{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T05:02:25Z","timestamp":1788238945856,"version":"build-2803163510"},"reference-count":43,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2006,3,27]],"date-time":"2006-03-27T00:00:00Z","timestamp":1143417600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J of Neuroscience Research"],"published-print":{"date-parts":[[2006,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Manganese (Mn) is an essential trace element, though at elevated exposures it is also a neurotoxicant. Several mechanisms underlying manganese toxicity have been investigated, although a consistent mechanism(s) of action at low exposures has not been fully elucidated. Here we systematically evaluated the effects of in vitro manganese exposure on intracellular iron (Fe) homeostasis and iron\u2010regulatory protein (IRP) binding activity in undifferentiated PC12 cells over a range of manganese exposure concentrations (1, 10, 50, and 200 \u03bcM MnCl<jats:sub>2<\/jats:sub>) and exposure durations (12, 24, 36, and 48 hr), to test the hypothesis that moderately elevated manganese exposure disrupts cellular iron regulation. Results demonstrate that manganese exposure produces a rapid and sustained dose\u2010dependent dysregulation of cellular iron metabolism, with effects occurring as early as 12 hr exposure and at manganese doses as low as 1 \u03bcM. Manganese exposure altered the dynamics of IRP\u20101 binding and the intracellular abundance of IRP\u20102, and altered the cellular abundance of transferrin receptor, ferritin, and mitochondrial aconitase protein levels. Cellular levels of labile iron were significantly increased with manganese exposure, although total cellular iron levels were not. The overall pattern of effects shows that manganese produced an inappropriate cellular response akin to iron deficiency, to which the cells were able to mount a compensatory response. Consistent with our previous studies, these data indicate that even low to moderate exposures to Manganese in vitro significantly disrupt cellular iron metabolism, which may be an important contributory mechanism of manganese neurotoxicity. \u00a9 2006 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/jnr.20836","type":"journal-article","created":{"date-parts":[[2006,3,27]],"date-time":"2006-03-27T23:47:51Z","timestamp":1143503271000},"page":"1601-1610","source":"Crossref","is-referenced-by-count":53,"title":["Temporal responses in the disruption of iron regulation by manganese"],"prefix":"10.1002","volume":"83","author":[{"given":"Catherine","family":"Kwik\u2010Uribe","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donald R.","family":"Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2006,3,27]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1042\/bj2910901"},{"key":"e_1_2_6_3_1","first-page":"546","article-title":"Iron loading of endothelial cells augments oxidant damage","volume":"116","author":"Balla G","year":"1990","journal-title":"J Lab Clin Med"},{"key":"e_1_2_6_4_1","doi-asserted-by":"crossref","first-page":"7498","DOI":"10.1016\/S0021-9258(18)83262-8","article-title":"Transcriptional regulation of ferritin H and L subunits in adult erythroid and liver cells from the mouse. 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