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Previous studies have showed that PFOS gestational exposure is associated with offspring lung damage in rat. However, the underlying mechanisms remain poorly understood. In this study, we investigated the role of gasdermin E (GSDME) in lung injury of offspring and its underlying mechanisms using in vivo and in vitro approaches. Pregnant SD rats were exposed to PFOS (1\u00a0mg\/kg BW\/d) between gestational day 12\u201318, and the lung tissue of the offspring was evaluated on postnatal day 7. PFOS treated animals exhibited alveolar septal thickening and inflammation-related damages, with an increased expression of GSDME in alveolar type II epithelial cells (AECII). Furthermore, in vitro experiments demonstrated that PFOS exposure (with 225\u00a0\u03bcM and up) upregulated the caspase-3\/GSDME signaling pathway in AECII. Also, ultrastructure analysis revealed significant changes in the endoplasmic reticulum (ER) structure in PFOS-induced pyroptotic cells, which is consistent with the ER stress detected in these cells. Additionally, PFOS exposure led to increased expression of ER stress-related proteins, including p-PERK, p-eIF2\u03b1, ATF4, and CHOP. Subsequently, using specific inhibitors, we found that the PERK\/ATF4 pathway acted as an upstream signal regulating GSDME-dependent pyroptosis. Overall, our findings show that GSDME-dependent pyroptosis plays a crucial role in the lung injury induced by gestational PFOS exposure, and the PERK\/ATF4 pathway may function as a possible mediator of this process.<\/jats:p>","DOI":"10.1007\/s00204-023-03626-w","type":"journal-article","created":{"date-parts":[[2023,11,13]],"date-time":"2023-11-13T13:02:13Z","timestamp":1699880533000},"page":"207-221","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Caspase-3\/GSDME dependent pyroptosis contributes to offspring lung injury induced by gestational PFOS exposure via PERK\/ATF4 signaling"],"prefix":"10.1007","volume":"98","author":[{"given":"Cong","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huishan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiali","family":"Mo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingye","family":"Zuo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1319-5607","authenticated-orcid":false,"given":"Leping","family":"Ye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,11,13]]},"reference":[{"key":"3626_CR1","doi-asserted-by":"publisher","DOI":"10.1016\/j.scitotenv.2020.141251","volume":"748","author":"MB Ahmed","year":"2020","unstructured":"Ahmed MB, Johir MAH, McLaughlan R, Nguyen LN, Xu B, Nghiem LD (2020) Per- and polyfluoroalkyl substances in soil and sediments: occurrence, fate, remediation and future outlook. 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