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Although the effect of As(III) on the neurons is well studied, the involvement of the microglia remains unclear. In this study, the effects of sodium arsenite (NaAsO2) on microglial activation and the underlying NLRP3 inflammasome mechanism were determined. Pregnant rats were gavaged with NaAsO2 (0, 1, 4, and 10 mg\/kg body weight), which dissociates in aqueous solutions into bioactive arsenite species [As(OH)3], from gestational day 1 (GD1) to postnatal day 21 (PND21). The results showed that As(III) induces learning and memory impairments and microglial activation in the hippocampus of offspring rats (PND21). Increased expression of NLRP3, the activation of caspase-1, and the production of interleukin-1\u03b2 were observed in both the hippocampus of As(III)-exposed offspring rats and As(III)-exposed microglial BV2 cells under culture conditions. Interestingly, blocking the NLRP3 inflammasome using MCC950 mitigated its activation. Furthermore, inhibition of NADPH oxidase 2 (NOX2) using apocynin or specific siRNA significantly reduced As(III)-induced microglial NLRP3 inflammasome activation. In addition, inactivation of the microglial NLRP3 inflammasome or NOX2 markedly rescued As(III)-induced neurotoxicity in the hippocampal HT22 cells. Taken together, this study reveals that NOX2\/NLRP3-inflammasome-dependent microglial activation promotes As(III)-induced learning and memory impairments in developmental rats.<\/jats:p>","DOI":"10.3390\/toxics13070538","type":"journal-article","created":{"date-parts":[[2025,6,27]],"date-time":"2025-06-27T03:33:25Z","timestamp":1750995205000},"page":"538","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["NOX2\/NLRP3-Inflammasome-Dependent Microglia Activation Promotes As(III)-Induced Learning and Memory Impairments in Developmental Rats"],"prefix":"10.3390","volume":"13","author":[{"given":"Linlin","family":"Zhang","sequence":"first","affiliation":[{"name":"School of Public Health, Dalian Medical University, No. 9 West Section Lvshun South Road, Dalian 116044, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuyao","family":"Xiao","sequence":"additional","affiliation":[{"name":"College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, No. 6 Wangjing South Road, Beijing 102401, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Public Health, Dalian Medical University, No. 9 West Section Lvshun South Road, Dalian 116044, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuerong","family":"Han","sequence":"additional","affiliation":[{"name":"Dalian Municipal Center for Disease Control and Prevention Environmental Health Department, No. 151, Yueling West Street, Dalian 116013, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruoqi","family":"Zhou","sequence":"additional","affiliation":[{"name":"School of Public Health, Dalian Medical University, No. 9 West Section Lvshun South Road, Dalian 116044, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiying","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Public Health, Dalian Medical University, No. 9 West Section Lvshun South Road, Dalian 116044, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kexin","family":"Zhu","sequence":"additional","affiliation":[{"name":"School of Public Health, Dalian Medical University, No. 9 West Section Lvshun South Road, Dalian 116044, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junyao","family":"Wu","sequence":"additional","affiliation":[{"name":"School of Public Health, Dalian Medical University, No. 9 West Section Lvshun South Road, Dalian 116044, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiance","family":"Sun","sequence":"additional","affiliation":[{"name":"School of Public Health, Dalian Medical University, No. 9 West Section Lvshun South Road, Dalian 116044, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2787-6622","authenticated-orcid":false,"given":"Shuangyue","family":"Li","sequence":"additional","affiliation":[{"name":"School of Public Health, Dalian Medical University, No. 9 West Section Lvshun South Road, Dalian 116044, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1126\/science.aba1510","article-title":"Global threat of arsenic in groundwater","volume":"368","author":"Podgorski","year":"2020","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"117940","DOI":"10.1016\/j.envpol.2021.117940","article-title":"Environmental arsenic exposure and its contribution to human diseases, toxicity mechanism and management","volume":"289","author":"Rahaman","year":"2021","journal-title":"Environ. 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