Fluoride Stimulates Anxiety- and Depression-like Behaviors Associated with SIK2-CRTC1 Signaling Dysfunction
Guoyu Zhou1, Yue Hu1, Anqi Wang1
1Department of Environmental Health, School of Public Health, Zhengzhou University, Zhengzhou, Henan 450001, P. R. China.
Abstract:
Using Sprague-Dawley rats and rat PC12 cells treated with sodium fluoride (NaF), we investigated the effects of SIK2-CRTC1 signaling on the neurobehavioral toxicity induced by fluoride. The in vivo results demonstrated that NaF treatment induced anxiety- and depression-like behaviors in juvenile rats, resulting in histological and ultrastructural abnormalities in the rat hippocampus and medial prefrontal cortex. Moreover, NaF exposure induced neuronal loss and excessive apoptosis. We also found that NaF elevated the expression of SIK2 and reduced the expression of CRTC1, brain-derived neurotrophic factor (BDNF), and VGF. The in vitro results showed that NaF suppressed cell viability, induced SIK2-CRTC1 signaling dysfunction, and caused excessive apoptosis in PC12 cells. Notably, targeted knockout of SIK2 with SIK2-siRNA or blocking of SIK2-CRTC1 signaling with 7,8-dihydroxyflavone (7,8-DHF) (as well as venlafaxine) can reduce apoptosis and increase cell viability in vitro. These findings suggest that neuronal death resulting from abnormal SIK2-CRTC1 signaling contributes to neurobehavioral toxicity induced by fluoride.
Insights
Sodium fluoride (NaF) exposure causes anxiety and depression in rats by damaging brain cells and disrupting SIK2-CRTC1 signaling. Interventions targeting this pathway may mitigate fluoride-induced neurotoxicity.
Area of Science:
- Neuroscience
- Toxicology
- Molecular Biology
Background:
- Fluoride exposure is a growing concern for neurodevelopmental health.
- The precise molecular mechanisms underlying fluoride-induced neurotoxicity remain incompletely understood.
Purpose of the Study:
- To investigate the role of Salt-Inducible Kinase 2 (SIK2) and its downstream target, CREB-Regulated Transcription Coactivator 1 (CRTC1) signaling pathway, in fluoride-induced neurobehavioral toxicity.
- To explore potential therapeutic interventions targeting the SIK2-CRTC1 pathway.
Main Methods:
- Utilized Sprague-Dawley rats and rat PC12 cells exposed to sodium fluoride (NaF).
- Assessed neurobehavioral changes, hippocampal and medial prefrontal cortex histology, and ultrastructure.
- Quantified expression levels of SIK2, CRTC1, brain-derived neurotrophic factor (BDNF), and VGF.
- Investigated the effects of SIK2 knockout (SIK2-siRNA) and SIK2-CRTC1 pathway inhibitors (7,8-dihydroxyflavone and venlafaxine) on cell viability and apoptosis *in vitro*.
Main Results:
- NaF exposure induced anxiety- and depression-like behaviors in rats, accompanied by hippocampal and medial prefrontal cortex damage, neuronal loss, and apoptosis.
- NaF elevated SIK2 expression while reducing CRTC1, BDNF, and VGF expression.
- *In vitro*, NaF suppressed PC12 cell viability and induced SIK2-CRTC1 signaling dysfunction and apoptosis.
- SIK2 knockout or inhibition of the SIK2-CRTC1 pathway significantly reduced apoptosis and increased cell viability in PC12 cells.
Conclusions:
- Abnormal SIK2-CRTC1 signaling and subsequent neuronal death are key contributors to fluoride-induced neurobehavioral toxicity.
- Targeting the SIK2-CRTC1 pathway presents a potential therapeutic strategy for mitigating fluoride neurotoxicity.
