SCIENCE OF THE TOTAL ENVIRONMENT
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2022
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IF 10.753
Xiangjuan Wei,Daqian Yang,Boya Zhang,Xingpei Fan,Haining Du,Ruijiao Zhu,Xiaotong Sun,Meimei Zhao,Ning Gu
Di-(2-ethylhexyl) phthalate (DEHP), an endocrine-disrupting chemical (EDC) commonly used as a plasticizer, is responsible for widespread environmental pollution. Epidemiological and experimental data implicate DEHP and its metabolite mono(2-ethylhexyl) phthalate (MEHP) in the occurrence and development of metabolic syndrome. However, the specific effects and potential mechanisms of action of DEHP on glucose and lipid metabolism in adults are currently unclear. In the current study, adult male mice were continuously exposed to DEHP (0, 5, and 25 mg/kg/day) via oral administration and changes in glucose and lipid metabolism explored. Notably, exposure to DEHP led to a significant increase in plasma glucose and hepatic lipid accumulation but had no effect on insulin secretion. Western blot and real-time quantitative PCR showed that DEHP induced insulin resistance and promoted gluconeogenesis and lipid accumulation via overexpression of forkhead box protein O1 (FoxO1), in keeping with hepatic RNA sequencing data. Variations in gut microbiota aggravated these effects while inhibition of FoxO1 reversed the adverse effects of DEHP. Our findings support a key role of FoxO1 in disorders of glucose and lipid metabolism caused by DEHP.
研究领域:
内分泌学
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代谢学
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分子生物学
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环境健康
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产品关联
DOI
PubMed
高影响因子
Journal of Advanced Research
·
2022
·
IF 12.822
Yi Zhao,Ming-Shan Chen,Jia-Xin Wang,Jia-Gen Cui,Hao Zhang,Xue-Nan Li,Jin-Long Li
Introduction Male infertility is a multifactorial pathological condition and may be a harbinger of future health. Phthalates are ubiquitous environmental contaminants that have been implicated in the global decline in male fertility. Among them, di-(2-ethylhexyl) phthalate (DEHP) is the most prevalently used. Lycopene (LYC) is a possible preventive and therapeutic agent for male infertility owing to its antioxidant properties. The blood-testis barrier (BTB) is formed between Sertoli cells where it creates a unique microenvironment for spermatogenesis. Objectives We hypothesize that phthalate caused male infertility and LYC plays an important role in phthalate-induced male fertility disorders. Methods Hematoxylin-eosin (H&E) staining, ultrastructure observation, and fluorescence microscopy were used to examine the morphological changes. RNA-Seq, and western blotting were conducted to detect gene and protein levels. Routine testing for sperm morphology and sperm-egg binding assay were conducted to examine the morphological structure and function of sperm. Cell scratch assay and transepithelial electrical resistance (TER) were used to detect cell migration capacity and barrier integrity. Results In vivo experiments, we showed that LYC prevented DEHP-induced impairment of BTB integrity, which provided a guarantee for the smooth progress of spermatogenesis. LYC improved DEHP-induced change in sperm parameters and fertilization ability. Subsequent in vitro experiments, LYC alleviated MEHP-induced disruption of intercellular junctions in mouse Spermatogonia cells (GC-1 cells) and mouse Sertoli cells (TM4 cells). In MEHP-induced BTB impairment models of Sertoli cells, treatment with LYC or overexpressing connexin-43 (Cx43) promoted cell migration capacity and normalized BTB integrity. Cx43 knockdown inhibited cell migration capacity and perturbed BTB reassembly in LYC preventing DEHP-induced BTB impairment. Conclusion Our study provides evidence for the role of LYC in phthalates-induced spermatogenic disorders and points to Cx43 as a potential target for male fertility.
