WITHDRAWN: Human placental barrier-brain organoid-on-a-chip for modeling maternal PM2.5 exposure.

Fetal development is susceptible to various environmental stimuli, which possibly lead to lasting health effects. Of particular note is maternal environment that is increasingly recognized as an essential factor in fetal growth. However, the studies of the influences of environmental factors on fetal development are limited due to the species variation between animals and human as well as restricted source of human fetal tissues. Here, we construct a placental barrier-brain organoid-on-a-chip model, which enables to investigate the effects of maternal PM exposure on human fetal system including placental barrier and fetal brain. The multilayered microdevice is designed with the upper placental barrier and the bottom hiPSC-derived brain organoids, separated by porous membrane. This system represents multiple organs with physiological interactions between fetal and maternal side. Maternal PM exposure is simulated by introducing PM into the maternal side, and the subsequent effects are examined based on the multiorgan-on-a-chip (MOC) system. The results demonstrate that placental barrier is greatly injured with induced inflammatory responses. Moreover, brain organoids are potentially damaged including the impaired cell proliferation and cell differentiation, implying the adverse impacts of PM exposure on fetal neural development. These adverse responses caused by maternal PM exposure are potentially critical for the placental insufficiency, as well as abnormalities in fetal brain development. Together, human placental barrier-brain organoid-on-a-chip model presents a biomimetic fetal system to study the complex impacts of maternal environment on fetal development, and possibly advance our understanding of reproductive diseases and fetal disorders.