ENVIRONMENTAL POLLUTION
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2025
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IF 7.3
Yiyun Liu,Qi-Ping Tang,Si-Jia Zuo,Yuan Ding,Feng-Yi Guo,Bao-Fu Zhang,Qin-Hong Zhou,Dongmei Xie,De-Sheng Pei
The surge in global plastic usage has exacerbated the pollution of nanoplastics and plasticizers in aquatic ecosystems, causing widespread concern about population health issues. We used a zebrafish model to investigate the combined toxicity of polystyrene nanoparticles (PS-NPs) and plasticizer metabolite mono-(2-ethylhexyl) phthalate (MEHP), revealing the synergistic neurotoxic effects and potential mechanisms of compound exposure. Co-exposure amplifies the bioaccumulation of PS-NPs ( p < 0.05), causing innate immune damage ( p < 0.0001), severe oxidative stress ( p < 0.0001), and embryonic apoptosis ( p < 0.05), while inducing larval neuromotor dysfunction and changes in neural markers. Further exploration revealed that oxidative stress-induced lipid peroxidation disrupts glycerophospholipid metabolism and cholinergic synthesis, which can be an important mechanism for neurotoxicity caused by the co-exposure of PS-NPs and MEHP. This hypothesis is supported by dysregulation of acetylcholinesterase ( ache ), docking protein 7 ( dok7 ), and heparan sulfate proteoglycan 2 ( hspg2 ) genes linked to neurotransmission. In summary, this study reveals new synergistic toxicity mechanisms between nanoplastics and plasticizers, advancing the risk assessment framework for complex environmental pollutant interactions.
研究领域:
生态毒理学
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环境科学
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神经生物学
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DOI
PubMed
高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
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2025
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IF 8
Yao Yao,Yunshan Zhang,Binqing Xue,Weihua Chu
Mono-2-ethylhexyl phthalate (MEHP) is one of the major biologically active metabolites of phthalate plasticizers that pose a health threat to aquatic animals. In this study, we investigated the ecotoxicological effects of MEHP on liver damage and gut microbiota in crucian carp ( Carassius carassius ) and the mitigating effects of Lactobacillus brevis Lb-0401 as a dietary supplement. The results showed that MEHP induced hepatotoxicity and increased serum AST, ALT and triglyceride levels, while L. brevis Lb-0401 alleviated abnormalities in serum metabolic parameters and increased antioxidant enzymes (T-SOD, CAT, GSH-Px). Further transcriptome and microbiota analysis revealed that MEHP exposure caused hepatic glucose, lipid and purine metabolism disorders, inhibited energy production and disrupted gut microbial homeostasis. Administration of L. brevis Lb-0401 reversed all these changes. In conclusion, this study not only provides new mechanistic insights into the ecotoxicological effects of MEHP, but also suggests a potential strategy using intestinal autochthonous probiotic bacteria to mitigate the harmful effects of phthalate plasticisers on aquatic organisms.
研究领域:
生态毒理学
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水生毒理学
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微生物学
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环境科学
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分子生物学
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DOI
PubMed
高影响因子
ENVIRONMENTAL POLLUTION
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2023
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IF 8.9
Yifan Hong,Xiazhu Zhou,Qi Li,Jing Chen,Yuexin Wei,Siyuan Wang,Xiangqin Zheng,Jie Zhao,Chengjun Yu,Jun Pei,Jie Zhang,Chunlan Long,Lianju Shen,Shengde Wu,Guanghui Wei
Di (2-ethylhexyl) phthalate (DEHP), one of phthalic acid esters, has been widely used in daily products. Its main metabolite, mono (2-ethylhexyl) phthalate (MEHP) was reported to possess higher testicular toxicity than DEHP. To explore the precise mechanism in MEHP-induced testis damage, multiple transcriptomic sequencing was employed in spermatogonia cell line GC-1 cells treated with MEHP (0, 100, and 200 μM) for 24 h. Integrative omics analysis and empirical validation revealed that Wnt signaling pathway was downregulated and wnt10a , one of hub genes, may be the key player in this process. Similar results were observed in DEHP-exposed rats. MEHP-induced disturbance of self-renewal and differentiation was dose-dependent. Moreover, self-renewal proteins were downregulated; the differentiation level was stimulated. Meanwhile, GC-1 proliferation was decreased. Stable transformation strain of wnt10a overexpression GC-1 cell line constructed from lentivirus was utilized in this study. The upregulation of Wnt10a significantly reversed the dysfunction of self-renewal and differentiation and promoted the cell proliferation. Finally, retinol, predicted to be useful in CONNECTIVITY MAP (cMAP), failed to rescue the damage caused by MEHP. Cumulatively, our findings revealed that the downregulation of Wnt10a induced the imbalance of self-renew and differentiation, and inhibition of cell proliferation in GC-1 cells after MEHP exposure.
