JOURNAL OF HAZARDOUS MATERIALS
·
2025
·
IF 11.3
Jia-Gen Cui,Hao Zhang,Yue-Qi Zhang,Bing Sun,Xue-Nan Li,Yi Zhao,Jin-Long Li
The widespread use of di(2-ethylhexyl) phthalate (DEHP) as a plasticizer raises concerns due to its environmental persistence and cardiotoxicity. Nevertheless, the precise mechanisms through which DEHP induces cardiac damage, particularly concerning myocardial injury, remain inadequately understood. Using a mouse model, this investigation employed UPLC-MS/MS to demonstrate that exposure to DEHP significantly elevated the concentration of its primary metabolite, mono(2-ethylhexyl) phthalate (MEHP), in cardiac tissue, while DEHP itself did not exhibit a significant difference. DEHP-induced myocardial injury in mice was evidenced by disorganized myocardial fibers, collagen deposition and elevated serum creatine kinase-MB (CK-MB) and C-reactive protein (CRP). Further analysis through database screening and experimental validation indicated that DEHP mediates myocardial injury by activating the sphingolipid metabolic pathway involving the sphingosine kinases 1 (SPHK1)/ sphingosine 1-phosphate receptor 2 (S1PR2) axis. Molecular docking and cellular thermal shift assays (CETSA) confirmed that MEHP could directly bind to and enhance the stability of SPHK1. DEHP exposure also increased pyroptosis-related proteins, reversible via SPHK1 inhibitor PF543 or S1PR2 siRNA. In conclusion, this study first links DEHP-induced cardiac pyroptosis to SPHK1/S1PR2 signaling in mice, providing novel insights into DEHP-associated cardiotoxicity, contributing to cardiac damage and thereby offering new theoretical insights into DEHP-related cardiac toxicity.
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高影响因子
Cell Death & Disease
·
2026
·
IF 12.2
Liu Yanyan,Guan Chenxi,Xu Linlin,Yang Jianhua,Wang Jinglei,Yang Si,Chen Jiaxiang
Impaired Leydig cell function leads to low testosterone levels, which is associated with male reproductive developmental defects and functional disorders. Exposure to di(2-ethylhexyl) phthalate (DEHP), an endocrine-disrupting chemical, can cause damage to Leydig cells, yet the underlying mechanism remains unclear. In this study, we found that DEHP exposure decreased serum testosterone levels and triggered ferroptosis of mouse Leydig cells by inhibiting GPX4 expression. Subsequently, mono(2-ethylhexyl) phthalate (MEHP), the primary active metabolite of DEHP, was shown to suppress the transcription of Gpx4 gene in TM3 cells by downregulation of HOXA3, which bound to the −264 to −258 region (RE3) of Gpx4 gene promoter. Concurrently, MEHP promoted HSC70 to recognize and degradate GPX4 protein via chaperone-mediated autophagy (CMA). Furthermore, both overexpression of HOXA3 and inhibition of CMA significantly abrogated MEHP-induced ferroptosis of TM3 cells through upregulating the expression of GPX4. Ultimately, tannic acid (TA), a natural polyphenol, was identified to increase the expression of GPX4 and inhibit MEHP-induced ferroptosis of TM3 cells, thereby alleviating DEHP-caused testicular damage in mice through the upregulation of HOXA3 and inhibition of CMA.
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Food & Function
·
2021
·Vol. 12
·期 24
·12256-12264
·
IF 5.396
Yi Zhao,Ling-Ge Cui,Milton Talukder,Jia-Gen Cui,Hao Zhang,Jin-Long Li
Lycopene (LYC) is a potent antioxidant synthesized by red vegetables or plants. Di-2-ethylhexyl phthalate (DEHP) is frequently detected in diverse agricultural environments and considered as a reproductive toxicant. The present research was designed to assess the potential mechanisms of DEHP-induced testicular toxicity and the treatment efficacy of LYC. In this study, after the oral administration of LYC at the dose of 5 mg per kg b.w. per day, mice were given 500 or 1000 mg per kg b.w. per day of DEHP. This research suggested that LYC prevented the DEHP-induced disorder at the levels of activity and content of CYP450 enzymes. LYC attenuated DEHP-caused enhancement in nuclear xenobiotic receptors (NXRs) and the phase I metabolizing enzymes (CYP1, CYP2, CYP3, etc.) levels. Furthermore, endoplasmic reticulum (ER) stress was induced by DEHP and triggered unfolded protein response (UPR). Interestingly, LYC could effectively ameliorate these “hit”. The present study suggested that LYC prevents DEHP-induced ER stress in testis via regulating NXRs and UPRER.
