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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.
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.
JOURNAL/nrgr/04.03/01300535-202412000-00031/figure1/v/2024-04-08T165401Z/r/image-tiff Neonatal hypoxic-ischemic brain injury is the main cause of hypoxic-ischemic encephalopathy and cerebral palsy. Currently, there are few effective clinical treatments for neonatal hypoxic-ischemic brain injury. Here, we investigated the neuroprotective and molecular mechanisms of exogenous nicotinamide adenine dinucleotide, which can protect against hypoxic injury in adulthood, in a mouse model of neonatal hypoxic-ischemic brain injury. In this study, nicotinamide adenine dinucleotide (5 mg/kg) was intraperitoneally administered 30 minutes before surgery and every 24 hours thereafter. The results showed that nicotinamide adenine dinucleotide treatment improved body weight, brain structure, adenosine triphosphate levels, oxidative damage, neurobehavioral test outcomes, and seizure threshold in experimental mice. Tandem mass tag proteomics revealed that numerous proteins were altered after nicotinamide adenine dinucleotide treatment in hypoxic-ischemic brain injury mice. Parallel reaction monitoring and western blotting confirmed changes in the expression levels of proteins including serine (or cysteine) peptidase inhibitor, clade A, member 3N, fibronectin 1, 5′-nucleotidase, cytosolic IA, microtubule associated protein 2, and complexin 2. Proteomics analyses showed that nicotinamide adenine dinucleotide ameliorated hypoxic-ischemic injury through inflammation-related signaling pathways (e.g., nuclear factor-kappa B, mitogen-activated protein kinase, and phosphatidylinositol 3 kinase/protein kinase B). These findings suggest that nicotinamide adenine dinucleotide treatment can improve neurobehavioral phenotypes in hypoxic-ischemic brain injury mice through inflammation-related pathways.
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