研究领域:
生殖生物学
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毒理学
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药理学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL BIODETERIORATION & BIODEGRADATION
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2022
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IF 4.907
Yimin Xie,Xiaoyuan Guo,Zhiwei Liang,Hojae Shim
Di-2-ethylhexyl phthalate (DEHP) widely exists in the environment and has raised an increasing global concern. A bacterial strain capable of degrading DEHP was isolated from the activated sludge at a local wastewater treatment plant and identified as Bacillus sp. MY156. A nearly complete degradation of DEHP at 500 mg L −1 was reached within 5 days when MY156 was grown at pH 8 and 30 °C. The biodegradation of DEHP (50–600 mg L −1 ) followed the first-order kinetics. Mass balance analysis showed the efficient degradation of DEHP with the ratio of biomass to DEHP at 0.72. The dehydrogenase activity was positively related to the biodegradation of DEHP, while the extracellular polymeric substance (EPS) might have played a key role in overcoming the potential inhibition caused by DEHP. The microelements (Fe 3+ , Zn 2+ , and Mn 2+ ) supplements stimulated the DEHP degradation while copper (Cu 2+ ) showed inhibitory. The proposed intermediate metabolites of the DEHP degradation included mono-ethylhexyl phthalate, diethyl phthalate, dimethyl phthalate, phthalic acid, and protocatechuate. Together with the micro-morphological observation, biodegradation experiments in saline and different real water environments suggested the isolate possessing strong halo-tolerance and potential applicable ability to adapt to various environmental conditions. The isolate could be used as a potential and efficient phthalic acid esters (PAEs) degrader for the bioremediation of contaminated sites.
研究领域:
环境微生物学
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生物技术
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污水处理
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降解与代谢
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产品关联
DOI
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2025
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IF 6.1
Yicheng Wang,Miaoyun Qiu,Bixuan Yue,Mingliang Wang,Luoxing Xia,Fengfeng Li,Chaobo Yang,Zhigao Song,Yushan Liao,Wei Liu,Zhi Zeng
Di-(2-ethylhexyl) phthalate (DEHP), a widely utilized plasticizer, has been increasingly associated with cardiovascular risks. However, the involvement of DEHP in abdominal aortic aneurysm (AAA) remains unclear. To address this gap, C57BL/6 J mice were intragastrically administered with DEHP for 4 weeks in a CaCl₂-induced AAA model. We found that DEHP exacerbated AAA progression, as evidenced by a notable enlargement in the maximal diameter of the abdominal aorta, enhanced vascular inflammation, and accelerated elastin degradation. In vitro experiments confirmed that DEHP, along with its primary metabolite mono-(2-ethylhexyl) phthalate (MEHP), induced M1 macrophage polarization, leading to increased secretion of inducible nitric oxide synthase (iNOS), matrix metalloproteinase-9 (MMP9), and pro-inflammatory factors, including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β). Mechanistically, we demonstrated that DEHP and MEHP triggered the activation of the nuclear factor-kappa B (NF-κB) pathway by upregulating phosphorylated p65 and inducing p65 nuclear translocation, which drove M1 macrophage polarization. These findings were further confirmed using a mouse AAA model in vivo. Additionally, DEHP and MEHP promoted the proliferation and migration of primary human aortic vascular smooth muscle cells (VSMCs). Phenotypic switching of VSMCs was markedly accelerated following DEHP and MEHP treatment, potentially through the PI3K-AKT pathway, as characterized by reducing contractile markers (ACTA2 and CNN1) and enhancing proliferative markers (PCNA and SPP1). Overall, our study underscores the pivotal role that DEHP plays in exacerbating AAA by promoting M1 macrophage polarization and VSMCs phenotypic switching, which provides new insights into the adverse health effects of environmental pollution-relevant cardiovascular disease progression.
