Maternal phthalates exposure promotes neural stem cell differentiation into phagocytic astrocytes and synapse engulfment via IRE1α/XBP1s pathway

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

doi:10.1016/j.celrep.2024.115126

Maternal phthalates exposure promotes neural stem cell differentiation into phagocytic astrocytes and synapse engulfment via IRE1α/XBP1s pathway

Cell Rep. 2025 Jan 2;44(1):115126. doi: 10.1016/j.celrep.2024.115126. Online ahead of print.

Authors

Fengzhen Cui¹, Shiyu Deng², Yan Fu², Tongtong Xu², Shuangshuang Bao³, Siyi Wang⁴, Yahang Lin⁴, Xianghui Wang⁵, Faming Zhao⁶, Tingting Zhang⁶, Shunqing Xu⁵, Zhijun Zhang², Wanlu Li², Guo-Yuan Yang², Huanwen Tang⁷, Jixian Wang⁸, Xia Sheng⁹, Yaohui Tang¹⁰

Affiliations

¹ Shanghai 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, China.
² Shanghai Jiao Tong University Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200031, China.
³ MOE Key Laboratory of Population Health Across Life Cycle, Anhui Medical University, Hefei 230032, China.
⁴ Department of Neurology, Wuhan Fourth Hospital, Wuhan 430033, China.
⁵ Department of Environmental Health, School of Environmental Science and Engineering, Hainan University, Haikou 570228, China.
⁶ School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
⁷ School of Public Health, Guangdong Medical University, Dongguan 523808, China.
⁸ Department of Rehabilitation, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China. Electronic address: [email protected].
⁹ Department 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. Electronic address: [email protected].
¹⁰ Shanghai Jiao Tong University Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200031, China. Electronic address: [email protected].

PMID: 39752254
DOI: 10.1016/j.celrep.2024.115126

Abstract

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.

Keywords: CP: Neuroscience; CP: Stem cell research; XBP1s; monobutyl phthalate; neural stem cells; neurodevelopmental deficit; reactive astrocyte; synapse phagocytosis.