Silver nanoparticles exposure induces developmental neurotoxicity in hiPSC-derived cerebral organoids.

Silver nanoparticles (AgNPs) are used in various research fields. Although the neurotoxicity of AgNPs has been explored in animal models and 2D cell-culture models, including human stem cells, these models cannot accurately mimic the development of the human brain. Therefore, the potential mechanisms of AgNPs-induced developmental neurotoxicity in humans are still largely unclear. In this study, cerebral organoids derived from induced pluripotent stem cells were treated with 0.1 µg/mL or 0.5 µg/mL AgNPs for 7 days. At the low concentration (0.1 µg/mL), AgNPs increased the cell proliferation and inhibited the neural apoptosis in the organoids, but impaired the cilium assembly and elongation, which may perturb the cell cycle and induce abnormal cerebral-organoid growth. Conversely, at the high concentration (0.5 µg/mL), AgNPs significantly inhibited cell proliferation and induced apoptosis in cerebral organoids. High-concentration AgNPs reduced the expression and co-localization of the cytoskeleton proteins F-actin, myosin, and tubulin, thereby perturbing neurite growth. In conclusion, AgNPs exposure induces developmental neurotoxic effects in cerebral organoids and is thus a potential congenital risk factor.

Exposure to cadmium induces neuroinflammation and impairs ciliogenesis in hESC-derived 3D cerebral organoids.

Cadmium (Cd) is an environmental heavy metal toxicant with central nervous system toxicity and has a greater negative impact on fetal neurodevelopment. However, the causative mechanisms for the neurodevelopmental toxicity of Cd have remained unclear. The human cerebral organoids can better mimic the three-dimensional structure of the early fetal nerve tissue, which can be used to study the developmental neurotoxicity under the condition of maternal exposure to Cd. Our study identified that Cd exposure specifically induced apoptosis in neurons and inhibited the proliferation of neural progenitor cells, but neural differentiation was not significantly affected in cerebral organoids. Cd exposure also elicited overexpression of GFAP, a marker of astrocytes and resulted in IL-6 release. This study revealed that mineral absorption was significantly disturbed with metallothioneins expression up-regulation. Moreover, we found Cd exposure inhibited cilium-related gene expression and reduced ciliary length with increasing dose. In conclusion, our study has shown that Cd exposure regulated neural cell proliferation and death, induced neuroinflammation, enhanced metal ion absorption, and impaired ciliogenesis, which hinder the normal development of the fetal brain.