Involvement of TMAO in exacerbating arsenic-induced neurotoxicity by activating the PERK/eIF2α/ATF4 pathway
Arsenic (As), a widely recognized environmental pollutant, has been implicated in the pathogenesis of various neuropsychiatric disorders, including anxiety and depression. Trimethylamine N-oxide (TMAO), a microbiota-host co-metabolite derived from dietary quaternary amines (e.g., choline), has been...
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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/S014765132501036X |
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| author | Hong Zhang Kai Ren Xiaoting Ni Liwang Lin Longyu Li Wenlei Zhang Zengliang Gao Shiao Ren Lili Fan Xin Hai |
| author_facet | Hong Zhang Kai Ren Xiaoting Ni Liwang Lin Longyu Li Wenlei Zhang Zengliang Gao Shiao Ren Lili Fan Xin Hai |
| author_sort | Hong Zhang |
| collection | DOAJ |
| description | Arsenic (As), a widely recognized environmental pollutant, has been implicated in the pathogenesis of various neuropsychiatric disorders, including anxiety and depression. Trimethylamine N-oxide (TMAO), a microbiota-host co-metabolite derived from dietary quaternary amines (e.g., choline), has been associated with the progression of multiple neurological disorders. This study demonstrates that the gut microbiota-derived metabolite TMAO potentiates As-induced neurotoxicity. Using network toxicology, we identified genes targeted by As and TMAO in depression, revealing significant enrichment in pathways related to apoptosis, ferroptosis, and endoplasmic reticulum (ER) stress. In C57BL/6 mice, a high-choline diet exacerbated As-induced depressive behaviors, hippocampal damage, and astrocyte depletion, which were mediated by elevated TMAO levels. High-performance liquid chromatography-hydride generation-atomic fluorescence spectrometry (HPLC-HG-AFS) analysis confirmed that TMAO enhanced arsenic accumulation in plasma and brain tissues. In vitro experiments further demonstrated that TMAO exacerbated As-induced oxidative stress, DNA damage, mitochondrial dysfunction, apoptosis, and ferroptosis. Mechanistically, TMAO upregulated the ER stress PERK/eIF2α/ATF4 signaling pathway in response to As exposure. Knockdown of PERK attenuated As- and TMAO-mediated apoptosis and ferroptosis in cultured cells. Collectively, these findings indicate that dietary choline exacerbates arsenic-induced depressive-like phenotypes by increasing TMAO levels and activating the PERK/eIF2α/ATF4 signaling pathway. |
| format | Article |
| id | doaj-art-4979673fbe214e2ca03cbcf99e8da215 |
| institution | DOAJ |
| issn | 0147-6513 |
| language | English |
| publishDate | 2025-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Ecotoxicology and Environmental Safety |
| spelling | doaj-art-4979673fbe214e2ca03cbcf99e8da2152025-08-20T03:03:53ZengElsevierEcotoxicology and Environmental Safety0147-65132025-09-0130211869110.1016/j.ecoenv.2025.118691Involvement of TMAO in exacerbating arsenic-induced neurotoxicity by activating the PERK/eIF2α/ATF4 pathwayHong Zhang0Kai Ren1Xiaoting Ni2Liwang Lin3Longyu Li4Wenlei Zhang5Zengliang Gao6Shiao Ren7Lili Fan8Xin Hai9Department of Pharmacy, First Affiliated Hospital of Harbin Medical University, 23 YouZheng Str, Nangang District, Harbin, ChinaDepartment of Pharmacy, First Affiliated Hospital of Harbin Medical University, 23 YouZheng Str, Nangang District, Harbin, ChinaDepartment of Pharmacy, First Affiliated Hospital of Harbin Medical University, 23 YouZheng Str, Nangang District, Harbin, ChinaDepartment of Pharmacy, First Affiliated Hospital of Harbin Medical University, 23 YouZheng Str, Nangang District, Harbin, ChinaDepartment of Pharmacy, First Affiliated Hospital of Harbin Medical University, 23 YouZheng Str, Nangang District, Harbin, ChinaDepartment of Pharmacy, First Affiliated