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Perfluorinated iodine alkanes promote the differentiation of mouse embryonic stem cells by regulating estrogen receptor signaling

Guibin Jiang , Zhihua Ren , Xiaoxi Yang , Tingting Ku , Qian S. Liu , Jiefeng Liang , Qunfang Zhou , Francesco Faiola


Received October 23, 2022,Revised , Accepted February 13, 2023, Available online February 20, 2023

Volume 36,2024,Pages 443-454

Investigating the development toxicity of perfluorinated iodine alkanes (PFIs) is critical, given their estrogenic effects through binding with estrogen receptors (ERs). In the present study, two PFIs, including dodecafluoro-1,6-diiodohexane (PFHxDI) and tridecafluorohexyl iodide (PFHxI), with binding preference to ERα and ERβ, respectively, were selected to evaluate their effects on proliferation and differentiation of the mouse embryonic stem cells (mESCs). The results revealed that, similar to E2, 50 µmol/L PFHxDI accelerated the cell proliferation of the mESCs. The PFI stimulation at the exposure concentrations of 2–50 µmol/L promoted the differentiation of the mESCs as characterized by the upregulation of differentiation-related biomarkers (i.e., Otx2 and Dnmt3β) and downregulation of pluripotency genes (i.e., Oct4, Nanog, Sox2, Prdm14 and Rex1). Comparatively, PFHxDI exhibited higher induction effect on the differentiation of the mESCs than did PFHxI. The tests on ER signaling indicated that both PFI compounds induced exposure concentration-dependent expressions of ER signaling-related biomarkers (i.e., ERα, ERβ and Caveolin-1) in the mESCs, and the downstream ER responsive genes (i.e., c-fos, c-myc and c-jun) well responded to PFHxI stimulation. The role of ER in PFI-induced effects on the mESCs was further validated by the antagonistic experiments using an ER inhibitor (ICI). The findings demonstrated that PFIs triggered ER signaling, and perturbed the differentiation program of the mESCs, causing the potential health risk during early stage of development.

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