研究领域:
环境毒理学
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心血管疾病
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分子生物学
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免疫学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
TOXICOLOGY
·
2024
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IF 4.8
Junke Wang,Yuexin Wei,Yuhao Wu,Tianxin Zhao,Lian Kang,Lindong Han,Jiadong Chen,Chunlan Long,Guanghui Wei,Lianju Shen,Shengde Wu
As one of the most prevalent environmental endocrine disruptors, di-(2-ethylhexyl) phthalate (DEHP) is known for its significant developmental toxicity to the male reproductive system in humans and mice. Prepubertal exposure to DEHP has been shown to cause testicular damage, but the underlying mechanisms require further investigation. To investigate this effect, prepubertal mice were exposed to 250 or 500 mg/kg body weight (bw) of DEHP for 14 days, which resulted in impaired histological structure and increased apoptosis of the testes. RNA sequencing (RNA-seq) of testicular tissue suggested that DEHP led to injury in Leydig and Sertoli cells. To further elucidate these mechanisms, we conducted experiments using immature mouse Leydig (TM3) and Sertoli (TM4) cells, and exposed them to 200 μM mono-(2-ethylhexyl) phthalate (MEHP), the primary metabolite of DEHP, for 24 h. We found that MEHP exposure induced oxidative stress injury and promoted cell apoptosis, and that cotreatment with N-acetylcysteine partially reversed these injuries. Given the close association between oxidative stress and mitochondrial calcium levels, we demonstrated that MEHP exposure disrupted mitochondria and increased mitochondrial calcium levels. This effect facilitated the formation of mitochondria-associated endoplasmic reticulum membranes (MAMs), upregulated protein expression and enhanced the interactions of the IP3R3-Grp75-VDAC1 complex. Furthermore, inhibition of calcium transfer in the IP3R3-Grp75-VDAC1-MCU axis relieved MEHP-induced mitochondrial injury, oxidative stress and apoptosis in TM3 and TM4 cells. This study highlights the importance of MAM-mediated mitochondrial calcium overload and the subsequent apoptosis of Leydig and Sertoli cells as pivotal factors contributing to testicular injury induced by prepubertal exposure to DEHP.
研究领域:
环境科学
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毒理学
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生殖生物学
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细胞生物学
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内分泌学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Genes & Diseases
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2023
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IF 6.8
Yifan Hong,Xiazhu Zhou,Qi Li,Jing Chen,Yuexin Wei,Chunlan Long,Lianju Shen,Xiangqin Zheng,Dinggang Li,Xia Wang,Chenjun Yu,Shengde Wu,Guanghui Wei
As a widely used plasticizer, di-(2-ethylhexyl) phthalate (DEHP) is known to induce significant testicular injury. However, the potential mechanism and effects of pubertal exposure to DEHP on testis development remain unclear. In vivo , postnatal day (PND) 21 male rats were gavaged with 0, 250, and 500 mg/kg DEHP for ten days. Damage to the seminiferous epithelium and disturbed spermatogenesis were observed after DEHP exposure. Meanwhile, oxidative stress-induced injury and pyroptosis were activated. Both endoplasmic reticulum (ER) stress and mitophagy were involved in this process. Monoethylhexyl phthalate (MEHP) was used as the biometabolite of DEHP in vitro . The GC-1 and GC-2 cell lines were exposed to 0, 100 μM, 200 μM, and 400 μM MEHP for 24 h. Reactive oxygen species (ROS) generation, oxidative stress damage, ER stress, mitophagy, and pyroptosis were significantly increased after MEHP exposure. The ultrastructure of the ER and mitochondria was destroyed. X-box binding protein 1 (XBP1) was observed to be activated and translocated into the nucleus. ROS generation was inhibited by acetylcysteine. The levels of antioxidative stress, ER stress, mitophagy, and pyroptosis were decreased as well. After the administration of the ER stress inhibitor 4-phenyl-butyric acid, both mitophagy and pyroptosis were inhibited. Toyocamycin-induced XBP1 down-regulation decreased the levels of mitophagy and pyroptosis. The equilibrium between pyroptosis and mitophagy was disturbed by XBP1 accumulation. In summary, our findings confirmed that DEHP induced a ROS-mediated imbalance in pyroptosis and mitophagy in immature rat testes via XBP1. Moreover, XBP1 might be the key target in DEHP-related testis dysfunction.
