2, 2′, 4, 4′-tetrabromodiphenyl ether induces thyroid toxicity by targeting BRAF-mediated MEK-ERK-NIS pathway in human thyroid follicular epithelial cells
2, 2’, 4, 4’-tetrabromodiphenyl ether (BDE-47), one of the most abundant and toxic congeners of polybrominated diphenyl ethers (PBDEs), has been implicated in thyroid disorders, but its thyroid toxicity in human thyroid cells and underlying mechanisms remain unclear. Given the pivotal role of the V-...
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Elsevier
2025-09-01
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| Series: | Ecotoxicology and Environmental Safety |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0147651325009224 |
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| author | Guangshan Xie Jinping Lu Jiayi Song Jianqing Zhang |
| author_facet | Guangshan Xie Jinping Lu Jiayi Song Jianqing Zhang |
| author_sort | Guangshan Xie |
| collection | DOAJ |
| description | 2, 2’, 4, 4’-tetrabromodiphenyl ether (BDE-47), one of the most abundant and toxic congeners of polybrominated diphenyl ethers (PBDEs), has been implicated in thyroid disorders, but its thyroid toxicity in human thyroid cells and underlying mechanisms remain unclear. Given the pivotal role of the V-Raf murine sarcoma viral oncogene homolog B (BRAF) and the downstream mitogen-activated protein kinase kinase (MEK)- signal-regulated kinase (ERK) pathway in cell proliferation, differentiation, cell cycle and thyroid functions, in this study, we constructed BRAF knockout (BRAF-KO) and overexpression (BRAF-OE) cell models using Nthy-ori 3-1 cells, to evaluate the effect of BDE-47 on human thyroid cells and explore the potential mechanisms. Our results showed that exposure to BDE-47 resulted in reduced cell viability, Gap 2 (G2)/mitosis (M) phase cell cycle arrest, enhanced cell migration, and decreased cell invasion. BRAF overexpression significantly exacerbated BDE-47-triggered cell cycle arrest and cell migration but alleviated its suppression of invasion, while BRAF knockout showed no significant effects, underscoring the crucial role of BRAF in BDE-47-induced cytotoxicity. Moreover, BRAF overexpression amplified BDE-47-triggered upregulation of phosphorylated MEK1/2 and ERK1/2 downregulation of sodium-iodide symporter (NIS), a well-known indicator of cellular iodine uptake. Molecular docking further indicated that BDE-47 likely activated the MEK-ERK- NIS signal cascade by directly binding to BRAF. This study demonstrated for the first time that BDE-47 led to reduced cell proliferation, cell cycle arrest, altered migration and invasion, and impaired iodine uptake through targeted activation of the BRAF-MEK-ERK signaling pathway. These findings elucidated a novel mechanism of BDE-47-induced thyroid toxicity, highlighting BRAF as a critical mediator for PBDEs-related thyroid dysfunction, offering insights for targeted interventions. |
| format | Article |
| id | doaj-art-9e888b5cb9b8475bbafea8ef6024f147 |
| institution | Kabale University |
| issn | 0147-6513 |
| language | English |
| publishDate | 2025-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Ecotoxicology and Environmental Safety |
| spelling | doaj-art-9e888b5cb9b8475bbafea8ef6024f1472025-08-20T03:41:50ZengElsevierEcotoxicology and Environmental Safety0147-65132025-09-0130211857710.1016/j.ecoenv.2025.1185772, 2′, 4, 4′-tetrabromodiphenyl ether induces thyroid toxicity by targeting BRAF-mediated MEK-ERK-NIS pathway in human thyroid follicular epithelial cellsGuangshan Xie0Jinping Lu1Jiayi Song2Jianqing Zhang3Department of POPs Lab, Shenzhen Center for Disease Control and Prevention, Shenzhen, Guangdong 518055, PR ChinaDepartment of POPs Lab, Shenzhen Center for Disease Control and Prevention, Shenzhen, Guangdong 518055, PR ChinaDepartment of POPs Lab, Shenzhen Center for Disease Control and Prevention, Shenzhen, Guangdong 518055, PR ChinaCorrespondence to: Department of POPs