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BDE-47 flame retardant exposure induces microglial pyroptosis and cognitive deficits by activating the mtROS-NLRP3 axis via Sirt3 downregulation and is salvaged by honokiol.
- Source :
- Environmental Pollution; Oct2023, Vol. 334, pN.PAG-N.PAG, 1p
- Publication Year :
- 2023
-
Abstract
- The brominated flame retardant 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47) is widely distributed in the environment and poses a certain risk to human health. Studies have reported that oxidative stress is a key mechanism underlying BDE-47-induced neurotoxicity. Mitochondrial reactive oxygen species (mtROS) is a crucial mediator of NLRP3 inflammasome activation, which is involved in cognitive dysfunction induced by environmental toxins. However, the function of the mtROS-NLRP3 inflammasome pathway in BDE-47-elicited cognitive deficits and the underlying mechanisms remain elusive. Our data illustrated that eight weeks of BDE-47 (20 mg/kg) gavage led to cognitive deficits and hippocampal neuronal injury in mice. BDE-47 exposure downregulated Sirt3 expression and decreased the activity and expression level of SOD2, thereby inhibiting mtROS scavenging and activating NLRP3 inflammasome-mediated pyroptosis in the mouse hippocampus and BV-2 cells. In vitro, BDE-47-evoked microglial pyroptosis relied on NLRP3 inflammasome activation. Moreover, a mtROS scavenger (TEMPO) attenuated NLRP3 inflammasome activation and subsequent microglial pyroptosis under BDE-47 stress. Furthermore, Sirt3 overexpression restored the activity and expression of SOD2 and enhanced mtROS scavenging, thereby suppressing NLRP3 inflammasome activation and ameliorating microglial pyroptosis. Notably, honokiol (HKL), a pharmacological agonist of Sirt3, mitigated BDE-47-evoked hippocampal neuronal injury and cognitive impairment by inhibiting mtROS-NLRP3 axis-mediated pyroptosis via Sirt3 upregulation. [Display omitted] • BDE-47 exposure induces microglial pyroptosis and cognitive deficits. • NLRP3 inflammmasome activation contributes to microglial pyroptosis. • Sirt3 dysfunction is essential for BDE-47-induced mtROS accumulation. • Honokiol suppresses microglial pyroptosis through restoring Sirt3-SOD2 pathway. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 02697491
- Volume :
- 334
- Database :
- Supplemental Index
- Journal :
- Environmental Pollution
- Publication Type :
- Academic Journal
- Accession number :
- 171392909
- Full Text :
- https://doi.org/10.1016/j.envpol.2023.122158