研究领域:
毒理学
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生殖生物学
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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
PubMed
高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
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2024
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IF 3.3
Li-Lan Liu,Jun-Zhe Yue,Zhen-Yu Lu,Ru-Ya Deng,Can-Can Li,Ye-Na Yu,Wen-Jin Zhou,Min Lin,Hai-Tao Gao,Jiaming Liu,Ling-Zi Xia
Phthalates (PEs), such as di(2-ethylhexyl) phthalate (DEHP), dibutyl phthalate (DBP) and butyl benzyl phthalate (BBP) could cause reproductive and developmental toxicities , while human beings are increasingly exposed to them at low-doses. Phytochemical quercetin (Que) is a flavonoid that has estrogenic effect, anti-inflammatory and anti-oxidant effects. This study was conducted to assess the alleviative effect of Que. on male reproductive toxicity induced by the mixture of three commonly used PEs (MPEs) at low-dose in rats, and explore the underlying mechanism. Male rats were treated with MPEs (16 mg/kg/day) and/or Que. (50 mg/kg/d) for 91 days. The results showed that MPEs exposure caused male reproductive injuries, such as decreased serum sex hormones levels, abnormal testicular pathological structure, increased abnormal sperm rate and changed expressions of PIWIL1 and PIWIL2. Furthermore, MPEs also changed the expression of steroidogenic proteins in steroid hormone metabolism, including StAR, CYP11A1 , CYP17A1 , 17β-HSD, CYP19A1 . However, the alterations of these parameters were reversed by Que. MPEs caused male reproductive injuries in rats; Que. inhibited MPEs' male reproductive toxicity, which might relate to the improvement of testosterone biosynthesis.
研究领域:
毒理学
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生殖生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
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2022
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IF 5.572
Jia Lv,Yanling Li,Jianrong Chen,Rong Li,Chao Bao,Zheng Ding,Wenqiang Ren,Zhiping Du,Sheng Wang,Yichao Huang,Qu-nan Wang
Prenatal DEHP exposure can cause offspring neurodevelopmental toxicity, but the persistent effects of such exposure window are unclear. This study aimed to investigate the lasting neurobehavioral impact of DEHP on offspring following early exposure from GD9.5 (fetal neural tube closure) to GD16.5 (fetal thyroxin , TH, synthesis). Data showed maternal exposure to DEHP during the thyroid hormone-dependent stage induced a range of neurobehavioral phenotypic changes in adult and middle-aged mice, including anxiety, depression and cognitive impairment . Significant reductions in free TH, TH transporters, and TH metabolic enzyme deiodinase II (D2) were observed in the fetal brain, whereas D3 was elevated, indicating that TH signaling disruption was caused by in utero exposure. Gene expression analyses suggested the expression levels of the TH receptors Trα1 , Trβ1 and their downstream target, brain-derived neurotrophic factor, were significantly attenuated, which may partially explain the mechanisms of neurodevelopmental impairment. This study provides new evidence of the persistent effects of sex-specific neurodevelopmental impairment due to in utero DEHP exposure, possibly through damage to the fetal brain TH signaling systems that causes lifelong brain damage. These results further suggest a profound neurobehavioral toxicity of DEHP that may be programmed during early developmental stage exposure and manifested later in life.
研究领域:
神经科学
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毒理学
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发育生物学
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内分泌学
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DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2024
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IF 5.7
Yi Zhao,Yuan-Hang Chang,Hao-Ran Ren,Ming Lou,Fu-Wei Jiang,Jia-Xin Wang,Ming-Shan Chen,Shuo Liu,Yu-Sheng Shi,Hong-Mei Zhu,Jin-Long Li
Di-(2-ethylhexyl) phthalate (DEHP), as the most common phthalate, has been extensively used as a plasticizer to improve the plasticity of agricultural products, which pose severe harm to human health. Mitochondrial dynamics and endoplasmic reticulum (ER) homeostasis are indispensable for maintaining mitochondria-associated ER membrane (MAM) integrity. In this study, we aimed to explore the effect of DEHP on the nervous system and its association with the ER–mitochondria interaction. Here, we showed that DEHP caused morphological changes, motor deficits, cognitive impairments, and blood–brain barrier disruption in the brain. DEHP triggered ER stress, which is mainly mediated by protein kinase R-like endoplasmic reticulum kinase (PERK) signaling. Moreover, DEHP-induced mitofusin-2 (Mfn2) downregulation results in imbalance of the mitochondrial dynamics. Interestingly, DEHP exposure impaired MAMs by inhibiting the Mfn2-PERK interaction. Above all, this study elucidates the disruption of the Mfn2-PERK axis-mediated ER–mitochondria interaction as a phthalate-induced neurotoxicity that could be potentially developed as a novel therapy for neurological diseases.
