FOOD CHEMISTRY
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2022
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IF 9.231
Jiawen Ji,Changsheng Li,Bingjie Zhang,Wenjuan Wu,Jianli Wang,Jianhui Zhu,Desheng Liu,Rumin Gao,Yongqiang Ma,Sen Pang,Xuefeng Li
N-(1,3-dimethylbutyl)-N′-phenyl-p-phenylenediamine (6PPD) and N-(1,3-dimethylbutyl)-N′-phenyl-p-phenylenediamine-quinone (6PPDQ) can pose a threat to human health through the food chain because of their ubiquitous presence in the environment and the biotoxicity on organisms. In this work, we developed modified QuEChERS methods coupled with high performance liquid chromatography tandem mass spectrometry (HPLC/MS-MS) to explore whether 6PPD and 6PPDQ are present in fish and honey. The proposed methods showed acceptable limits of quantification (0.00043-0.001 mg/kg), linearity (R 2 > 0.99), recovery (73.3%-108.3%), matrix effect (70.4%-95.6%) and repeatability (RSD < 8.4%). Accordingly, 6PPD and 6PPDQ have been discovered in snakehead , weever and Spanish mackerel fish, while none of which have been detected in the honey samples. The results of our work contributed to increasing public attention to 6PPD and 6PPDQ in agricultural products and provided important reference for the analysis of them.
研究领域:
食品科学
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环境科学
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分析化学
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PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2025
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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
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神经科学
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代谢性疾病
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信号转导
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药理学
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公共卫生
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高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2026
·Vol. 74
·期 32
·25102-25118
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IF 6.7
Wang Caihong,Song Yunmeng,Ma Mingqiang,Fu Zhipeng,Zhang Nan,Jin Yuanxiang
N -(1,3-dimethylbutyl)- N ′ -phenyl- p -phenylenediamine-quinone (6PPDQ),
the primary oxidative
metabolite of rubber antioxidant N -(1,3-dimethylbutyl)- N ′ -phenyl- p -phenylenediamine (6PPD),
is an emerging global contaminant with multiorgan toxicity and has
been detected in human breast milk and urine. Its mammary toxicity
and molecular mechanisms remain poorly defined. Here, we integrated
network toxicology, transcriptomics, and in vivo/in vitro validation
to investigate 6PPDQ triggered mammary toxicity during adolescent
exposure in mice. Network toxicology screened core targets and identified
the MAPK signaling pathway as a key regulatory axis. Adolescent 6PPDQ
exposure decreased mammary gland weight and length, induced pathological
lesions, inhibited epithelial proliferation, and disrupted apoptotic
homeostasis. Further assays confirmed that 6PPDQ caused mitochondrial
dysfunction, oxidative stress, and inflammation. Mechanistically,
6PPDQ mediated mammary injury through p38 MAPK cascade activation,
and p38 inhibition alleviated such adverse effects. This study elucidates
a distinct p38 MAPK-dependent mechanism driving 6PPDQ-related developmental
mammary toxicity, advancing the mechanistic understanding of health
risks posed by rubber-derived quinone contaminants.
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ENVIRONMENT INTERNATIONAL
·
2025
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IF 9.7
Chuan Yi,Chunyan Xu,Pan Gao,Hengtao Wang,Yao Dang,Song Hou,Ruowen Zhang,Mingdeng Xiang
Previous research has demonstrated acute toxicity of 6PPD-quinone (6PPDQ), the ozonation product of tire-manufacturing additive 6PPD; however, chronic effects on aquatic organisms under real-world conditions remain unclear. We exposed 2-month-old zebrafish to 6PPDQ at concentrations of 2, 20 and 200 µg/L for 30 days. Whole-body desorption electrospray ionization–mass spectrometry (DESI–MS) revealed accumulation mainly in the muscle, abdomen, and brain of zebrafish exposed to 200 µg/L 6PPDQ, which was verified by MS quantification of muscle and brain tissues. Based on velocity and distance moved, 2 µg/L 6PPDQ induced zebrafish hyperactivity, whereas 20 and 200 µg/L significantly inhibited activity. H&E staining revealed that chronic exposure to 6PPDQ caused brain damage in zebrafish, characterized by vacuolation and ventriculomegaly. Transcriptomic analyses indicated that 6PPDQ exposure disturbed neuron-related signaling pathways, especially glutamatergic/GABAergic, dopaminergic, cholinergic, and serotoninergic pathways. Downregulation of genes related to neurotransmission pathways was noted following exposure to 200 µg/L 6PPDQ. Reduced neurotransmitters, serotonin, 5-hydroxyindolacetic acid, dopamine, γ-aminobutyric acid, glutamate, acetylcholinesterase, 3,4-dihydroxyphenylacetic acid and homovanillic acid levels were also observed after 20 µg/L 6PPDQ exposure. Here, prolonged exposure to environmentally relevant concentrations of 6PPDQ induced neurotoxicity in zebrafish, and the neurotransmission system may be central to this process. These findings may help identify acceptable levels of aquatic 6PPDQ.