研究领域:
毒理学
·
生殖生物学
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药理学
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ENVIRONMENTAL TOXICOLOGY
·
2023
·
IF 4.5
Jiadong Chen,Tianxin Zhao,Xiangqin Zheng,Lian Kang,Junke Wang,Yuexin Wei,Yuhao Wu,Lianju Shen,Chunlan Long,Guanghui Wei,Shengde Wu
Di(2-ethylhexyl) phthalate (DEHP), an environmental endocrine disruptor, is one of the most common plasticizers and is widely used in various plastic products. DEHP induces apoptosis and oxidative stress and has been shown to have androgenic toxicity. However, the methods to combat DEHP-induced testicular damage and the mechanisms involved remain to be elucidated. In the present study, we used melatonin, which has strong antioxidant properties, to intervene in prepubertal mice and mouse Leydig cells (TM3) treated with DEHP or its metabolite mono(2-ethylhexyl) phthalate (MEHP). The results showed that melatonin protected against DEHP-induced testicular damage in prepubertal mice, mainly by protecting against DEHP-induced structural destruction of the germinal tubules and by attenuating the DEHP-induced decrease in testicular organ coefficients and testosterone levels. Transcriptomic analysis found that melatonin may attenuate DEHP-induced oxidative stress and apoptosis in prepubertal testes. In vitro studies further revealed that MEHP induces oxidative stress injury and increases apoptosis in TM3 cells, while melatonin reversed this damage. In vitro studies also found that MEHP exposure inhibited the expression levels of molecules related to the PI3K/AKT signaling pathway, and melatonin reversed this change. In conclusion, these findings suggest that melatonin protects against DEHP-induced prepubertal testicular injury via the PI3K/AKT signaling pathway, and provide a theoretical basis and experimental rationale for combating male reproductive dysfunction.
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Journal of Advanced Research
·
2024
·
IF 11.4
Yi Zhao,Xue-Qi Wang,Rui-Qi Liu,Fu-Wei Jiang,Jia-Xin Wang,Ming-Shan Chen,Hao Zhang,Jia-Gen Cui,Yuan-Hang Chang,Jin-Long Li
Introduction Phthalates exposure is a major public health concern due to the accumulation in the environment and associated with levels of testosterone reduction, leading to adverse pregnancy outcomes. However, the relationship between phthalate-induced testosterone level decline and ferroptosis remains poorly defined. Objectives Herein, we aimed to explore the mechanisms of phthalates-induced testosterone synthesis disorder and its relationship to ferroptosis. Methods We conducted validated experiments in vivo male mice model and in vitro mouse Leydig TM3 cell line, followed by RNA sequencing and metabolomic analysis. We evaluated the levels of testosterone synthesis-associated enzymes and ferroptosis-related indicators by using qRT-PCR and Western blotting. Then, we analyzed the lipid peroxidation, ROS, Fe 2+ levels and glutathione system to confirm the occurrence of ferroptosis. Results In the present study, we used di (2-ethylhexyl) phthalate (DEHP) to identify ferroptosis as the critical contributor to phthalate-induced testosterone level decline. It was demonstrated that DEHP caused glutathione metabolism and steroid synthesis disorders in Leydig cells. As the primary metabolite of DEHP, mono-2-ethylhexyl phthalate (MEHP) triggered testosterone synthesis disorder accompanied by a decrease in the expression of solute carri1er family 7 member 11 (SLC7A11) protein. Furthermore, MEHP synergistically induced ferroptosis with Erastin through the increase of intracellular and mitochondrial ROS, and lipid peroxidation production. Mechanistically, overexpression of SLC7A11 counteracts the synergistic effect of co-exposure to MEHP-Erastin. Conclusion Our research results suggest that MEHP does not induce ferroptosis but synergizes Erastin-induced ferroptosis. These findings provide evidence for the role of ferroptosis in phthalates-induced testosterone synthesis disorder and point to SLC7A11 as a potential target for male reproductive diseases. This study established a correlation between ferroptosis and phthalates cytotoxicity, providing a novel view point for mitigating the issue of male reproductive disease and “The Global Plastic Toxicity Debt”.
