ENVIRONMENT INTERNATIONAL
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2025
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IF 9.7
Jiaqi Shi,Yan Li,Qi Wei,Xin Zhu,Shaohua Cao,Wenyi Xie,Yang Guo,Jing Wei,Zekai Li,Tao Long
The widely used rubber antioxidant N-(1,3-Dimethylbutyl)-N’-phenyl-p-phenylenediamine (6PPD) and its ozonated product, 6PPD-quinone (6PPD-Q), are highly toxic to aquatic life, yet understanding on their environmental behaviors is limited. This study comprehensively investigated their adsorption and transformation processes on natural Fe-Mn nodules (NFMN), which commonly exist in sediments and soils through a combination of diverse experimental and computational methods. The maximum adsorption capacity of 6PPD-Q (719.2 μg·g −1 ) is significantly higher than that of 6PPD (133.8 μg·g −1 ) at 293 K, and it is more difficult to desorb. They follow different kinetic and isothermal adsorption models, and environmental conditions (including temperature, pH, and anions) exert distinct influences on the adsorption of the two substances. Adsorption mechanisms involving electrostatic attraction, charge transfer, hydrogen bonding, and Lewis acid-base complexation were unveiled. For 6PPD, electrostatic adsorption and Lewis acid-base complexation contribute significantly to its adsorption. Conversely, for 6PPD-Q, the contribution of Lewis acid-base complexation outweighs that of hydrogen bonding, while the effect of electrostatic adsorption is relatively negligible. The stronger electrostatic attraction, more efficient charge transfer, and a greater number of binding sites for hydrogen bonding and Lewis acid-base complexation with NFMN results in more robust adsorption of 6PPD-Q. Furthermore, 6PPD can transform into 6PPD-Q on NFMN, facilitated by dissolved Mn(III). This study advances understanding of the adsorption behavior and mechanism of 6PPD and 6PPD-Q, and highlights a new pathway for 6PPD-Q formation, which provides valuable reference for assessing the water body exposure risks and formulating environmental remediation strategies for such pollutants. Environmental Implication This study offers the first comprehensive insight into the interactions between 6PPD/6PPD-Q and NFMN, illuminating their environmental behavior in water and soil systems. It reveals the adsorption discrepancy between 6PPD and 6PPD-Q, and elucidates the mechanisms underlying the difference in adsorption. Additionally, it uncovers a novel pathway for 6PPD-Q formation, offering valuable implications for risk assessment and environmental remediation strategies.
研究领域:
环境科学
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化学
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产品关联
DOI
PubMed
高影响因子
Journal of Environmental Sciences
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2024
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IF 5.9
Shike Zhang,Xinyi Su,Jiada Zhang,Tingting He,Lei Tang,Zepei Zhao,Linying Cao
N-phenyl-N′-(1,3-dimethylbutyl)-p-phenylenediamine (6PPD) is a tire rubber antioxidant that can be oxidized to form derivative 6PPD-quinone (6PPD-Q). 6PPD and 6PPD-Q have been detected in human urine with concentrations reaching nanomolar levels. However, their human adverse effects and toxic mechanism are not explicit. This study elucidated their lipid metabolism disruption effects on hepatic cells (HepG2) and revealed a potential molecular mechanism via estrogen-related receptor γ (ERRγ) pathway. The results of fluorescence competitive binding assay showed that 6PPD and 6PPD-Q could bind to ERRγ with an IC 50 (the concentration of a ligand competing 50% probe from ERRγ) of 9 nmol/L and 6 nmol/L, respectively. The reporter gene assay indicated that 6PPD-Q activated ERRγ in a concentration-dependent mode with the lowest observable effective concentration (LOEC) of 100 nmol/L and the maximum induction rate of 320%, while 6PPD displayed weak ERRγ activity. The molecular docking showed that the binding energies of 6PPD/6PPD-Q with agonistic ERRγ were much lower than those with antagonistic ERRγ, implying that 6PPD/6PPD-Q tended to display ERRγ agonistic binding mode. The BODIPY fluorescence staining and triglyceride (TG) assay revealed that 6PPD and 6PPD-Q promoted lipid accumulation and TG production in HepG2 cells with LOEC of 10 nmol/L and 100 nmol/L, respectively. The ERRγ antagonist (GSK5182) co-exposure reversed the lipid induction effects of 6PPD/6PPD-Q, which confirmed the regulatory roles of ERRγ. Overall, our study revealed a novel endocrine disruption mechanism of 6PPD and 6PPD-Q via ERRγ and their hepatic lipid inducing risks, providing novel information for their health hazard evaluation.