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CHEMICAL RESEARCH IN TOXICOLOGY
·
2026
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IF 4.1
Naijie Wei,Xiaowen Yan,Mingyue Yu,Rong Li,Zhixin Xiao,Shi Chen,Limin Yang,Qiuquan Wang,Qian Liu,Guibin Jiang
N-(1,3-Dimethylbutyl)-N’-phenyl-p-phenylenediamine Quinone (6PPDQ) not only causes acute mortality in salmon but also induces toxicities in other living organisms. The electrophilic quinone moiety in the 6PPDQ molecular structure can participate in binding to the cysteine residues that ubiquitously exist in protein nucleophiles, which are responsible for its toxicities. Out of the 82 6PPDQ-bonded proteins found in the human model cell line A549 on the sulfhydryl-reactive proteomics platform, which enables the precise identification of covalent binding protein targets of a pollutant, we discovered three 6PPDQ-bonded mitochondrial proteins─NDUS6, COX5B, and ATP5PB─that are involved in mitochondrial dysfunction for the first time. They impede the function of mitochondria, as witnessed by the decreased enzymatic activities of mitochondrial respiratory chain Complexes I (27.63%) and IV (23.11%), the decreased cellular ATP content (19.94%), and the reduced mitochondrial membrane potential (3.2-fold), as well as the elevated mitochondrial ROS level (2.2-fold) under the environmentally relevant 8.9 μg/L 6PPDQ exposure compared to the controls. Our findings provide experimental evidence for elucidating 6PPDQ’s toxicities at the molecular level, and the knowledge learned will enhance the public’s awareness of the adverse impacts of environmental pollution on health.
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ENVIRONMENTAL POLLUTION
·
2026
·
IF 7.2
Wenjie Zhang,Jiale Chen,Qi Wang,Qi Jing,Meiling Yang,Anping Ma,Banghua Wu,Yiru Qin
6PPDQ exposure induces oxidative stress-driven cytotoxicity in RAW 264.7 macrophages. • Multi-omics identifies glycerophospholipid metabolism as a key disturbed pathway. • LPA accumulation and Gpat3/Lpar2 upregulation link lipid alteration to inflammation. • 6PPDQ activates NF-κB signaling and elevates TNF-α, IL-6, and iNOS expression. • NAC pretreatment attenuates ROS, lipid alteration, and inflammatory responses. N -(1,3-dimethylbutyl)- N′ -phenyl- p -phenylenediamine quinone (6PPDQ), a transformation product of the tire antioxidant 6PPD, is an emerging environmental contaminant with increasing toxicological concern. While macrophages are critical in recognizing and managing chemical stress, how 6PPDQ exposure perturbs their innate immune functions and intracellular metabolic homeostasis remains largely unexplored. Here, RAW 264.7 macrophages were exposed to 6PPDQ and examined using biochemical assays, integrated transcriptomic and metabolomic analyses, and N -acetylcysteine (NAC)-based antioxidant intervention. Exposure to 6PPDQ caused dose-dependent cellular injury, characterized by increased membrane damage, excessive reactive oxygen species (ROS) accumulation, glutathione depletion, inflammatory mediator upregulation, mitochondrial dysfunction, and enhanced apoptosis. Multi-omics analysis further revealed significant alterations in glycerophospholipid-related metabolic profiles, accompanied by enrichment of TNF and NF-κB inflammatory signaling. Several phospholipid species levels were decreased, whereas the level of lysophosphatidic acid (LPA) and the expression of its related genes Gpat3 and Lpar2 were markedly elevated. Pretreatment with NAC not only suppressed ROS accumulation, but also attenuated both lipid metabolic and inflammatory alterations induced by 6PPDQ. Collectively, these findings suggest that oxidative stress is closely associated with alterations in glycerophospholipid-related metabolic profiles and inflammatory responses during 6PPDQ-induced macrophage injury. Download: Download high-res image (192KB) Download: Download full-size image
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ENVIRONMENTAL SCIENCE & TECHNOLOGY
·
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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SCIENCE OF THE TOTAL ENVIRONMENT
·
2022
·
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
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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.