研究领域:
毒理学
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生殖生物学
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分子生物学
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药理学
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高影响因子
ENVIRONMENTAL POLLUTION
·
2021
·
IF 8.071
Yi Zhao,Hui-Xin Li,Yu Luo,Jia-Gen Cui,Milton Talukder,Jin-Long Li
Di (2-ethylhexyl) phthalate (DEHP) is a hazardous chemical which is used as a plasticizer in the plastic products. Lycopene (LYC) is a carotenoid that has protective roles against cellular damage in different organs. The present study sought to explore the role of the interaction between mitophagy and mitochondrial unfolded protein response (UPR mt ) in the LYC mitigating DEHP-induced hepatic mitochondrial quality control disorder. The mice were treated with LYC (5 mg/kg) and/or DEHP (500 or 1000 mg/kg). In our findings, LYC prevented DEHP-induced histopathological alterations including steatosis and fibrosis, and ultrastructural injuries including decreased mitochondrial membrane potential (ΔΨm) and mitochondria volume density. Furthermore, LYC alleviated DEHP-induced mitochondrial biogenesis disorder by suppressing SIRT1–PGC-1α axis, PINK1-mediated mitophagy and the activation of mitochondrial unfolded protein response (UPR mt ). This research suggested that LYC could prevent DEHP-induced hepatic mitochondrial quality control disorder via regulating SIRT1/PINK1/mitophagy axis and UPR mt . The present study provided a current understanding about the potential implication of the SIRT1/PINK1/mitophagy axis and UPR mt in LYC preventing DEHP-induced hepatic mitochondrial quality control disorder.
研究领域:
毒理学
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药理学
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分子生物学
·
细胞生物学
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高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2026
·
IF 6.7
Zhang Hao,Cui Jia-Gen,Wang Jia-Xin,Chen Ming-Shan,Zhao Yi,Li Jin-Long
Di(2-ethylhexyl)phthalate (DEHP), a common environmental
endocrine
disruptor and agricultural organic pollutant, has drawn wide concern
for its hepatotoxicity. However, the molecular mechanisms underlying
DEHP-induced hepatic fibrosis remain unclear. Through network toxicology
analysis, lipid metabolism and autophagy pathways are involved in
DEHP-related hepatic fibrosis. Subchronic DEHP exposure (50–500
mg/kg) induced dose-dependent hepatic fibrosis in mice, while its
metabolite MEHP synergized with TGF-β1 to promote LX2 cell activation in vitro . Crucially, MEHP activates lipophagy by targeting
Beclin1, thereby mobilizing energy for the activation of hepatic stellate
cells (HSCs). Attenuating autophagy with 3-Methyladenine (3-MA) or
Chloroquine (CQ), or via Beclin1 knockdown, all rescued the activation
phenotype induced by MEHP. These results suggest that DEHP acts as
a trigger for fibrosis, promoting this process by inducing the activation
of HSCs. This work identifies the lipophagy pathway as a crucial mechanistic
link between environmental toxin exposure and HSC-mediated hepatic
fibrosis progression.
