ATF4 participates in perfluorooctane sulfonate-induced neurotoxicity by regulating ferroptosis
Evidence from animal and human research suggests that perfluorooctane sulfonate (PFOS), a prevalent persistent organic pollutant (POP), exerts neurotoxic effects, but the precise mechanisms remain unclear. Additionally, the function of activating transcription factor 4 (ATF4), a crucial modulator of...
Saved in:
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-07-01
|
| Series: | Ecotoxicology and Environmental Safety |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0147651325006396 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850231801072582656 |
|---|---|
| author | Fangling Zhu Nan Wang Yichao Xu Xiaohua Su Ziliang Deng Yongdui Ruan Daifan Lin Yun Chen Zhuoni Kuang Guanlin Chen Chengcheng Yu Xiaoxuan Ling Linhua Liu |
| author_facet | Fangling Zhu Nan Wang Yichao Xu Xiaohua Su Ziliang Deng Yongdui Ruan Daifan Lin Yun Chen Zhuoni Kuang Guanlin Chen Chengcheng Yu Xiaoxuan Ling Linhua Liu |
| author_sort | Fangling Zhu |
| collection | DOAJ |
| description | Evidence from animal and human research suggests that perfluorooctane sulfonate (PFOS), a prevalent persistent organic pollutant (POP), exerts neurotoxic effects, but the precise mechanisms remain unclear. Additionally, the function of activating transcription factor 4 (ATF4), a crucial modulator of cellular metabolism, redox balance, and survival, in PFOS-induced neurotoxicity has not been fully elucidated. In vitro metabolomics studies revealed that PFOS elevated the intracellular concentration of reactive oxygen species (ROS) and lowered the levels of reduced L-glutathione (GSH). Significant alterations in the mRNA and protein expression levels of ferroptosis-related biomarkers, including ferroptosis-related genes [NRF2, nuclear receptor coactivator 4 (NCOA4), KEAP1, xCT/SLC7A11, GPX4, and FTH1], cellular iron, and lipid peroxidation were observed. Moreover, erastin (Ers) exacerbated lipid peroxidation, which was alleviated by ferrostatin-1 (Fer-1) and N-acetyl-L-cysteine (NAC). In mice, PFOS exposure damaged the structure and function of the hippocampus, including decreasing the number of neurons and impairing spatial learning and memory capacity. Importantly, ferroptosis was also observed in vivo, concomitant with the inhibition of ATF4, which was also observed in vitro. ATF4 silencing further increased ROS levels, lipid peroxidation, and ferroptosis induced by PFOS, whereas NAC and Fer-1 abrogated the effects of ATF4 silencing. Treatment with E235, an ATF4 activator, alleviated PFOS-induced ferroptosis. In conclusion, this study revealed that ATF4-mediated ferroptosis is involved in PFOS-induced neurotoxicity, offering novel mechanistic insights into the neurotoxic effects of PFOS and potentially paving the way for new therapeutic strategies. |
| format | Article |
| id | doaj-art-a9843be0d48549c3988f7520b0ac2a48 |
| institution | OA Journals |
| issn | 0147-6513 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Ecotoxicology and Environmental Safety |
| spelling | doaj-art-a9843be0d48549c3988f7520b0ac2a482025-08-20T02:03:25ZengElsevierEcotoxicology and Environmental Safety0147-65132025-07-0129911830310.1016/j.ecoenv.2025.118303ATF4 participates in perfluorooctane sulfonate-induced neurotoxicity by regulating ferroptosisFangling Zhu0Nan Wang1Yichao Xu2Xiaohua Su3Ziliang Deng4Yongdui Ruan5Daifan Lin6Yun Chen7Zhuoni Kuang8Guanlin Chen9Chengcheng Yu10Xiaoxuan Ling11Linhua Liu12Dongguan Key Laboratory of Environmental Medicine, The First Dongguan Affiliated Hospital, School of Public Health, Guangdong Medical University, Dongguan, Guangdong