研究领域:
毒理学
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分子生物学
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细胞生物学
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生殖生物学
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DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2019
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IF 4.527
Yuezhu Zhang,Shuyue Wang,Tianyang Zhao,Liwei Yang,Shuangyu Guo,Yanbin Shi,Xueting Zhang,Liting Zhou,Lin Ye
Mono-2-ethylhexyl phthalate (MEHP), as the major metabolite of Di-(2-ethylhexyl) phthalate (DEHP), can induce lipid accumulation in hepatocytes and further leads to non-alcoholic fatty liver disease (NAFLD), while the underlying mechanism is unclear. We aim to clarify the effects of JAK2/STAT5 pathway on lipid accumulation induced by MEHP and the role of oxidation stress in NAFLD. BRL-3A hepatocytes were exposed to MEHP (0, 10, 50, 100 and 200 μM) for 24 h and 48 h. Then the lipid droplets in cells were observed by Oil-Red-O staining and quantified by isopropyl alcohol . The levels of TG, SOD, TBARS, AST and ALT were all detected by commercial kits. RT-PCR was used to detect mRNA expression, and western blotting was used to detect the expression of proteins encoded by JAK2/STAT5 pathway genes and lipid metabolism-related genes. As a result, MEHP promoted the lipid synthesis and accumulation in BRL-3A cells. MEHP down-regulated the expression and inhibited the activation of JAK2/STAT5. Moreover, the lipid metabolism-related kinases levels were elevated after MEHP exposure. In addition, the SOD levels were gradually decreased and the TBARS levels were increased in MEHP-treated groups. The lipid metabolism-related proteins levels were correlated with the oxidation stress levels. Furthermore, the ALT and AST levels were elevated after MEHP exposure. Therefore, we concluded that MEHP led to lipid accumulation through inhibiting JAK2/STAT5 pathway, resulted in damaging liver parenchyma and NAFLD by aggravating oxidation stress.
研究领域:
毒理学
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细胞生物学
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肝病学
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DOI
PubMed
高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
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2022
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IF 10.753
Yiwei Fang,Zhiliang Chen,Jinyu Chen,Minqi Zhou,Yuanyao Chen,Rong Cao,Chunyan Liu,Kai Zhao,Min Wang,Huiping Zhang
Mono(2-ethylhexyl) phthalate (MEHP) is a metabolite of DEHP which is one of phthalic acid esters (PAEs) widely used in daily necessities. Moreover, MEHP has been proven to have stronger biological toxicity comparing to DEHP. In particular, several recent population-based studies have reported that intrauterine exposure to MEHP results in adverse pregnancy outcomes. To explore the mechanisms and metabolic biomarkers of MEHP exposure, we examined the metabolic status of HTR-8/Svneo cell lines exposed to different doses of MEHP (0, 1.25, 5.0, 20 μM). Global and dose–response metabolomics tools were used to identify metabolic perturbations and sensitive markers associated with MEHP. Only 22 metabolic features (accounted for <1 %) were significantly changed when exposed to 1.25 μM. However, when the exposure dose was increased to 5 or 20 μM, the number of significantly changed metabolic features exceeded 300 (approximately 10 %). In particular, amino acid metabolism, pyrimidine metabolism and glutathione metabolism were widely affected according to the enrich analysis of those significant altered metabolites, which has and have previously been reported to be closely related to fetal development. Moreover, 5′-UMP and N -acetylputrescine with the lowest effective concentrations (EC −10 = 0.1 μM and EC +10 = 0.11 μM, respectively) were identified as sensitive endogenous biomarkers of MEHP exposure.