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FOOD AND CHEMICAL TOXICOLOGY
·
2022
·
IF 5.572
Yuqi Wang,Yilei Zhang,Xinyue Sun,Xu Shi,Shiwen Xu
With the widespread use of plastics, microplastics (MPs) and di(2-ethylhexyl) phthalate (DEHP) have become emerging environmental pollutants. The combined toxicity of MPs and DEHP on the mouse pancreas and the specific mechanism of toxicity remain unclear. To establish in vitro and in vivo models to address these questions, mice were continuously exposed to 200 mg/kg/d DEHP and 10 mg/L MPs for 4 weeks. In vitro, MIN-6 cells were treated with 200 μg/mL MPs and 200 μM DEHP for 24 h. Based on toxicity assessed using CCK8 of the equivalent TU binary mixture, the IC50 of the TU-mix of DEHP and MPs 0.692 < 0.8, indicating a synergistic effect of the two toxicants. Meanwhile, our data revealed that compared to the control group, MPs and DEHP combined treatment increased ROS levels, inhibited the activity, and enhanced the expression of GRP78 , and CHOP. Simultaneously, activated CHOP decreased the expression of Bcl-2, and increased the expression of Bax. In conclusion, DEHP and MPs synergistically induce oxidative stress , and activate the GRP78/CHOP/Bcl-2 pathway to induce pancreatic apoptosis in mice. Our finding provides a new direction for the research on the specific mechanism of MPs and DEHP combined toxicity.
研究领域:
环境毒理学
·
细胞生物学
·
分子生物学
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SCIENCE OF THE TOTAL ENVIRONMENT
·
2016
·
IF 3.976
Hai-Ming Zhao,Huan Du,Jing Lin,Xue-Bin Chen,Yan-Wen Li,Hui Li,Quan-Ying Cai,Ce-Hui Mo,Hua-Ming Qin,Ming-Hung Wong
A newly isolated strain Agromyces sp. MT-O could utilize various phthalates and efficiently degraded di-(2-ethylhexyl) phthalate (DEHP). Response surface methodology was successfully employed for the optimization of culture conditions including pH (7.2), temperature (29.6), and inoculum size (OD 600 of 0.2), resulting in almost complete degradation of DEHP (200 mg L − 1 ) within 7 days. At different initial concentrations (50–1000 mg L − 1 ), DEHP degradation curves were fitted well with the first-order kinetic model, and the half-life of DEHP degradation ranged from 0.83 to 2.92 days. Meanwhile, the substrate inhibition model was used to describe the special degradation rate with q max , K s , and K i of 0.6298 day − 1 , 86.78 mg L − 1 , and 714.3 mg L − 1 , respectively. The GC–MS analysis indicated that DEHP was degraded into mono-ethylhexyl phthalate and phthalate acid before its complete mineralization. Bioaugmentation of DEHP-contaminated soils with strain MT-O has greatly enhanced DEHP disappearance rate in soils, providing great potential for efficiently remediating DEHP-contaminated environment.
研究领域:
环境科学
·
微生物学
·
生物技术
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高影响因子
JOURNAL OF NUTRITIONAL BIOCHEMISTRY
·
2026
·
IF 5.2
Yuting Dong,Xiaodan Wang,Shize Wang,Kang Yang,Tong Xu,Hongjin Lin
DEHP induces thymus injury in chickens by activating the NF-κB/TNF-α pathway, triggering oxidative stress and PANoptosis. • QUE can alleviate the activation of the NF-κB/TNF-α pathway, oxidative stress and PANoptosis induced by DEHP in chickens. • QUE exerts a targeted effect on NF-κB, thereby mitigating DEHP-induced thymus injury in chickens. Quercetin (Que), a natural dietary flavonoid, possesses significant antioxidative and immunoregulatory properties. Di(2-ethylhexyl) phthalate (DEHP), a pervasive environmental endocrine-disrupting chemical, triggers oxidative stress (OS) and elicits immunotoxic effects in various species. However, whether Que can target NF-κB to alleviate DEHP-induced OS and PANoptosis in the chicken thymus remains unclear to date. To investigate the mechanism of thymus damage induced by DEHP and the intervention effect of Que, we established an in vivo chicken model treated with DEHP and/or Que. Based on the results of network pharmacology, molecular docking, molecular dynamics simulations, and Cell Thermal Shift Assay (CETSA), we predicted that NF-κB is the key target for the protective effect of Que. Subsequently, through H&E staining, CCK-8, immunofluorescence, Western blot and other techniques, we verified the effects of DEHP and/or Que on OS, the assembly of PANoptosome, and cellular PANoptosis in chicken thymus tissue and chicken lymphocyte cell line (MSB-1). Meanwhile, to clarify