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- Title
Excessive Lysosomal Stress Response and Consequently Impaired Autophagy Contribute to Fluoride-Induced Developmental Neurotoxicity.
- Authors
Xu, Wanjing; Hu, Zeyu; Tang, Yanling; Zhang, Jingjing; Xu, Shangzhi; Niu, Qiang
- Abstract
Fluoride can cause developmental neurotoxicity; however, the precise mechanism has yet to be determined. We aimed to explore the possible role and mechanism of fluoride-induced developmental neurotoxicity, specifically the significance of the lysosomal stress response. As an in vivo model, Sprague Dawley rats were exposed to sodium fluoride (NaF) from embryo to 2 months of age. We found that NaF caused autophagic flux blockage and apoptosis in the rat hippocampus. These results were validated in human neuroblastoma (SH-SY5Y) cells in vitro. In addition, in SH-SY5Y cells, NaF hindered autophagosome-lysosome fusion, decreased lysosomal degradation, and elevated lysosomal pH, which is the most prominent hallmark of a lysosomal stress response. Interestingly, rapamycin promoted autophagosome-lysosome fusion, effectively restoring autophagic flux and reducing apoptosis. Notably, bafilomycin A1, a lysosomal lumen alkalizer, unsurprisingly exacerbated the NaF-induced increase in lysosomal pH and decreased lysosomal degradability, as well as enhanced apoptosis of SH-SY5Y cells. In conclusion, our results suggest that NaF exposure initiates excessive lysosomal stress response, resulting in elevated lysosomal pH, decreased lysosomal degradation, and blocked autophagic flux, which leads to neuronal apoptosis. Thus, the lysosomal stress response may be a promising target for the prevention and treatment of fluoride-induced developmental neurotoxicity. Highlights: 1. NaF caused autophagic flux blockage and apoptosis in vivo and in vitro 2. NaF hindered autophagosome-lysosome fusion and elevated lysosomal pH 3. NaF caused excessive lysosomal stress response and impaired lysosomal degradation
- Subjects
NEUROTOXICOLOGY; SPRAGUE Dawley rats; AUTOPHAGY; SODIUM fluoride
- Publication
Biological Trace Element Research, 2023, Vol 201, Issue 9, p4472
- ISSN
0163-4984
- Publication type
Article
- DOI
10.1007/s12011-022-03511-0