Embryonic 6:2 Fluorotelomer Alcohol Exposure Disrupts the Blood‒Brain Barrier by Causing Endothelial‒to‒Mesenchymal Transition in the Male Mice

  • Mol Neurobiol. 2024 Oct 17. doi: 10.1007/s12035-024-04540-7.
Yunhui Xia  1  2 ,  Junhan Chen  1  2 ,  Ping Dong  1  2 ,  Luqing Zhang  1  2 ,  Yibing Ding  2  3 ,  Weidong Ding  1  2 ,  Xiaodong Han  1  2 ,  Xiaojian Wang  4 ,  Dongmei Li  5  6
Affiliations
  • 1. State Key Laboratory of Analytical Chemistry for Life Science, Division of Anatomy and Histo-Embryology, Medical School, Nanjing University, Nanjing, 210093, Jiangsu, China.
  • 2. Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, 210093, Jiangsu, China.
  • 3. Translational Medicine Core Facilities, Medical School, Nanjing University, Nanjing, 210093, Jiangsu, China.
  • 4. Institute of Advanced Synthesis, School of Chemistry and Molecular Engineering, Nanjing Tech University, Nanjing, 211816, Jiangsu, China. [email protected].
  • 5. State Key Laboratory of Analytical Chemistry for Life Science, Division of Anatomy and Histo-Embryology, Medical School, Nanjing University, Nanjing, 210093, Jiangsu, China. [email protected].
  • 6. Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, 210093, Jiangsu, China. [email protected].
PMID: 39417922 DOI: 10.1007/s12035-024-04540-7
Abstract

6:2 Fluorotelomer alcohol (6:2 FTOH) is a raw material used in the manufacture of short-chain poly- and perfluoroalkyl substances. Our previous study revealed that gestational exposure to 6:2 FTOH can impair blood‒brain barrier (BBB) function in offspring, accompanied by anxiety-like behavior and learning memory deficits. The aim of this study was to further investigate the specific mechanism by which maternal exposure to 6:2 FTOH resulted in impaired BBB function in offspring mice. Pregnant mice were orally administered different doses of 6:2 FTOH (0, 5, 25, and 125 mg/kg/day) from gestation day 8.5 until delivery. These results confirmed that maternal 6:2 FTOH exposure impaired BBB function and disrupted the brain immune microenvironment. Subsequent investigations revealed that endothelial-to-mesenchymal transition (EndMT) in the cerebral microvascular endothelium of offspring may be the mechanism mediating functional disruption of the BBB. Mechanistic studies revealed that exposure to 6:2 FTOH upregulated ETS proto-oncogene 1 (ETS1) expression via the tumor necrosis factor-α/extracellular signal-regulated kinase 1/2 signaling pathway, which mediated disturbances in energy metabolism, leading to impaired actin dynamics and subsequently triggering the EndMT phenotype. This is the first finding indicating that gestational 6:2 FTOH exposure caused functional impairment of the BBB through ETS1-mediated EndMT in cerebral microvascular endothelial cells, potentially providing novel insight into the environmental origins of neurodevelopmental disorders.

Keywords
6:2 Fluorotelomer alcohol; Actin dynamics; Blood–brain barrier; Cerebral microvascular endothelial cells; Endothelial mesenchymal transition; Mitochondrial metabolism.
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