Lab, Shenzhen Center for Disease Control and Prevention, No.8, Longyuan Road, Longzhu Avenue, Nanshan District, Shenzhen, Guangdong 518055, PR China.; Department of POPs Lab, Shenzhen Center for Disease Control and Prevention, Shenzhen, Guangdong 518055, PR China2, 2’, 4, 4’-tetrabromodiphenyl ether (BDE-47), one of the most abundant and toxic congeners of polybrominated diphenyl ethers (PBDEs), has been implicated in thyroid disorders, but its thyroid toxicity in human thyroid cells and underlying mechanisms remain unclear. Given the pivotal role of the V-Raf murine sarcoma viral oncogene homolog B (BRAF) and the downstream mitogen-activated protein kinase kinase (MEK)- signal-regulated kinase (ERK) pathway in cell proliferation, differentiation, cell cycle and thyroid functions, in this study, we constructed BRAF knockout (BRAF-KO) and overexpression (BRAF-OE) cell models using Nthy-ori 3-1 cells, to evaluate the effect of BDE-47 on human thyroid cells and explore the potential mechanisms. Our results showed that exposure to BDE-47 resulted in reduced cell viability, Gap 2 (G2)/mitosis (M) phase cell cycle arrest, enhanced cell migration, and decreased cell invasion. BRAF overexpression significantly exacerbated BDE-47-triggered cell cycle arrest and cell migration but alleviated its suppression of invasion, while BRAF knockout showed no significant effects, underscoring the crucial role of BRAF in BDE-47-induced cytotoxicity. Moreover, BRAF overexpression amplified BDE-47-triggered upregulation of phosphorylated MEK1/2 and ERK1/2 downregulation of sodium-iodide symporter (NIS), a well-known indicator of cellular iodine uptake. Molecular docking further indicated that BDE-47 likely activated the MEK-ERK- NIS signal cascade by directly binding to BRAF. This study demonstrated for the first time that BDE-47 led to reduced cell proliferation, cell cycle arrest, altered migration and invasion, and impaired iodine uptake through targeted activation of the BRAF-MEK-ERK signaling pathway. These findings elucidated a novel mechanism of BDE-47-induced thyroid toxicity, highlighting BRAF as a critical mediator for PBDEs-related thyroid dysfunction, offering insights for targeted interventions.http://www.sciencedirect.com/science/article/pii/S0147651325009224BDE-47Thyroid toxicityBRAFMEK-ERK signaling pathwayHuman thyroid cell |
| spellingShingle | Guangshan Xie Jinping Lu Jiayi Song Jianqing Zhang 2, 2′, 4, 4′-tetrabromodiphenyl ether induces thyroid toxicity by targeting BRAF-mediated MEK-ERK-NIS pathway in human thyroid follicular epithelial cells Ecotoxicology and Environmental Safety BDE-47 Thyroid toxicity BRAF MEK-ERK signaling pathway Human thyroid cell |
| title | 2, 2′, 4, 4′-tetrabromodiphenyl ether induces thyroid toxicity by targeting BRAF-mediated MEK-ERK-NIS pathway in human thyroid follicular epithelial cells |
| title_full | 2, 2′, 4, 4′-tetrabromodiphenyl ether induces thyroid toxicity by targeting BRAF-mediated MEK-ERK-NIS pathway in human thyroid follicular epithelial cells |
| title_fullStr | 2, 2′, 4, 4′-tetrabromodiphenyl ether induces thyroid toxicity by targeting BRAF-mediated MEK-ERK-NIS pathway in human thyroid follicular epithelial cells |
| title_full_unstemmed | 2, 2′, 4, 4′-tetrabromodiphenyl ether induces thyroid toxicity by targeting BRAF-mediated MEK-ERK-NIS pathway in human thyroid follicular epithelial cells |
| title_short | 2, 2′, 4, 4′-tetrabromodiphenyl ether induces thyroid toxicity by targeting BRAF-mediated MEK-ERK-NIS pathway in human thyroid follicular epithelial cells |
| title_sort | 2 2 4 4 tetrabromodiphenyl ether induces thyroid toxicity by targeting braf mediated mek erk nis pathway in human thyroid follicular epithelial cells |
| topic | BDE-47 Thyroid toxicity BRAF MEK-ERK signaling pathway Human thyroid cell |
| url | http://www.sciencedirect.com/science/article/pii/S0147651325009224 |
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