The uses of 3D human brain organoids for neurotoxicity evaluations: A review

Neurotoxicity studies aim at understanding the toxic effects and mechanisms of toxicants to human central nervous systems (CNS). However, human brains are the most complex organs, whereas the most commonly used models, such as 2D cell cultures and animal brains, are probably too simple to predict the responses of human brains. Embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs)-based 3D human brain organoids hold unprecedented promise for the understanding of neurodevelopment and brain disease development. This review summarizes recent advances of using 3D human brain organoids for neurotoxicity studies. Comparative studies showed that 3D human brain organoids could support the findings obtained by animal or cohort studies, indicating that 3D human brain organoids are reliable models to evaluate the developmental neurotoxicity. 3D human brain organoids have been used to understand the toxicological mechanisms by using both conventional toxicological methods to investigate the signaling pathway changes as well as single cell RNA-sequencing to understand the neuron diversity. Some studies also used brain organoids carrying gene mutations or with virus infections to understand the toxicological responses of brains under diseased conditions. Although there are still limitations associated, 3D human brain organoids are promising tools for future neurotoxicity studies.