研究领域:
毒理学
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生殖生物学
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代谢组学
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DOI
PubMed
高影响因子
TOXICOLOGY
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2021
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IF 4.221
Shuangyu Guo,Bo Zhang,Wen Qi,Xiaolian Cao,Yixuan Xu,Xueting Zhang,Xu Li,Liting Zhou,Lin Ye
Estrogen receptors are involved in regulating the proliferation and invasion process of neuroblastoma . As a kind of estrogen-like environmental endocrine disruptors (EEDs), whether mono-2-ethylhexyl phthalate (MEHP) can affect the proliferation and invasion of neuroblastoma cells via ERs is unknown. The present study aimed to explore the role of ERα in MEHP-induced proliferation, migration, and invasion of SH-SY5Y cells. SH-SY5Y cells were cultured in DMEM with 10 % FBS. Wild-type SH-SY5Y cells and ERα-knockdown SH-SY5Y cells were treated with MEHP (0, 10, 50, and 250 μM) for 12 h and 24 h. The viability of SH-SY5Y cells was detected with a CCK8 kit and cell cycle was measured by flow cytometry. Cell migration was measured using a scratch assay, and cell invasion was tested using a Transwell migration assay. The expression levels of proliferating cell nuclear antigen (PCNA), matrix metalloproteinase 2 (MMP-2), matrix metalloproteinase 9 (MMP-9), tissue inhibitor of matrix metalloproteinase 2 (TIMP-2), ERα, and ERβ were detected with real-time qPCR and western blotting . MEHP promoted the proliferation of SH-SY5Y cells. The results also showed that MEHP significantly increased the relative migration distance of wild-type SH-SY5Y cells. Conversely, MEHP treatment did not increase the relative migration distance of ERα-knockdown SH-SY5Y cells, suggesting that MEHP promotes the migration of neuroblastoma through ERα. Similarly, MEHP significantly increased the relative number of invaded wild-type SH-SY5Y cells, while the MEHP-induced invasion effect was significantly decreased in ERα-knockdown SH-SY5Y cells. Moreover, the expression levels of PCNA, MMP-2, MMP-9, and ERα cells were upregulated by MEHP in wild-type SH-SY5Y, and the expression level of its tissue inhibitor TIMP-2 was downregulated. In contrast, the expression of PCNA, MMP-2, MMP-9, and ERα was significantly downregulated in ERα-knockdown SH-SY5Y cells, while the expression of TIMP-2 was significantly upregulated. In conclusion, MEHP can upregulate PCNA, MMP-2, and MMP-9, and downregulate TIMP-2, further promoting proliferation, migration, and invasion of neuroblastoma through ERα.
研究领域:
癌症生物学
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毒理学
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细胞生物学
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DOI
PubMed
高影响因子
REPRODUCTIVE TOXICOLOGY
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2025
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IF 2.8
Li-Ping Tan,Liu Yuan,Yan Zhang,Jun-Lin He,Xin Yin,Yi-Dan Ma,Xue-Mei Chen,Wei-Ke Li,Fang-Fang Li,Ru-Fei Gao
DEHP is a pervasive endocrine disrupting chemical with multiple adverse effects on the female reproductive system. However, its impact on endometrial decidualization, the foundation for embryo implantation and successful pregnancy, remains poorly defined, and the underlying regulatory mechanisms have been rarely explored. In present study, we utilized several assays with DEHP-exposed mouse decidual tissues to clarify whether DEHP exposure confers adverse effects on decidualization. The results showed that 1000 mg/kg/d DEHP exposure led to a significant reduction in the weight and area of the uterine deciduoma, accompanied by a significant decrease in the expression of decidualization markers on GD6, GD8 of pregnancy, and PD8 of pseudopregnancy in mice. Moreover, the in vitro findings revealed that exposure to 12.5 μM MEHP, the primary and active metabolite of DEHP, disturbed the cytoskeletal remodeling and downregulated the marker molecules during endometrial stromal cell decidualization. Meanwhile, we detected that Mtmr6 as identified by proteomics analysis, was up-regulated after DEHP and MEHP exposure in vivo and in vitro . Knockdown of Mtmr6 alleviated the deficiencies in stromal cell decidualization induced by DEHP’ metabolite MEHP. Furthermore, we also found that the active-site residue ALA-131 of Mtmr6 may be the direct binding site for MEHP by performing molecular docking. This study uncovered the adverse effects of DEHP on endometrial decidualization and revealed the possible mechanisms, providing potential strategies for minimizing their toxicological effects on female reproductive health.