研究领域:
毒理学
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细胞生物学
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分子生物学
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产品关联
DOI
高影响因子
ENVIRONMENTAL RESEARCH
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2025
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IF 7.7
Zhe Wang,Mingjun Zhu,Yao Hu,Jiaxi Liu,Xiaoyu Ma,Hong Zhou
The antioxidant 6PPD and its oxidized product 6PPD-Quinone (6PPDQ) have attracted considerable attention due to their various acute toxicities to aquatic organisms. However, the chronic toxicity of two compounds in aquatic animals is still unknown. Here, adult zebrafish were exposed to 6PPD and 6PPDQ at environmentally relevant concentrations (20 μg/L) for 28 days, and histological analysis showed that 6PPD caused more severe hepatic vacuolization than 6PPDQ. Meanwhile, 6PPD induced more serious lipid accumulation and a higher increase in triglyceride and total cholesterol levels than 6PPDQ, suggesting higher hepatotoxicity of 6PPD. Furthermore, transcriptomic analysis revealed that both compounds disturbed glucolipid metabolism to different degrees by altering the expression of different peroxisome proliferator-activated receptors (PPARs), in which 6PPD inhibited gene expressions in glucolipid metabolism possibly by PPARα, PPARβ and RXR, while 6PPDQ disrupted the expressions of partial genes in similar pathways probably via PPARγ. Additionally, 6PPD but not 6PPDQ increased Fe 2+ content, decreased the protein levels of ferroportin 1, ferritin and glutathione peroxidase 4, accompanied with the increase of malondialdehyde level and the decrease of glutathione content, suggesting ferroptotic response by 6PPD. Overall, our data deepened the understanding of 6PPD- and 6PPDQ-induced hepatotoxicity association with glucolipid metabolism disorders and ferroptotic responses.
研究领域:
环境毒理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
ENVIRONMENTAL RESEARCH
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2024
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IF 7.7
Xingyao Ye,Xiaojun Niu,Ling Li,Mengyu Lv,Dongqing Zhang,Deye Chen,Yu Line,Zhiquan Yang
N-(1,3-Dimethylbutyl)-N′-phenyl-p-phenylenediamine (6PPD) is an antioxidant commonly used in tire manufacturing, and its release into the environment has significantly increased due to rapid urbanization. When subjected to ozonation, 6PPD converts into the harmful pollutant 6PPD quinone (6PPDQ). These substances enter wastewater treatment plants (WWTPs) via stormwater runoff and pipelines, posing significant risks to the functional microorganisms. Anammox, a strictly controlled and sensitive microbial nitrogen removal process, is especially susceptible to the effects of the pollutants. This study investigates the comprehensive impact of 6PPD-Q and 6PPD on anammox communities based on characterization analysis and metagenomics. At environmental concentrations, 6PPD-Q at 200 ng/L-1000 ng/L led to the disintegration of anammox granules. Extended exposure to both 6PPD-Q and 6PPD significantly reduces the population of anammox bacteria (AnAOB). By utilizing organic matter from dead cells and incoming carbonate as a carbon source, the system evolved into a nitrogen metabolism network primarily focused on denitrification and dissimilatory nitrate reduction to ammonium (DNRA). This transformation was accompanied by a reshuffling of the microbial community and associated genes, resulting in an accumulation of NH 4 + -N. These findings underscore the toxicity of 6PPD-Q and 6PPD to anammox and stress the importance of incorporating 6PPD into regulatory and preventive strategies.
