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Sex differences in terms of nervous and immune systems' responsiveness to excessive Mn in the DW are understudied. Thus, this study investigated behavioral and sex differences in response to Mn DW treatment (0.4\u2009g Mn\/L for up to 8\u2009weeks) and a lipopolysaccharide (LPS) challenge of adult C57BL\/6 mice with GFP\u2010tagged monocytes\/microglia. After 6\u2009weeks, in motor function tests, Mn exposure resulted in decreased activity and gait deficits. In two different mood tests (open field test [OFT]\/elevated zero maze), Mn\u2010exposed mice exhibited decreased fear\/anxiety\u2010like behavior. Two weeks after behavioral assessment, when mice were challenged with LPS, circulating inflammatory cytokines, and acute phase proteins increased in both sexes. After 8\u2009weeks of Mn exposure, liver and brain Mn levels were increased, but Mn alone did not affect circulating cytokines in either sex. Notably, Mn\u2010exposed\/LPS\u2010challenged males had potentiated plasma cytokine output, whereas the reverse was seen in females. Males, but not females, continued to exhibit increased fearlessness (i.e., increased OFT center time), even when challenged with LPS. Overall, our results show that Mn DW exposure increases brain Mn levels and it leads to behavioral alterations in both sexes. However, males might be more susceptible to the effect of Mn on mood, and this effect is recalcitrant to an inflammagen challenge. Mn augmented post\u2010LPS cytokine production only in males, further indicating that important Mn effects are sex\u2010biased.<\/jats:p>","DOI":"10.1002\/jat.4739","type":"journal-article","created":{"date-parts":[[2024,12,8]],"date-time":"2024-12-08T19:49:31Z","timestamp":1733687371000},"page":"669-684","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Behavioral Alterations in Mice Exposed to Manganese via Drinking Water: Effects of Sex and a Lipopolysaccharide Challenge"],"prefix":"10.1002","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9639-7492","authenticated-orcid":false,"given":"Helaina\u00a0D.","family":"Ludwig","sequence":"first","affiliation":[{"name":"Department of Physiology and Pharmacology University of Georgia  Athens Georgia USA"},{"name":"Interdisciplinary Toxicology Program University of Georgia  Athens Georgia 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