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高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2023
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IF 6.8
Bo Xu,Tiantian He,Hong Yang,Wenjie Dai,Ling Liu,Xiaoqian Ma,Jiaxue Ma,Guoqin Yang,Rui Si,Xing Du,Xufeng Fu,Xiuying Pei
Di-(2-ethylhexyl) phthalate (DEHP) is widely used in various plastics but has been demonstrated to cause female reproductive toxicity. However, the exact mechanism underlying the ovarian damage induced by DEHP remains unclear. In this study, DEHP was administered orally to 5-week-old female mice for 30 days at doses of 0, 250, 500, and 1000 mg/kg/day. The findings demonstrated that DEHP exposure disrupted ovarian function and follicular development as well as induced oxidative stress and autophagy in ovarian granulosa cells (GCs). Further, 200 µM mono-(2-ethylhexyl) phthalate (MEHP), the primary metabolite of DEHP in vivo , induced autophagy in both human ovarian granulosa cells line (KGN) and mouse primary GCs within 24 h in vitro . However, it did not affect the p62-dependent autophagy flux. Furthermore, MEHP-induced autophagy was inhibited by the autophagy inhibitor 3-MA and exacerbated by the autophagy activator rapamycin, indicating that MEHP induces excessive autophagy in GCs. Subsequently, we found that MEHP-induced autophagic cell death was primarily attributed to oxidative damage from elevated intracellular ROS levels. Meanwhile, MEHP exposure induced nuclear translocation of erythroid-derived factor 2-related factor (Nrf2), a key regulator of antioxidant activity resulting in activating antioxidant effects. Interestingly, we also found that MEHP-induced increase in p62 competitively binds Keap1, thereby facilitating nuclear translocation of Nrf2 and establishing a positive feedback loop in antioxidant regulation. Therefore, this study demonstrated that inhibition of Nrf2 could aggravate oxidative damage and enhance excessive autophagy caused by MEHP, while activation of Nrf2 could reverse the trend. These findings have also been reinforced in studies of cultured ovaries in vitro . Our study suggests that the p62-Keap1-Nrf2 pathway may serve as a potential protective mechanism against DEHP-induced oxidative stress and excessive autophagy in mouse GCs.
研究领域:
生殖毒理学
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分子生物学
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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
Journal of Advanced Research
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2024
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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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产品关联
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2020
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IF 4.872
Yuhao Wu,Junke Wang,Tianxin Zhao,Yuexin Wei,Lindong Han,Lianju Shen,Chunlan Long,Shengde Wu,Guanghui Wei
Di-(2-ethylhexyl) phthalate (DEHP), one of the most commonly used endocrine-disrupting chemicals, has been shown to cause reproductive dysfunction in humans and animal models. However, very few studies have investigated the impact of DEHP at the post-transcriptional level in mouse testes, and the underlying mechanisms remain unclear. In the present research, TM3 Leydig cells were treated with 200 µM phthalic acid mono-2-ethylhexyl ester (MEHP, bio-metabolite of DEHP), and then the mRNA and lncRNA sequencing of TM3 Leydig cells was performed. Mice were exposed prepubertally to 0 or 500 mg DEHP/kg/day. RNA sequencing of mouse testes was performed to verify the RNA-seq results in vitro . The expression patterns of relevant genes and proteins were verified using real-time quantitative polymerase chain reaction (RT-qPCR) and western blotting. DEHP and MEHP exposure led to testicular damage and accelerated cell aging via ROS accumulation. RNA sequencing analyses indicated that FOXO signaling and longevity regulation pathways were activated in resistance to ROS accumulation. FOXO signaling and longevity regulation pathway-related genes and proteins were also activated. By constructing a competing endogenous RNA (ceRNA) network, we observed that the ceRNA network might play a role in regulating FOXO signaling and longevity regulation pathways in response to excessive ROS accumulation and cell aging. In summary, our data here suggests that the ceRNA network may play a role in regulating FOXO signaling and longevity pathways in response to DEHP exposure in mouse testes.
