[en] Highlights: • PM_2.5 caused severe cytotoxic effects on hESCs by elevating ROS level. • PM_2.5 induced down-regulation of Nrf2 signaling pathway in hESCs. • Akt and Erk pathways were not changed in PM_2.5-treated hESCs. • NAC could block cell apoptosis and rescue the activity of Nrf2 signaling pathway. -- Abstract: While the effects of fine particulate matter (PM_2.5) on embryonic toxicity are widely accepted, its exact mechanisms have not yet been fully elucidated, which partially attribute to lack of ideal research model. Embryonic stem cells (ESCs) have the capacity to differentiate into all cell types of three germ layers. Thus, they are ideal resources for the reproductive toxicity assessment in vitro. In the present study, we investigated the effects of PM_2.5 exposure on the oxidative stress and apoptosis of human ESCs (hESCs) and its possible mechanism. Our results showed that strong cytotoxicity high reactive oxygen species (ROS) level and fragmentation of nuclei were observed in the PM_2.5-treated hESCs. Meanwhile, up-regulation of apoptosis as well as down-regulation of Nrf2 signaling pathway were also observed after PM_2.5 treatment. However, we did not detect significant expression change or phosphorylation of Akt and Erk in PM_2.5-treated hESCs. Interestingly, scavenging of PM_2.5-induced ROS by N-acetylcysteine (NAC) could block cell apoptosis and rescue the activity of Nrf2 signaling pathway. In conclusion, we demonstrate that PM_2.5 is toxic to hESCs by inhibition of ROS-mediated Nrf2 pathway activity. Our findings suggest activation of Nrf2 pathway will help develop new strategies for the prevention and treatment of PM_2.5-associated disease.