ENVIRONMENTAL RESEARCH
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2017
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IF 3.835
Ping Xiang,Rong-Yan Liu,Hong-Jie Sun,Yun-Wen Yang,Xin-Yi Cui,Lena Q. Ma
As a replacement for polybrominated diphenyl ethers , bis-(2-ethylhexyl) tetrabromophthalate (TBPH) is widely used as a novel flame retardant and has been detected in many environmental matrix including human blood. TBPH can be metabolized into mono-(2-ethyhexyl) tetrabromophthalate (TBMEHP) by carboxylesterase. However, their adverse effects on human vascular endothelium and their potential impacts on human cardiovascular disease are unknown. In this study, their adverse effects and associated molecular mechanisms on human vascular endothelial cells (HUVECs) were investigated. A concentration-dependent inhibition on HUVECs' viability and growth was observed for TBMEHP but not for TBPH. TBMEHP induced a marked G 0 /G 1 cell cycle arrest and robust cell apoptosis at 1 μg/mL by inducing expression of p53, GADD45α and cyclin dependent kinase (CDK) inhibitors ( p21 and p27 ) while suppressing the expression of cyclin D1, CDK2, CDK6, and Bcl-2. Unlike TBMEHP, TBPH caused early apoptosis after G 2 /M phase arrest only at 10 μg/mL via up-regulation of p21 and down-regulation of CDK2 and CDK4. TBMEHP decreased mitochondrial membrane potential and increased caspase-3 activity at 1 μg/mL, suggesting that activation of p53 and mitochondrial pathway were involved in the cell apoptosis. The data showed that TBPH and TBMEHP induced different cell cycle arrest and apoptosis through different molecular mechanisms with much higher toxicity for TBMEHP. Our study implies that the metabolites of TBPH, possibly other novel brominated flame retardants, may be of potential concern for human cardiovascular disease.
研究领域:
毒理学
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环境健康
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细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
Journal of Environmental Sciences
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2026
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IF 6.5
Jiawei Yang,Tao Zhou,Haichen Zhang,Qiong Zhang,Lening Chen,Qianqian Xiao,Qinghe Meng,Jianjun Jiang,Weidong Hao,Xuetao Wei
TBPH correlated with altered glycerophospholipid profiles in serum and intestine. • Compositional shifts in the gut microbiota were observed following TBPH exposure. • Elevated thyroid hormones and serum PLA2 activity co-occurred with TBPH exposure. • Systemic PC remodeling had a statistical association with gut microbiota changes. Bis(2-ethylhexyl) tetrabromophthalate (TBPH), a replacement for polybrominated diphenyl ethers, poses health concerns due to environmental ubiquity and potential endocrine disruption. Here, we investigated TBPH‑induced metabolic dysregulation mechanisms focusing on glycerophospholipid homeostasis and gut microbiota. Male Sprague‑Dawley (SD) rats were orally exposed to TBPH (0, 5, 50, 500 mg/kg) for 28 days; only control and 500 mg/kg groups underwent untargeted metabolomics (serum and intestinal) and 16S rRNA sequencing. At the highest dose, TBPH was significantly associated with disruption of the glycerophospholipid metabolism pathway, with marked alterations in phosphatidylcholines (PCs) and lysophosphatidylcholines (LPCs) in both serum and intestinal contents. This exposure was also associated with compositional shifts in the gut microbiota, characterized by a reduction in potentially beneficial genera (e.g., Akkermansia and Parabacteroides ), an enrichment of genera associated with dysbiosis (e.g., Desulfovibrio and Mucispirillum ), and a rewiring of microbial co‑occurrence networks. At the highest dose tested, TBPH was associated with increased serum phospholipase A2 (PLA2) activity. Partial least squares path modeling (PLS‑PM) identified statistical associations consistent with the hypothesis that TBPH may be indirectly associated with serum PLA2 activity through pathways involving the gut microbiota and its associated PC metabolites, as well as through elevated thyroid hormones. All findings were correlational and hypothesis‑generating; direct extrapolation to human health risk was not possible from this high‑dose animal study. Collectively, our findings generated the hypothesis that TBPH exposure was associated with host lipid homeostasis alterations through coordinated associations with the gut microbial ecosystem and endocrine signaling, warranting further investigation into its metabolic toxicity. Download: Download high-res image (288KB) Download: Download full-size image