研究领域:
神经科学
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毒理学
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细胞生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH
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2020
·Vol. 27
·期 28
·35261-35271
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IF 3.056
Zhao Tian-Xin,Wei Yue-Xin,Wang Jun-Ke,Han Lin-Dong,Sun Mang,Wu Yu-Hao,Shen Lian-Ju,Long Chun-Lan,Wu Sheng-De,Wei Guang-Hui
Di-(2-ethylhexyl) phthalate (DEHP) is a common plasticizer, which is known to be an environmental endocrine-disrupting chemical that can jeopardize the male reproductive system. Prepuberal exposure to DEHP leads to steroidogenesis disorders. However, the specific mechanism remains ambiguous. Therefore, Sprague Dawley (SD) rats underwent prepuberal DEHP exposure at a dose of 500 mg/kg per day through gavage. Additionally, the resulting testicular injury was evaluated to confirm the disturbed steroidogenesis. Changes in testicular histology, significant reduction of serum testosterone ( P < 0.01) and luteinizing hormone ( P < 0.001), and significantly decreased expressions of steroidogenic acute regulatory protein ( P < 0.01) and 3-beta-hydroxysteroid dehydrogenase ( P < 0.05) were found in DEHP-treated rats. DEHP exposure resulted in obvious intestinal damage and oxidative stress imbalance, primarily in the jejunum. Both the activation of the nuclear factor-E2-related factor 2 (Nrf2) signaling pathway and alterations of microbiota profiles were observed in all three gut specimens, but were most notable in the jejunum. We hypothesize that the gut-microbiota-testis axis, which is mediated by the activation of the Nrf2 antioxidant pathway, could be involved in the dysfunction of prepuberal steroidogenesis induced by DEHP.
研究领域:
毒理学
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内分泌学
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生殖生物学
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微生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
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2023
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IF 9.8
Xiaolong Yu,Huanhuan Xing,Jianteng Sun,Xiaodong Du,Guining Lu,Lizhong Zhu
Di-(2-ethylhexyl) phthalate (DEHP) as widely utilized plasticizer has aroused increasing concerns since its endocrine disrupting effects and continuous accumulation in biota. To date, the interaction mechanism between DEHP and rice plants has not been clearly illustrated at molecular level. Here, we investigated biological transformation and response of rice plants ( Oryza sativa L.) to DEHP at realistic exposure concentrations. Nontargeted screening by UPLC-QTOF-MS was used to verify 21 transformation products derived from phase I metabolism (hydroxylation and hydrolysis) and phase II metabolism (conjugation with amino acids, glutathione, and carbohydrates) in rice. MEHHP-asp, MEHHP-tyr, MEHHP-ala, MECPP-tyr and MEOHP-tyr as the conjugation products with amino acids are observed for the first time. Transcriptomics analyses unraveled that DEHP exposure had strong negative effects on genes associated with antioxidative components synthesis, DNA binding, nucleotide excision repair, intracellular homeostasis, and anabolism. Untargeted metabolomics revealed that metabolic network reprogramming in rice roots was induced by DEHP, including nucleotide metabolism, carbohydrate metabolism, amino acid synthesis, lipid metabolism, synthesis of antioxidant component, organic acid metabolism and phenylpropanoid biosynthesis. The integrated analyses of interaction between differentially expressed genes (DEGs) and differentially expressed metabolites (DEMs) endorsed that metabolic network regulated by DEGs was significantly interfered by DEHP, resulting in cell dysfunction of roots and visible growth inhibition. Overall, these finding generated fresh perspective for crops security caused by plasticizer pollution and enhanced the public focus on dietary risk.
研究领域:
环境科学
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植物科学
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分子生物学
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毒理学
✓ 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）