Hospital of Harbin Medical University, 23 YouZheng Str, Nangang District, Harbin, ChinaDepartment of Pharmacy, First Affiliated Hospital of Harbin Medical University, 23 YouZheng Str, Nangang District, Harbin, ChinaDepartment of Pharmacy, First Affiliated Hospital of Harbin Medical University, 23 YouZheng Str, Nangang District, Harbin, ChinaDepartment of Children’s and Adolescent Health, Public Health College, Harbin Medical University, Harbin, ChinaDepartment of Pharmacy, First Affiliated Hospital of Harbin Medical University, 23 YouZheng Str, Nangang District, Harbin, China; Correspondence to: Department of Pharmacy, First Affiliated Hospital of Harbin Medical University, Harbin Medical University, 23 Youzheng Street, Nangang District, Harbin 150001, China.Arsenic (As), a widely recognized environmental pollutant, has been implicated in the pathogenesis of various neuropsychiatric disorders, including anxiety and depression. Trimethylamine N-oxide (TMAO), a microbiota-host co-metabolite derived from dietary quaternary amines (e.g., choline), has been associated with the progression of multiple neurological disorders. This study demonstrates that the gut microbiota-derived metabolite TMAO potentiates As-induced neurotoxicity. Using network toxicology, we identified genes targeted by As and TMAO in depression, revealing significant enrichment in pathways related to apoptosis, ferroptosis, and endoplasmic reticulum (ER) stress. In C57BL/6 mice, a high-choline diet exacerbated As-induced depressive behaviors, hippocampal damage, and astrocyte depletion, which were mediated by elevated TMAO levels. High-performance liquid chromatography-hydride generation-atomic fluorescence spectrometry (HPLC-HG-AFS) analysis confirmed that TMAO enhanced arsenic accumulation in plasma and brain tissues. In vitro experiments further demonstrated that TMAO exacerbated As-induced oxidative stress, DNA damage, mitochondrial dysfunction, apoptosis, and ferroptosis. Mechanistically, TMAO upregulated the ER stress PERK/eIF2α/ATF4 signaling pathway in response to As exposure. Knockdown of PERK attenuated As- and TMAO-mediated apoptosis and ferroptosis in cultured cells. Collectively, these findings indicate that dietary choline exacerbates arsenic-induced depressive-like phenotypes by increasing TMAO levels and activating the PERK/eIF2α/ATF4 signaling pathway.http://www.sciencedirect.com/science/article/pii/S014765132501036XTrimethylamine N-oxideArsenicNeurotoxicityDepressionPERK/eIF2α/ATF4 |
| spellingShingle | Hong Zhang Kai Ren Xiaoting Ni Liwang Lin Longyu Li Wenlei Zhang Zengliang Gao Shiao Ren Lili Fan Xin Hai Involvement of TMAO in exacerbating arsenic-induced neurotoxicity by activating the PERK/eIF2α/ATF4 pathway Ecotoxicology and Environmental Safety Trimethylamine N-oxide Arsenic Neurotoxicity Depression PERK/eIF2α/ATF4 |
| title | Involvement of TMAO in exacerbating arsenic-induced neurotoxicity by activating the PERK/eIF2α/ATF4 pathway |
| title_full | Involvement of TMAO in exacerbating arsenic-induced neurotoxicity by activating the PERK/eIF2α/ATF4 pathway |
| title_fullStr | Involvement of TMAO in exacerbating arsenic-induced neurotoxicity by activating the PERK/eIF2α/ATF4 pathway |
| title_full_unstemmed | Involvement of TMAO in exacerbating arsenic-induced neurotoxicity by activating the PERK/eIF2α/ATF4 pathway |
| title_short | Involvement of TMAO in exacerbating arsenic-induced neurotoxicity by activating the PERK/eIF2α/ATF4 pathway |
| title_sort | involvement of tmao in exacerbating arsenic induced neurotoxicity by activating the perk eif2α atf4 pathway |
| topic | Trimethylamine N-oxide Arsenic Neurotoxicity Depression PERK/eIF2α/ATF4 |
| url | http://www.sciencedirect.com/science/article/pii/S014765132501036X |
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