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高影响因子
Frontiers in Pharmacology
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2026
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IF 5.4
Huichao Pan,Dong Wang,Shengguang Chen,Jun Zhou,Lei Song,Min Zhang
Introduction Bis(2-ethylhexyl)-2,3,4,5-tetrabromophthalate (TBPH) is used as a nonreactive brominated flame retardant used in industrial products, particularly in flexible polyvinyl chloride and rigid and flexible polyurethane foams. Although TBPH exposure poses potential health risks, its association with atherosclerosis remains poorly understood. Methods This study integrated network toxicology, machine learning, molecular docking, and molecular dynamics (MD) simulations to elucidate the influence of TBPH on high-fat diet–induced atherosclerosis. Results TBPH exhibited significant predicted toxicity across multiple organs. In total, 167 potential TBPH targets and 690 atherosclerosis-associated targets were identified, with 108 overlapping targets obtained through intersectional analysis. A PPI network was constructed based on these 108 overlapping genes, and the top 20 hub genes were identified. In a parallel independent analysis using a public transcriptomic dataset, 111 differentially expressed genes (DEGs) were identified by comparing atherosclerotic and normal tissues. Subsequent intersection analysis of the 108 overlapping targets and 111 DEGs identified candidate genes that were both TBPH-related and differentially expressed in atherosclerosis. Public transcriptomic data showed higher matrix metalloproteinase 9 (MMP9) level in atherosclerotic tissues. The corresponding receiver operating characteristic (ROC) curve yielded an AUC of 0.806 (95% confidence interval [CI]: 0.698–0.914). Molecular docking and MD simulations indicated favorable predicted binding modes and computational stability between TBPH and MMP9. In vivo experiments further demonstrated an association between TBPH exposure, increased MMP9 expression, and high–fat diet–induced atherosclerotic lesions. Discussion These findings suggest that TBPH may be associated with high-fat diet–induced atherosclerosis progression through the dysregulation of key mediators, providing insight into environmental pollutant–driven disease development.
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PubMed
高影响因子
ENVIRONMENTAL RESEARCH
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2026
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IF 8.2
Jiawei Yang,Qiong Zhang,Haichen Zhang,Tao Zhou,Lening Chen,Qianqian Xiao,Qinghe Meng,Jianjun Jiang,Weidong Hao,Xuetao Wei
Bis(2-ethylhexyl) tetrabromophthalate (TBPH), an emerging brominated flame retardant, has raised environmental concern due to its endocrine-disrupting potential. While epidemiological evidence and our previous animal studies have linked TBPH to thyroid disruption, the molecular mechanisms remain unclear. This study aimed to identify potential molecular targets and downstream pathways involved in TBPH-induced effects on thyroid. We found that TBPH (100 nM) significantly upregulated the expression of key thyroid hormone synthesis markers PAX-8, TPO, and TG in human thyroid follicular cells (Nthy-ori 3-1). In silico docking identified S1PR3 as a potential interactor with moderate predicted affinity, and cellular thermal shift assay (CETSA) provided initial evidence of target engagement. S1 pr 3 knockdown partially attenuated TBPH-induced marker upregulation. Mechanistically, TBPH increased interleukin-10 (IL-10) in an S1PR3-dependent manner, coupled with activation of a non-canonical JAK-STAT pathway (JAK3, TYK2, STAT2, and STAT5). Further, overexpression of Il-10 enhanced downstream effector expression, whereas overexpression of Jak3 similarly promoted PAX-8 and TPO levels; conversely, Tyk2 knockdown reduced these markers, supporting a functional role for this alternative signaling cascade. Importantly, key elements of this pathway were recapitulated in thyroid tissues of TBPH-treated rats, providing in vivo corroboration for the cellular observations. Collectively, our results suggest a S1PR3/IL-10/non-canonical JAK-STAT axis as a candidate mechanism for TBPH-induced thyroid marker upregulation, providing a hypothesis-generating framework for future toxicological investigations of TBPH and related emerging brominated flame retardants.
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高影响因子
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