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JOURNAL OF HAZARDOUS MATERIALS
·
2024
·
IF 12.2
Qicai Zhang,Xianli Wang,Chengbin Liu,Huaxi Li,Zhongsheng Deng,Chunxia Yao,Yameng Li,Qinxiong Rao,Weiguo Song
Given the high toxicity of N-(1,3-dimethylbutyl)-N′-phenyl- p -phenylenediamine (6PPD) derivatives, such as 6PPD quinone (6PPDQ) to salmon, as well as their ubiquitous presence in the environment, the contaminant of aquatic food products has drawn significant attention. However, analytical methods for p -Phenylenediamines (PPDs) and their transformation products (TPs) in aquatic products remain underdeveloped. In particular, the degradation of some compounds and strong matrix effects complicate detection. In this study, we present a stable, rapid, and sensitive method combining salt-out assisted extraction, antioxidant protection, and multi-plug filtration clean-up (m-PFC) to detect two PPDs and five TPs in aquatic products. Crucially, the appropriate selection of antioxidants prevented the degradation of the easily oxidized target compounds. Further, the m-PFC method significantly enhanced the purification efficiency, achieving satisfactory recoveries (62.1–115 %), and method detection limits (MDLs) ranging from 0.00300 to 0.400 μg/kg. Subsequently, the method was applied to monitor PPDs and their TPs in aquatic products systematically, revealing the presence of 6PPD and N-isopropyl-N′-phenyl-1,4-phenylenediamine (IPPD) in white shrimp from aquafarms, whereas none of the seven target analytes were detected in fish and crab samples. These findings contribute to the detection of PPDs, their TPs and other unstable chemicals in aquatic products, thereby providing insights into their concentrations in these products.
研究领域:
分析化学
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环境科学
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食品安全
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高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
·
2023
·
IF 9.8
Liya Fang,Chanlin Fang,Shanshan Di,Yundong Yu,Caihong Wang,Xinquan Wang,Yuanxiang Jin
N-(1,3-dimethylbutyl)- N ′-phenyl- p -phenylenediamine (6PPD) is a widely used additive for protecting various rubber products, and its product of oxidation N-(1,3-Dimethylbutyl)- N ′-phenyl- p -phenylenediamine-quinone (6PPDQ) has attracted extensive attention in aquatic toxicity. However, the toxicity of 6PPD and 6PPDQ in mammals has not been reported yet. In this study, the effects of 6PPD and 6PPDQ on the liver of C57BL/6 mice were assessed by orally administering different doses of 6PPD and 6PPDQ (10, 30, and 100 mg/kg) in mice for 6 weeks. 6PPD and 6PPDQ were found to bioaccumulate in the liver in a dose-dependent manner. Moreover, a high dose of 6PPD and 6PPDQ exposure increased not only the liver weights but also liver triglyceride levels, indicating that 6PPD and 6PPDQ exposure induced hepatotoxicity in mice. Furthermore, transcriptomic analysis revealed that 6PPD and 6PPDQ induced differential expression of genes mainly enriched in glycolipid metabolism, immune-related, and glutathione metabolism pathways. Therefore, 6PPD and 6PPDQ altered hepatic metabolism in mice. Furthermore, 6PPDQ could induce an immune response by upregulating the transcription of immune-related genes and promoting macrophage infiltration in the liver. In conclusion, our study revealed the toxic effects of 6PPD and 6PPDQ exposure on multi-endpoints in the liver of mice and improve our understanding of the health risks of 6PPD and 6PPDQ to mammals. The findings of our study may help formulate better safety regulations for the use and disposal of rubber products.
研究领域:
毒理学
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分子生物学
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环境科学
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药理学
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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.
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高影响因子
危险品化学品经营许可证（带存储）