研究领域:
环境科学
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微生物学
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DOI
PubMed
高影响因子
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
TOXICOLOGY
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2025
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IF 4.6
Liya Fang,Jinhua Xu,Chanlin Fang,Yuanxiang Jin
N-(1,3-dimethylbutyl)-N′-phenyl-p-phenylenediamine (6PPD) is a commonly used rubber protectant that continuously enters the environment via groundwater. Its oxidation product, N-(1,3-dimethylbutyl)-N′-phenyl-p-phenylenediamine quinone (6PPDQ), has garnered significant concern due to its reported toxicity in animals. This study aims to evaluate the intestinal toxicity and potential metabolic impact of 6PPD and 6PPDQ in mice following oral exposure to various doses. Our results demonstrate that both compounds compromise the intestinal barrier, as evidenced by significant increases in the expression of tight junction proteins (claudin-1 and occludin) and mucin protein (MUC2). These changes suggest an impairment of both the physical and chemical barriers of the intestine. Following exposure, there was a marked increase in pro-inflammatory cytokines (IL-6, IL-22, and NOD-1), indicating an inflammatory response associated with the disruption of lipid metabolism and macrophage polarization. Specifically, the shift from M2 to M1 macrophage polarization correlates with increased expression of M1 markers despite no change in the M1/M2 ratio over prolonged exposure. Furthermore, 6PPD exposure significantly reduced gut microbiota richness and evenness, with more pronounced changes observed in the 6PPDQ-treated group. Correlation analysis suggested that these microbial shifts may influence host carnitine and lipid metabolism pathways. Ultimately, both 6PPD and 6PPDQ exposure led to elevated levels of total cholesterol (TC), triglycerides (TG), and low-density lipoprotein (LDL) in the bloodstream, attributed to decreased TC esterification. These findings highlight the potential long-term health risks associated with environmental exposure to 6PPD and 6PPDQ, particularly concerning gut integrity and metabolic dysregulation. Synopsis This study investigates the toxicity of 6PPD and its transformation product 6PPDQ, revealing their detrimental effects on intestinal health, disruption of gut microbiota, and alterations in lipid metabolism, highlighting significant implications for both environmental and human health.
研究领域:
毒理学
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环境健康
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分子生物学
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代谢学
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微生物组学
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免疫学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
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2023
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IF 13.6
Chenguang Li,Yanlei Zhang,Shiqi Yin,Qin Wang,Yuanyuan Li,Qiang Liu,Liuqingqing Liu,Xianxiang Luo,Lingyun Chen,Hao Zheng,Fengmin Li
p -Phenylenediamines (PPDs), an important type of rubber antioxidants, have received little study on their environmental fate , particularly for their vital photodegradation process in water environment. Accordingly, N -(1,3-dimethylbutyl)- N′ -phenyl-1,4-phenylenediamine (6PPD), as a representative of PPDs, was investigated experimentally and theoretically for its photodegradation in water. Rapid photodegradation occurred when 6PPD was exposed to illumination especially UV region irradiation. Under acidic conditions, the photodegradation of 6PPD accelerated mainly due to the increased absorption of long wavelength irradiation by ionized 6PPD. Nine photodegradation products (e.g., 6PPD - quinone (6PPDQ)) of 6PPD were identified by an ultra-performance liquid chromatography QTOF mass spectrometry . Molar yields of photoproducts such as 6PPDQ, aniline, 4-aminodiphenylamine, and 4-hydroxydiphenylamine were 0.03 ± 0.00, 0.10 ± 0.01, 0.03 ± 0.02, and 0.08 ± 0.01, respectively. Mechanisms involved in 6PPD photodegradation include photoexcitation , direct photolysis, self-sensitized photodegradation, and 1 O 2 oxidation , as demonstrated by electron paramagnetic resonance (EPR) analysis, scavenging experiments, and the time-dependent density functional theory (TD-DFT). Notably, the toxicity of the reaction solution formed during the photodegradation of 6PPD was increased by the formation of highly toxic products (e.g., 6PPDQ). This study provides the first explanation for photodegradation mechanisms of 6PPD and confirms the pathway of 6PPDQ produced by the photoreaction in water environment.