Province 523808, PR China; Department of Preventive Medicine, School of Public Health, Guangdong Medical University, Dongguan, Guangdong Province 523808, PR ChinaDongguan Key Laboratory of Environmental Medicine, The First Dongguan Affiliated Hospital, School of Public Health, Guangdong Medical University, Dongguan, Guangdong Province 523808, PR ChinaDongguan Key Laboratory of Environmental Medicine, The First Dongguan Affiliated Hospital, School of Public Health, Guangdong Medical University, Dongguan, Guangdong Province 523808, PR ChinaLaboratory Animal Center, Guangdong Medical University, Dongguan 523808, PR ChinaDepartment of Histology and Embryology of the Basic Medical College, Guangdong Medical University, Dongguan, Guangdong Province 523808, PR ChinaDongguan Key Laboratory of Environmental Medicine, The First Dongguan Affiliated Hospital, School of Public Health, Guangdong Medical University, Dongguan, Guangdong Province 523808, PR ChinaDongguan Key Laboratory of Environmental Medicine, The First Dongguan Affiliated Hospital, School of Public Health, Guangdong Medical University, Dongguan, Guangdong Province 523808, PR ChinaOccupational Health Monitoring, Foshan Institute of Occupational Disease Prevention and Control (Foshan Institute of Occupational Health), Foshan 528000, PR ChinaOccupational Health Monitoring, Foshan Institute of Occupational Disease Prevention and Control (Foshan Institute of Occupational Health), Foshan 528000, PR ChinaOccupational Health Monitoring, Foshan Institute of Occupational Disease Prevention and Control (Foshan Institute of Occupational Health), Foshan 528000, PR ChinaHealth Surveillance Department, Foshan Institute of Occupational Disease Prevention and Control (Foshan Institute of Occupational Health), Foshan 528000, PR ChinaDongguan Key Laboratory of Environmental Medicine, The First Dongguan Affiliated Hospital, School of Public Health, Guangdong Medical University, Dongguan, Guangdong Province 523808, PR China; Experimental Teaching Center, School of Public Health, Guangdong Medical University, Dongguan, Guangdong Province 523808, PR China; Corresponding authors at: Dongguan Key Laboratory of Environmental Medicine, The First Dongguan Affiliated Hospital, School of Public Health, Guangdong Medical University, Dongguan, Guangdong Province 523808, PR China.Dongguan Key Laboratory of Environmental Medicine, The First Dongguan Affiliated Hospital, School of Public Health, Guangdong Medical University, Dongguan, Guangdong Province 523808, PR China; Department of Preventive Medicine, School of Public Health, Guangdong Medical University, Dongguan, Guangdong Province 523808, PR China; Corresponding authors at: Dongguan Key Laboratory of Environmental Medicine, The First Dongguan Affiliated Hospital, School of Public Health, Guangdong Medical University, Dongguan, Guangdong Province 523808, PR China.Evidence from animal and human research suggests that perfluorooctane sulfonate (PFOS), a prevalent persistent organic pollutant (POP), exerts neurotoxic effects, but the precise mechanisms remain unclear. Additionally, the function of activating transcription factor 4 (ATF4), a crucial modulator of cellular metabolism, redox balance, and survival, in PFOS-induced neurotoxicity has not been fully elucidated. In vitro metabolomics studies revealed that PFOS elevated the intracellular concentration of reactive oxygen species (ROS) and lowered the levels of reduced L-glutathione (GSH). Significant alterations in the mRNA and protein expression levels of ferroptosis-related biomarkers, including ferroptosis-related genes [NRF2, nuclear receptor coactivator 