Maternal phthalates exposure promotes neural stem cell differentiation into phagocytic astrocytes and synapse engulfment via IRE1α/XBP1s pathway
Summary: Humans are widely exposed to phthalates, a common chemical plasticizer. Previous cohort studies have revealed that maternal exposure to monobutyl phthalate (MBP), a key metabolite of phthalates, is associated with neurodevelopmental defects. However, the molecular mechanism remains unclear....
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| Format: | Article |
| Language: | English |
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Elsevier
2025-01-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124724014773 |
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| author | Fengzhen Cui Shiyu Deng Yan Fu Tongtong Xu Shuangshuang Bao Siyi Wang Yahang Lin Xianghui Wang Faming Zhao Tingting Zhang Shunqing Xu Zhijun Zhang Wanlu Li Guo-Yuan Yang Huanwen Tang Jixian Wang Xia Sheng Yaohui Tang |
| author_facet | Fengzhen Cui Shiyu Deng Yan Fu Tongtong Xu Shuangshuang Bao Siyi Wang Yahang Lin Xianghui Wang Faming Zhao Tingting Zhang Shunqing Xu Zhijun Zhang Wanlu Li Guo-Yuan Yang Huanwen Tang Jixian Wang Xia Sheng Yaohui Tang |
| author_sort | Fengzhen Cui |
| collection | DOAJ |
| description | Summary: Humans are widely exposed to phthalates, a common chemical plasticizer. Previous cohort studies have revealed that maternal exposure to monobutyl phthalate (MBP), a key metabolite of phthalates, is associated with neurodevelopmental defects. However, the molecular mechanism remains unclear. Here, we demonstrate that maternal exposure to MBP enhances neural stem cell (NSC) differentiation into astrocytes with highly expressed C3 and LCN2 in mouse offspring, resulting in increased synapse phagocytosis and cognitive dysfunction. Mechanistically, we find that MBP exposure activates the IRE1α/XBP1s (spliced XBP1) stress response pathway, which regulates key genes involved in astrocyte differentiation (SOX9 and ATF3) and reactivity (C3 and LCN2). Conditional knockout or pharmacological inhibition of IRE1α markedly inhibits NSC differentiation into astrocytes and astrocyte reactivity, attenuates synapse phagocytosis, and improves cognitive function. This phenotype is further recapitulated in a human brain organoid model. Together, these findings unveil the molecular mechanism underlying the neurodevelopmental deficits caused by a widespread environmental pollutant. |
| format | Article |
| id | doaj-art-414e205796ce406099a7a11aeb5dd753 |
| institution | Kabale University |
| issn | 2211-1247 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj-art-414e205796ce406099a7a11aeb5dd7532025-01-03T04:08:38ZengElsevierCell Reports2211-12472025-01-01441115126Maternal phthalates exposure promotes neural stem cell differentiation into phagocytic astrocytes and synapse engulfment via IRE1α/XBP1s pathwayFengzhen Cui0Shiyu Deng1Yan Fu2Tongtong Xu3Shuangshuang Bao4Siyi Wang5Yahang Lin6Xianghui Wang7Faming Zhao8Tingting Zhang9Shunqing Xu10Zhijun Zhang11Wanlu Li12Guo-Yuan Yang13Huanwen Tang14Jixian Wang15Xia Sheng16Yaohui Tang17Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200031, China; School of Public Health, Guangdong Medical University, Dongguan 523808, ChinaShanghai Jiao Tong University Affiliated Sixth People’s Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200031, ChinaShanghai Jiao Tong University Affiliated Sixth People’s Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200031, ChinaShanghai Jiao Tong University Affiliated Sixth People’s Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200031, ChinaMOE Key Laboratory of Population Health Across Life Cycle, Anhui Medical University, Hefei 230032, ChinaDepartment of Neurology, Wuhan Fourth Hospital, Wuhan 430033, ChinaDepartment of Neurology, Wuhan Fourth Hospital, Wuhan 430033, ChinaDepartment of Environmental Health, School of Environmental Science and Engineering, Hainan University, Haikou 570228, ChinaSchool