Bisphenol AF exposure induced synaptic plasticity and neurobehavioral impairments via triggering the ROS-mediated PERK-eIF2α-ATF4 signaling pathway in adolescent mice.

Bisphenol AF (BPAF), a fluorinated homolog of BPA, has been produced as a replacement for BPA. However, the consequences and mechanisms of adolescent exposure to BPAF in terms of neurobehavioral injury remain unclear. In this study, using an in vivo model, we found that BPAF is able to cross the blood-brain barrier (BBB) and lead to anxiety- and depression-like behaviors and cognitive dysfunction in adolescent mice. Furthermore, exposure of adolescent mice to BPAF induced a reduction in the number of pyramidal neurons, as well as a decrease in dendritic complexity and dendritic spine density in the hippocampus. In addition, BPAF exposure inhibits the CREB-BDNF pathway and activates the PERK-eIF2α-ATF4 axis in the prefrontal cortex and hippocampus of adolescent mice. The SH-SY5Y cell culture experiments showed that inhibition of the PERK-eIF2α-ATF4 axis attenuated BPAF-induced downregulation of the CREB-BDNF pathway. NAC, a scavenger of ROS, markedly suppressed the expression levels of the PERK-eIF2α-ATF4 axis and restored the expression levels of CREB-BDNF proteins in both mouse brain and SH-SY5Y cells. NAC also prevented hippocampal synaptic damage. Unsurprisingly, behavioral results showed that NAC obviously attenuated BPAF-induced anxiety- and depression-like behaviors and cognitive dysfunction in adolescent mice. In conclusion, these findings suggest that exposure to BPAF during adolescence leads to neurobehavioral impairments through the activation of the ROS-mediated PERK-eIF2α-ATF4 axis, which in turn inhibits the CREB-BDNF pathway and compromises synaptic plasticity.