Intermittent Propofol Exposure Induces Neurodevelopmental Alterations in Human Brain Organoids

The administration of anaesthesia during pregnancy may have implications for fetal brain development. This study used H1 embryonic stem cell-derived human brain organoids (HBOs) to investigate effects of intermittent propofol exposure (IPE). HBOs were subjected to early IPE from 47 to 50 days in vitro (div), or late IPE from 77 to 80 div, using a clinically supra-anaesthetic concentration of 50 µM propofol. This was followed by cultivation without propofol for an additional 10 div, and HBOs were subsequently analysed at 60 or 90 div. Determination of HBO growth and lactate release did not provide evidence of neurotoxicity. Multi-electrode array recordings indicated an increased neuronal activity at 60 div following early IPE, an effect not observed at 90 div following late IPE. RNA-sequencing revealed that IPE up-regulated genes associated with neurodevelopment and synapse functions at 60 div, which overlapped with naturally up-regulated genes during HBO development from 60 to 90 div. These findings indicate that early IPE accelerates brain maturation in HBOs, suggesting possible deviations from the normal developmental trajectory in the fetal brain.