4 (NCOA4), KEAP1, xCT/SLC7A11, GPX4, and FTH1], cellular iron, and lipid peroxidation were observed. Moreover, erastin (Ers) exacerbated lipid peroxidation, which was alleviated by ferrostatin-1 (Fer-1) and N-acetyl-L-cysteine (NAC). In mice, PFOS exposure damaged the structure and function of the hippocampus, including decreasing the number of neurons and impairing spatial learning and memory capacity. Importantly, ferroptosis was also observed in vivo, concomitant with the inhibition of ATF4, which was also observed in vitro. ATF4 silencing further increased ROS levels, lipid peroxidation, and ferroptosis induced by PFOS, whereas NAC and Fer-1 abrogated the effects of ATF4 silencing. Treatment with E235, an ATF4 activator, alleviated PFOS-induced ferroptosis. In conclusion, this study revealed that ATF4-mediated ferroptosis is involved in PFOS-induced neurotoxicity, offering novel mechanistic insights into the neurotoxic effects of PFOS and potentially paving the way for new therapeutic strategies.http://www.sciencedirect.com/science/article/pii/S0147651325006396ATF4PFOSferroptosisimpaired learning and memory abilities |
| spellingShingle | Fangling Zhu Nan Wang Yichao Xu Xiaohua Su Ziliang Deng Yongdui Ruan Daifan Lin Yun Chen Zhuoni Kuang Guanlin Chen Chengcheng Yu Xiaoxuan Ling Linhua Liu ATF4 participates in perfluorooctane sulfonate-induced neurotoxicity by regulating ferroptosis Ecotoxicology and Environmental Safety ATF4 PFOS ferroptosis impaired learning and memory abilities |
| title | ATF4 participates in perfluorooctane sulfonate-induced neurotoxicity by regulating ferroptosis |
| title_full | ATF4 participates in perfluorooctane sulfonate-induced neurotoxicity by regulating ferroptosis |
| title_fullStr | ATF4 participates in perfluorooctane sulfonate-induced neurotoxicity by regulating ferroptosis |
| title_full_unstemmed | ATF4 participates in perfluorooctane sulfonate-induced neurotoxicity by regulating ferroptosis |
| title_short | ATF4 participates in perfluorooctane sulfonate-induced neurotoxicity by regulating ferroptosis |
| title_sort | atf4 participates in perfluorooctane sulfonate induced neurotoxicity by regulating ferroptosis |
| topic | ATF4 PFOS ferroptosis impaired learning and memory abilities |
| url | http://www.sciencedirect.com/science/article/pii/S0147651325006396 |
| work_keys_str_mv | AT fanglingzhu atf4participatesinperfluorooctanesulfonateinducedneurotoxicitybyregulatingferroptosis AT nanwang atf4participatesinperfluorooctanesulfonateinducedneurotoxicitybyregulatingferroptosis AT yichaoxu atf4participatesinperfluorooctanesulfonateinducedneurotoxicitybyregulatingferroptosis AT xiaohuasu atf4participatesinperfluorooctanesulfonateinducedneurotoxicitybyregulatingferroptosis AT ziliangdeng atf4participatesinperfluorooctanesulfonateinducedneurotoxicitybyregulatingferroptosis AT yongduiruan atf4participatesinperfluorooctanesulfonateinducedneurotoxicitybyregulatingferroptosis AT daifanlin atf4participatesinperfluorooctanesulfonateinducedneurotoxicitybyregulatingferroptosis AT yunchen atf4participatesinperfluorooctanesulfonateinducedneurotoxicitybyregulatingferroptosis AT zhuonikuang atf4participatesinperfluorooctanesulfonateinducedneurotoxicitybyregulatingferroptosis AT guanlinchen atf4participatesinperfluorooctanesulfonateinducedneurotoxicitybyregulatingferroptosis AT chengchengyu atf4participatesinperfluorooctanesulfonateinducedneurotoxicitybyregulatingferroptosis AT xiaoxuanling atf4participatesinperfluorooctanesulfonateinducedneurotoxicitybyregulatingferroptosis AT linhualiu atf4participatesinperfluorooctanesulfonateinducedneurotoxicitybyregulatingferroptosis |