Effects on Synaptic Plasticity Markers in Fetal Mice and HT22 Neurons upon F‑53B Exposure:The Role of PKA Cytoplasmic Retention

Chlorinated polyfluorinated ether sulfonate(F-53B),a chromium-fog depressant widely utilized as an alternative to perfluorooctanesulfonate,can transfer from mother to fetus.Recent research has demonstrated that prenatal exposure to F-53B results in synaptic damage in weaning mice.However,the mechanism underpinning F-53B-triggered synaptic damage during fetal development remains unclear.This study aims to investigate the role of the protein kinase A(PKA)/cAMP response element-binding protein(CREB)pathway,a crucial signaling mechanism known as“synaptic switch”,in the early neurotoxicity of F-53B exposure both in vivo and in vitro.Here,C57BL/6 fetal mice were subjected to exposure to F-53B(0,4,and 40μg/L)from gestation days(GD)0 to 14 to evaluate nerve injury prior to delivery.HT22 neurons exposed to F-53B(0,0.016,0.08,0.4,2,and 10μmol/L)for 24 h were utilized to elucidate the underlying mechanism.Our results demonstrated that F-53B significantly increased the fluorescence intensity of Nestin(a neural stem cell marker)in the fetal brain hippocampus(GD14).Subsequently,we found that F-53B downregulated the expression of synaptic plasticity markers(SYP,GAP43,and BDNF)in the fetal brain and HT22 neurons.Further molecular docking analysis revealed that F-53B fits into the ligand-binding pockets of PKA and CREB1.Results showed that F-53B inhibited the translocation of PKA protein from the cytoplasm to the neuronal nuclei and reduced the levels of PKA,CREB1,p-PKA(α/β/γ)-Thr197,and p-CREB1-S133 in the nucleus.Furthermore,the expression of synaptic plasticity markers altered by F-53B could be reversed by a PKA agonist and was intensified by a PKA antagonist.In summary,our findings suggest that intrauterine exposure to F-53B can weaken the expression of synaptic plasticity markers in the fetal brain,with this neurotoxicity being mediated by the cytoplasmic retention of PKA.