研究领域:
环境科学
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化学
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毒理学
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产品关联
DOI
PubMed
高影响因子
TOXICOLOGY LETTERS
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2025
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IF 2.9
Xiaoyu Mao,Dashuang Mo,Yuqin Cheng,Mengzhu Lv
N -(1,3-Dimethylbutyl)- N ′-phenyl- p -phenylenediamine (6PPD), a commonly used antioxidant in tire manufacturing, has been widely detected in the environment and shown to exhibit acute toxicity in several organs. However, the effects of 6PPD on immune responses, particularly following injury, remain poorly understood. In this study, we investigated the impact of 6PPD exposure on immune responses using zebrafish as a model. 6PPD exposure disrupted caudal fin regeneration at various stages of the regenerative process. Further analysis revealed that 6PPD impaired immune responses following fin amputation, as evidenced by the reduced number of lyz + /mpx + neutrophils and the downregulation of key immune-related genes. Besides, the morphology of neutrophils was changed upon 6PPD exposure, indicating the defective migration of immune cells. The incubation of zebrafish larvae with lipopolysaccharide (LPS), which induces global immune responses, also exhibited impaired immune function when combined with 6PPD exposure. Additionally, the injection of LPS into the egg yolk or trunk exacerbated immune responses at the injury site, yet 6PPD exposure significantly reduced neutrophil accumulation and downregulated the expression of immune-related genes, confirming the toxicity of 6PPD in immune responses. These findings provide new insights into the toxic effects of 6PPD on immune responses during injury, highlighting its potential to impair immune function in animals and human.
研究领域:
毒理学
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免疫学
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环境科学
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产品关联
DOI
PubMed
高影响因子
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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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
Mengzhu Lv,Xiaoyu Mao,Zheng Lu,Yanzhu Yang,Jiangtao Huang,Yuqin Cheng,Chuan Ye,Zhixu He,Liping Shu,Dashuang Mo
N -(1,3-dimethylbutyl)- N′ -phenyl- p -phenylenediamine (6PPD), which is widely used as an antiozonant in rubber tires, has recently got much attention for its acute aquatic toxicity. However, the developmental toxicity of 6PPD in cerebrovascular network remains unknown. Here, we investigated the effects of 6PPD exposure in cerebral vascular using zebrafish. 6PPD would not affect the body length and shape of zebrafish larvae at the concentrations ranging from 20 μg/L to 1000 μg/L. 6PPD induced developmental defects in the brain in a concentration-dependent manner. The trunk vascular development would not be affected while the cerebrovascular network was disrupted upon 6PPD exposure. 6PPD would trigger excessive Reactive Oxygen Species (ROS) in the brain, indicating abnormal oxidative stress. Mechanistically, brain-specific transcriptome analysis showed that 6PPD could potentially cause the blockage of arachidonic acid (AA) metabolism-related genes and the upregulation of ferroptosis-related genes. Besides, treatment with ferroptosis inhibitor N -Acetyl-L-cysteine (NAC) attenuated oxidative damage and improved the construction of cerebrovascular network upon 6PPD exposure. Moreover, using a human vascular endothelial cell line, we further confirmed that 6PPD could trigger abnormal oxidative stress and defective expansion capacity, implying the conserved toxicity cross species. These findings are useful for the elucidation of toxicity underlying 6PPD in cerebrovascular systems of both zebrafish and humans.
研究领域:
毒理学
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发育生物学
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环境科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Environmental Science-Processes & Impacts
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2025
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IF 3.9
Jiawen Ji,Siyue Zhu,Xinping Hu,Jianhui Zhu,Sen Pang,Yongqiang Ma,Xuefeng Li
Abamectin is one of the most widely used pesticides globally, known for its effectiveness in protecting crops and animal health. However, the residual risk of abamectin in agricultural products and the environment may be exacerbated by other pollutants, indicating greater potential hazards. One such emerging environmental pollutant is N-(1,3-dimethylbutyl)-N′-phenyl-p-phenylenediamine (6PPD), a common tire antioxidant found in various environments, including agricultural products and human urine. Our study first revealed the co-existence of 6PPD and abamectin in water and soil, and demonstrated that 6PPD significantly enhances the residual persistence of abamectin in environmental media and vegetables. Specifically, 6PPD extended the half-life of abamectin by 79% in pak choi and by 70% in cabbage. Additionally, 6PPD increased the photolysis half-life of abamectin in water by 191% and by 50% on soil surfaces. Furthermore, 6PPD also prolonged the photolysis half-life of four other macrolides in water. This study reveals the mechanism through which 6PPD extends the half-life of abamectin: by scavenging free radicals and inhibiting hydroxylation and oxidation, thus slowing its degradation. And this paper highlights that 6PPD significantly exacerbates the environmental risks and food safety issue associated with abamectin. Moreover, it provides valuable insights for studying the safe use of pesticides in complex environments with multiple contaminants.
研究领域:
环境科学
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农药安全
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食品科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
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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
✓ 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）