the key role of NF-κB in the above regulatory process, we conducted reverse validation experiments by introducing the NF-κB activator Act1 in cellular experiments. The results demonstrated that DEHP exposure markedly induces the upregulation of NF-κB and TNF-α(P<0.05), leading to a pronounced burst of reactive oxygen species (ROS) and consequent OS within the chicken thymus. This process further activates the ZBP1-mediated PANoptosis pathway, ultimately causing damage to chicken thymus tissue. Que intervention effectively suppresses NF-κB activation, blocking the transmission of the NF-κB/TNF-α/ROS signaling axis, thereby reversing DEHP-induced ZBP1-mediated PANoptosis in chicken thymus. Download: Download high-res image (290KB) Download: Download full-size image
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Frontiers in Cell and Developmental Biology
·
2022
·
IF 6.081
Fan Zhang,Hualong Zhen,Hengshun Cheng,Fengying Hu,Yunfei Jia,Binbin Huang,Minmin Jiang
As one kind of endocrine disrupting chemical, di-(2-ethylhexyl) phthalate (DEHP) has been reported to cause liver dysfunction in epidemiological and experimental studies. Abnormal liver function in pregnancy is associated with adverse maternal and perinatal outcomes. Few studies have investigated the potential effect of gestational DEHP exposure on the liver in pregnant mice, and the underlying mechanisms remain unclear. In the present study, pregnant ICR mice were exposed to doses (0, 500, 1,000 mg/kg/day) of DEHP in the presence or absence of 5 mg/kg/day ferrostatin-1 (Fer-1, ferroptosis inhibitor) by oral gavage from gestation day 4 to day 18. HepG2 cells were exposed to different doses of monoethylhexyl phthalate (MEHP, a major metabolite of DEHP) in vitro . Hepatic function and pathologic changes were observed. Oxidative stress, iron metabolism, and ferroptosis-related indicators and genes were evaluated both in vivo and in vitro . The results showed that gestational DEHP exposure induced disordered liver function and hepatocyte morphology changes in pregnant mice, along with increased malondialdehyde (MDA) and Fe 2+ content and decreased glutathione (GSH) levels. The expression levels of the selected ferroptosis-related genes Slc7a11 , Gpx4 , and Nfr2 were significantly decreased, and Ptgs2 and Lpcat3 were significantly increased. Notably, Fer-1 attenuated DEHP-induced liver injury and ferroptosis. Furthermore, MEHP exhibited a synergistic effect with RSL3 (a GPX4 inhibitor) in promoting ferroptosis in vitro . Taken together, the results demonstrated that DEHP induced liver injury and ferroptosis in pregnant mice, probably by inhibiting the GPX4 pathway through lipid peroxidation and iron accumulation.
研究领域:
毒理学
·
药理学
·
分子生物学
·
生殖健康
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高影响因子
JOURNAL OF HAZARDOUS MATERIALS
·
2021
·
IF 10.588
Zhuo Chen,Qianying Wu,Ying Xu,Jinhan Mo
Organic films were widely found on indoor impermeable surfaces exposed to gaseous organic compounds, but few studies have addressed the film growth details on different indoor substrates. In this study, we observed the topography evolution of phthalic acid ester (PAE) organic films on three impermeable substrates: polished glass (G-P), mirror-polished stainless steel (SS-M) and drawn stainless steel (SS-D). PAE organic films were preferentially formed upon the flat surface with sparse inherent nano-peaks of substrate G-P and in valleys of substrate SS-M and SS-D. Surface uniformity of substrates and viscosity of PAE molecules were inferred as critical parameters determining the surface average adhesion forces. We obtained the partition coefficients of DEP , DnBP, BBP and DEHP on substrate G-P, SS-M and SS-D by fitting the initial monolayer adsorption process. Organic films continuously grew instead of reaching adsorption equilibrium after long-term PAE exposure, indicating that multilayer adsorption may occur. The organic film growth rates in saturated gas-phase PAE concentrations were quantified as about one-tenth of the results in previous studies where substrates were simultaneously exposed to multiple pollutants. To sum up, the results outline PAE adsorption details on impermeable materials and provide a reference for better estimation on PAE exposure assessment.
研究领域:
环境科学
·
化学
·
材料科学
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高影响因子
危险品化学品经营许可证（带存储）