研究领域:
生殖生物学
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毒理学
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分子生物学
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基因组学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
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2022
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IF 14.224
Yi Zhao,Xue-Nan Li,Hao Zhang,Jia-Gen Cui,Jia-Xin Wang,Ming-Shan Chen,Jin-Long Li
Male infertility is an attracting growing concern owing to decline in sperm quality of men worldwide. Phthalates , in particular to di (2-ethylhexyl) phthalate (DEHP) or its main metabolite mono-2-ethylhexyl phthalate (MEHP), affect male reproductive development and function, which mainly accounts for reduction in male fertility. Lycopene (LYC) is a natural antioxidant agent that has been recognized as a possible therapeutic option for treating male infertility. Testosterone (T)/androgen receptor (AR) signaling pathway is involved in maintaining spermatogenesis and male fertility. How DEHP causes spermatogenesis disturbance and whether LYC could prevent DEHP-induced male reproductive toxicity have remained unclear. Using in vivo and vitro approaches, we demonstrated that DEHP caused T biosynthesis reduction in Leydig cell and secretory function disorder in Sertoli cell, and thereby resulted in spermatogenic impairment. Results also showed that MEHP caused mitochondrial damage and oxidative damage, which imposes a serious threat to the progress of spermatogenesis. However, LYC supplement reversed these changes. Mechanistically, DEHP contributed to male infertility via perturbing T/AR signaling pathway during spermatogenesis. Overall, our study reveals critical role for T/AR signal transduction in male fertility and provides promising insights into the protective role of LYC in phthalate-induced male reproductive disorders.
研究领域:
生殖生物学
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毒理学
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内分泌学
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营养学
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产品关联
DOI
PubMed
高影响因子
Redox Biology
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2022
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IF 10.787
Yi Zhao,Hao Zhang,Jia-Gen Cui,Jia-Xin Wang,Ming-Shan Chen,Hao-Ran Wang,Xue-Nan Li,Jin-Long Li
The global rate of human male infertility is rising at an alarming rate owing to environmental and lifestyle changes. Phthalates are the most hazardous chemical additives in plastics and have an apparently negative impact on the function of male reproductive system. Ferroptosis is a recently described form of iron-dependent cell death and has been linked to several diseases. Transferrin receptor (TfRC), a specific ferroptosis marker, is a universal iron importer for all cells using extracellular transferrin. We aim to investigate the potential involvement of ferroptosis during male reproductive toxicity, and provide means for drawing conclusions on the effect of ferroptosis in phthalates-induced male reproductive disease. In this study, we found that di (2-ethylhexyl) phthalate (DEHP) triggered blood-testis barrier (BTB) dysfunction in the mouse testicular tissues. DEHP also induced mitochondrial morphological changes and lipid peroxidation, which are manifestations of ferroptosis. As the primary metabolite of DEHP, mono-2-ethylhexyl phthalate (MEHP) induced ferroptosis by inhibiting glutathione defense network and increasing lipid peroxidation. TfRC knockdown blocked MEHP-induced ferroptosis by decreasing mitochondrial and intracellular levels of Fe 2+ . Our findings indicate that TfRC can regulate Sertoli cell ferroptosis and therefore is a novel therapeutic molecule for reproductive disorders in male patients with infertility.
研究领域:
生殖毒理学
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细胞生物学
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环境健康
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）