{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T18:59:20Z","timestamp":1785437960560,"version":"3.56.0"},"reference-count":66,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T00:00:00Z","timestamp":1761004800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T00:00:00Z","timestamp":1761004800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Biochem &amp;amp; Molecular Tox"],"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Both high\u2010cholesterol diet (HCD) and fine particulate matter (PM\n                    <jats:sub>2.5<\/jats:sub>\n                    ) exposure are associated with increased stroke risk; however, their combined effects\u2010particularly in females\u2010remain poorly understood. This study aimed to investigate the synergistic effects of HCD and PM\n                    <jats:sub>2.5<\/jats:sub>\n                    exposure on brain injury, behavior, and underlying molecular mechanisms in female mice. Female mice were exposed to HCD, PM\n                    <jats:sub>2.5<\/jats:sub>\n                    inhalation, or both for 3 months (3M) or 6 months (6M), with control groups for comparison. We assessed brain\u2010to\u2010body weight ratio, behavioral performance, histopathological changes, inflammatory markers (IL\u20106, TNF\u2010\u03b1), and expression of stroke\u2010 and blood\u2010brain barrier (BBB)\u2010related proteins. Additionally, we analyzed the epigenetic regulation of hypoxia\u2010inducible factor\u20101\u03b1 (HIF\u20101\u03b1) via chromatin immunoprecipitation (ChIP) assays. Co\u2010exposure to HCD and PM\n                    <jats:sub>2.5<\/jats:sub>\n                    led to greater alterations in the brain\u2010to\u2010body weight ratio, exacerbated neuropathology, behavioral deficits, and increased neuroinflammation compared to exposure to either factor alone. Moreover, HCD+PM\n                    <jats:sub>2.5<\/jats:sub>\n                    significantly altered the expression of HIF\u20101\u03b1 and genes involved in its downstream signaling pathway in the brain. ChIP assays revealed that HIF\u20101\u03b1 was directly regulated by histone deacetylase 4 (HDAC4) and histone H3 lysine 9 acetylation (H3K9ac), indicating epigenetic modulation in response to dual exposure. HCD and PM\n                    <jats:sub>2.5<\/jats:sub>\n                    synergistically promote brain injury in female mice, potentially through HDAC4\/H3K9ac\u2010mediated epigenetic activation of the HIF\u20101\u03b1 pathway. These findings highlight a novel molecular mechanism that may contribute to increased stroke risk in females exposed to both environmental and metabolic stressors.\n                  <\/jats:p>","DOI":"10.1002\/jbt.70568","type":"journal-article","created":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T06:47:08Z","timestamp":1761115628000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Combined Exposure to High\u2010Cholesterol Diet and PM\n                    <sub>2.5<\/sub>\n                    : Brain Injury, Behavioral Alteration and Regulatory Mechanism of HIF\u20101\u03b1 in Female Mice"],"prefix":"10.1002","volume":"39","author":[{"given":"Wenqi","family":"Chen","sequence":"first","affiliation":[{"name":"Institute of Environmental Science Shanxi University Taiyuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanshan","family":"Chen","sequence":"additional","affiliation":[{"name":"Institute of Environmental Science Shanxi University Taiyuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lirong","family":"Bai","sequence":"additional","affiliation":[{"name":"Institute of Environmental Science Shanxi University Taiyuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lifang","family":"Zhao","sequence":"additional","affiliation":[{"name":"Institute of Environmental Science Shanxi University Taiyuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Environmental Science Shanxi University Taiyuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuan","family":"Dong","sequence":"additional","affiliation":[{"name":"Institute of Environmental Science Shanxi University Taiyuan China"},{"name":"Institute of Judicial Identification Techniques for Environmental Damage Shanxi University and Shanxi Unisdom Testing Technology Co. 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