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

Shen-Pan Li; Hui-Xian Zeng; Shuang-Jian Qin; Qing-Qing Li; Lu-Yin Wu; Qi-Zhen Wu; Li-Zi Lin; Guang-Hui Dong; Xiao-Wen Zeng

doi:10.1021/envhealth.4c00098

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

Environ Health (Wash). 2024 Aug 16;2(11):776-785. doi: 10.1021/envhealth.4c00098. eCollection 2024 Nov 15.

Authors

Shen-Pan Li¹, Hui-Xian Zeng¹, Shuang-Jian Qin¹, Qing-Qing Li², Lu-Yin Wu¹, Qi-Zhen Wu¹, Li-Zi Lin¹, Guang-Hui Dong¹, Xiao-Wen Zeng¹

Affiliations

¹ Joint International Research Laboratory of Environment and Health, Ministry of Education, Guangdong Provincial Engineering Technology Research Center of Environmental Pollution and Health Risk Assessment, Department of Occupational and Environmental Health, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China.
² Acacia Lab for Implementation Science, Institute for Global Health, Dermatology Hospital of Southern Medical University, Guangzhou 510515, China.

Abstract

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 40 μg/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 10 μmol/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.