of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, ChinaSchool of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, ChinaDepartment of Environmental Health, School of Environmental Science and Engineering, Hainan University, Haikou 570228, ChinaShanghai Jiao Tong University Affiliated Sixth People’s Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200031, ChinaShanghai Jiao Tong University Affiliated Sixth People’s Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200031, ChinaShanghai Jiao Tong University Affiliated Sixth People’s Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200031, ChinaSchool of Public Health, Guangdong Medical University, Dongguan 523808, ChinaDepartment of Rehabilitation, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China; Corresponding authorDepartment of Environmental Health, School of Environmental Science and Engineering, Hainan University, Haikou 570228, China; School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Corresponding authorShanghai Jiao Tong University Affiliated Sixth People’s Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200031, China; Corresponding authorSummary: Humans are widely exposed to phthalates, a common chemical plasticizer. Previous cohort studies have revealed that maternal exposure to monobutyl phthalate (MBP), a key metabolite of phthalates, is associated with neurodevelopmental defects. However, the molecular mechanism remains unclear. Here, we demonstrate that maternal exposure to MBP enhances neural stem cell (NSC) differentiation into astrocytes with highly expressed C3 and LCN2 in mouse offspring, resulting in increased synapse phagocytosis and cognitive dysfunction. Mechanistically, we find that MBP exposure activates the IRE1α/XBP1s (spliced XBP1) stress response pathway, which regulates key genes involved in astrocyte differentiation (SOX9 and ATF3) and reactivity (C3 and LCN2). Conditional knockout or pharmacological inhibition of IRE1α markedly inhibits NSC differentiation into astrocytes and astrocyte reactivity, attenuates synapse phagocytosis, and improves cognitive function. This phenotype is further recapitulated in a human brain organoid model. Together, these findings unveil the molecular mechanism underlying the neurodevelopmental deficits caused by a widespread environmental pollutant.http://www.sciencedirect.com/science/article/pii/S2211124724014773CP: NeuroscienceCP: Stem cell research |
| spellingShingle | Fengzhen Cui Shiyu Deng Yan Fu Tongtong Xu Shuangshuang Bao Siyi Wang Yahang Lin Xianghui Wang Faming Zhao Tingting Zhang Shunqing Xu Zhijun Zhang Wanlu Li Guo-Yuan Yang Huanwen Tang Jixian Wang Xia Sheng Yaohui Tang Maternal phthalates exposure promotes neural stem cell differentiation into phagocytic astrocytes and synapse engulfment via IRE1α/XBP1s pathway Cell Reports CP: Neuroscience CP: Stem cell research |
| title | Maternal phthalates exposure promotes neural stem cell differentiation into phagocytic astrocytes and synapse engulfment via IRE1α/XBP1s pathway |
| title_full | Maternal phthalates exposure promotes neural stem cell differentiation into phagocytic astrocytes and synapse engulfment via IRE1α/XBP1s pathway |
| title_fullStr | Maternal phthalates exposure promotes neural stem cell differentiation into phagocytic astrocytes and synapse engulfment via IRE1α/XBP1s pathway |
| title_full_unstemmed | Maternal phthalates exposure promotes neural stem cell differentiation into phagocytic astrocytes and synapse engulfment via IRE1α/XBP1s pathway |
| title_short | Maternal phthalates exposure promotes neural stem cell differentiation into phagocytic astrocytes and synapse engulfment via IRE1α/XBP1s pathway |
| title_sort | maternal phthalates exposure promotes neural stem cell differentiation into phagocytic astrocytes and synapse engulfment via ire1α xbp1s pathway |
| topic | CP: Neuroscience CP: Stem cell research |
| url | http://www.sciencedirect.com/science/article/pii/S2211124724014773 |
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