{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,18]],"date-time":"2026-01-18T06:57:50Z","timestamp":1768719470867,"version":"3.49.0"},"reference-count":76,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T00:00:00Z","timestamp":1759881600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Chronic manganese (Mn) overexposure causes manganism, a Parkinson\u2019s disease-like neurological disorder, due to its preferential accumulation in the basal ganglia. Tamoxifen (TX), a selective estrogen receptor modulator (SERM), afforded neuroprotection against Mn toxicity, and RE1-silencing transcription factor (REST) in dopaminergic neurons mitigated Mn-induced neurotoxicity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>This study investigated whether dopaminergic REST played a role in TX\u2019s protection against Mn toxicity in the nigrostriatal regions using wild-type (WT) and dopaminergic REST-deleted (REST cKO) female mice. Behavioral studies, including open-field, rotarod, and novel object recognition tests, were conducted with molecular biology assays.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>TX mitigated Mn-induced deficits in several motor functions and cognition, as well as dopaminergic neuronal injury, parallel with the attenuation of Mn-decreased tyrosine hydroxylase (TH) and Mn-increased proapoptotic Bax in REST cKO mice. However, several Mn-dysregulated genes associated with oxidative stress and mitochondrial function, including catalase, superoxide dismutase 2 (SOD2), and optic atrophy 1 (OPA1), were attenuated by TX only in WT, but not in REST cKO. At the epigenetic levels, TX attenuated Mn-reduced acetylation of H3K27 in both WT and REST cKO, but Mn-decreased H3K27ac interaction with promoters of catalase, SOD2, and OPA1 was attenuated by TX only in WT, not REST cKO. TX attenuated Mn-decreased estrogen receptor (ER)-\u03b1 and ER-\u03b2 protein levels in both WT and REST cKO mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>Our findings suggest that TX significantly attenuated Mn-induced TH reduction and behavioral deficits in REST cKO, not to the levels of its protection in WT, since several genes involved in TX-induced protective pathways required dopaminergic REST. Taken together, while TX has some REST-independent protective effects, dopaminergic REST is critical for full neuroprotection.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphar.2025.1627400","type":"journal-article","created":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T05:41:47Z","timestamp":1759902107000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Dopaminergic REST is implicated in the tamoxifen-induced neuroprotection against manganese toxicity in female mice"],"prefix":"10.3389","volume":"16","author":[{"given":"Edward","family":"Pajarillo","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexis","family":"Digman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Itunu","family":"Ajayi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sanghoon","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Deok-Soo","family":"Son","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Aschner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eunsook","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,10,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"5","DOI":"10.2217\/epi-2023-0364","article-title":"Identification of histone acetylation modification sites in the striatum of subchronically manganese-exposed rats","volume":"16","author":"Ao","year":"2024","journal-title":"Epigenomics"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1989","DOI":"10.3390\/ijms18091989","article-title":"Quercetin attenuates manganese-induced neuroinflammation by alleviating oxidative stress through regulation of apoptosis, iNOS\/NF-\u03baB and HO-1\/Nrf2 pathways","volume":"18","author":"Bahar","year":"2017","journal-title":"Int. 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