Sevoflurane inhibits embryonic stem cell self-renewal and subsequent neural differentiation by modulating the let-7a-Lin28 signaling pathway.

The commonly used inhalational anesthetic, sevoflurane, can cause toxicity to the central nervous system of the developing fetus. Lin28 has been reported to regulate let-7a, thereby modulating embryo development, neurodegeneration, and even neuron-related tumorigenesis. We demonstrate that pregnant mice receiving sevoflurane treatment during the early stage of pregnancy give birth to fewer offspring presenting a lower birth weight. We have also treated mouse embryonic stem cells (mESCs) with sevoflurane for 6 h and determined that mESCs self-renewal is repressed, and that differentiation is initiated earlier than in controls. We have induced neural differentiation in the treated mESCs and determined that their neurogenesis is weakened. Furthermore, sevoflurane upregulates the level of let-7a, which might repress mESC self-renewal by directly targeting the Lin28 3'-untranslated region. Lin28 overexpression attenuates the influence of sevoflurane or of let-7a on the self-renewal of mESCs and their subsequent neural differentiation. The let-7a inhibitor also abolishes the influence of sevoflurane. Thus, the let-7a-Lin28 pathway is involved in the sevoflurane-induced inhibition of ESC self-renewal and subsequent neurogenesis. Our study demonstrates the molecular mechanism underlying the side effects of sevoflurane during early development, laying the foundation for studies on the safe and reasonable usage of other inhalational anesthetics.