the response sensitivity. • Smartphone-assist device offered a precise visual and on-site detection. • The YOLOv5 algorithm achieved a prediction accuracy of 99.6%. N-(1,3-Dimethylbutyl)- N ′-phenyl-p-benzoquinone (6PPD-Q) is ubiquitous in aquatic environments and poses big threats to food safety and public health. Therefore, there is an urgent need to develop timely and effective methods to detect 6PPD-Q. In this work, the Zn-doped silicon quantum dots and Au nanoclusters were embedded in the molecularly imprinted polymers to form ratiometric fluorescence sensor for the detection of 6PPD-Q in the concentration ranging from 0.0099 to 1.0 μg·mL −1 with the detection limit of 3.0 ng·mL −1 . The imprinting factor was calculated as 2.56. Then, a 3D-printing device was developed to capture fluorescence for images digital image colorimetry of 6PPD-Q while YOLOv5 algorithm was employed to achieve a prediction accuracy of 99.6%. The recovery rates for real sample analysis ranged from 95.5% to 108.0%. This method offers a simple and rapid strategy for detecting 6PPD-Q in food samples.
✓ 已验证
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2026
·
IF 6.6
Haitao Zhang,Chaofeng Chen,Dayu Wang,Yiwei Huang,Yang Liu,Zhiyuan Wang,Furui Fu,Hongyu Wang,Senjie Shi,Yijin Li,Jianchun Zeng,Caiping Shen,Chudan Zhong,Xiaozhou Liu,Jinlun Chen,Jie Li,Shufen Liu,Jin Huang,Yirong Zeng,Wenjun Feng
As an emerging environmental contaminant, N-(1,3-dimethylbutyl)-N′-phenyl-p-phenylenediamine-quinone (6PPD-Q) poses a potential threat to public health. However, the potential link between 6PPD-Q exposure and bone health remains largely unexplored. This study aims to systematically investigate the toxic effects of 6PPD-Q on bone metabolism and elucidate the underlying mechanisms by integrating transcriptomic sequencing, network toxicology, single-cell RNA, Molecular docking, molecular dynamics with both in vivo and in vitro experiments. Integrative analysis converged on mitophagy as a central mechanism in 6PPD-Q-induced osteoporosis, with single-cell sequencing identifying bone marrow-derived mesenchymal stem cells (BMSCs) as the key cell type and revealing CX43, MMP2, PDGFRB, and FYN as the principal targets. Molecular docking and MD simulations confirmed the targeted binding of 6PPD-Q to CX43. RNA-seq analysis of rat tibiae validated the differential expression of CX43 and the critical role of mitophagy. Both in vivo and in vitro experiments demonstrated that 6PPD-Q-induced bone loss was associated with the downregulation of CX43 and concomitant mitophagy dysregulation. In conclusion, this study elucidates that 6PPD-Q induces bone loss was associated with the downregulation of CX43 and concomitant mitophagy dysregulation. Our work establishes a comprehensive mechanistic framework for 6PPD-Q-induced bone damage and offers novel insights for future research into its bone toxicity. The 1 or 10 mg/kg dose used in this study, although higher than the typical environmental exposure level, is consistent with the effects observed in cadmium exposure and is close to the 8 mg/kg dose used in studies on mouse bone toxicity. Additionally, the 5 ng/mL concentration of 6PPD-Q used in the in vitro experiments is comparable to the concentration detected in freshwater, indicating its environmental relevance.
✓ 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）