Modeling early human cortical development and evaluating neurotoxicity with a forebrain organoid system

Area of Science:

• Neuroscience
• Developmental Biology
• Toxicology

Background:

• Human fetal brain development is complex and difficult to study regarding environmental toxicant effects.
• Pluripotent cell-derived organoids offer a promising model for studying human development and toxicity.
• Existing models lack the capacity to fully recapitulate early human cortical development.

Purpose of the Study:

• To establish a human forebrain organoid system to model early cortical development.
• To assess the utility of this organoid system for neurotoxicity testing using bisphenol A (BPA).
• To investigate potential therapeutic interventions for BPA-induced neurodevelopmental abnormalities.

Main Methods:

• Established a human forebrain organoid system from pluripotent stem cells.
• Recapitulated key spatiotemporal events of early human cortical development in vitro.
• Exposed organoids to bisphenol A (BPA) and evaluated developmental effects.
• Administered thyroid hormone (T3) to assess its protective role against BPA toxicity.

Main Results:

• The forebrain organoids successfully mimicked early human cortical development, including progenitor proliferation and neuronal differentiation.
• Bisphenol A (BPA) exposure significantly disrupted cortical development, inhibiting progenitor proliferation and causing aberrant layer patterning.
• Thyroid hormone (T3) supplementation attenuated the detrimental effects of BPA, suggesting an antagonistic interaction.

Conclusions:

• Human forebrain organoids provide a viable in vitro model for studying neural development and neurotoxicity.
• This model system can be used for efficient screening of environmental toxicants and testing potential remedies.
• The findings highlight the vulnerability of developing human brain to BPA and the protective potential of thyroid hormone.