Preclinical study shows lead induces hippocampal necroptosis via TNF-R1-RIPK1/RIPK3 signaling in mice, suggesting potential targets against heavy metal neurotoxicity.
Abstract Lead (Pb), a dense, soft, blue-gray metal, is widely used in metallurgy, cables, storage batteries, pigments, and other industrial applications. Pb has been shown to cause hippocampal neurodegeneration. Necroptosis, a newly described cell death modality, is closely associated with neurodegenerative diseases. Whether Pb can cause programmed neuronal cell death and its mechanisms has yet to be characterized. Here, we explored the role of the TNF-R1-RIPK1/RIPK3 signaling pathway in necroptosis induced by Pb. Our results showed that Pb exposure elevated lead levels in murine whole blood and hippocampal tissue in a dose-response relationship. Protein expression levels of PARP, c-PARP, RIPK1, p-RIPK1, RIPK3, MLKL, and p-MLKL in the hippocampal tissues were elevated, while the protein expression of caspase-8 was decreased. Furthermore, Pb exposure reduced the survival rates in HT-22 cells and primary mouse hippocampal neurons, while increasing the protein expressions of RIPK1 and p-MLKL. Collectively, these novel findings suggest that the TNF-R1/RIPK1/RIPK3 signaling pathway mediates Pb-induced necroptosis in hippocampal neurons in mice.
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Li et al. (2024) studied this question.
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