Prenatal Acetaminophen Exposure Does Not Disrupt Human Fetal Brain Development in Cortical Organoid Models.

Area of Science:

• Neuroscience
• Developmental Biology
• Toxicology

Background:

• Acetaminophen (APAP) is a common pregnancy analgesic, but its prenatal exposure is linked to neurodevelopmental disorders (NDDs) in conflicting epidemiological studies.
• Limited mechanistic data exists from human-relevant models to explain these associations.

Purpose of the Study:

• To investigate the mechanistic effects of prenatal APAP exposure on human fetal brain development using cortical organoids.
• To assess APAP's impact on organoid growth, viability, cellular composition, gene expression, and functional maturation.

Main Methods:

• Human induced pluripotent stem cell-derived cortical organoids (COs) were exposed to APAP (25, 50, 100 μM) during a critical developmental window.
• Assessed organoid growth, apoptosis, neuronal/progenitor ratios, RNA-sequencing, and electrophysiological activity over 2-4 months.

Main Results:

• APAP exposure did not affect organoid growth, cytoarchitecture, or viability, with apoptosis rates below 1%.
• No significant changes in neuronal and progenitor cell proportions were observed.
• Subtle, dose-dependent transcriptional changes were detected at higher APAP doses, enriched in neurodevelopmental pathways, but electrophysiological recordings showed normal network function.

Conclusions:

• Therapeutic APAP concentrations induced only modest transcriptional effects without structural or functional consequences in developing cortical organoids.
• Findings suggest that reported associations between prenatal APAP exposure and NDDs may be due to confounding factors.
• Mechanistic data provides reassurance that recommended APAP use during pregnancy is unlikely to disrupt fetal brain development.