{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,14]],"date-time":"2026-02-14T02:07:56Z","timestamp":1771034876685,"version":"3.50.1"},"reference-count":35,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2024,10,22]],"date-time":"2024-10-22T00:00:00Z","timestamp":1729555200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["R01DK123113"],"award-info":[{"award-number":["R01DK123113"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background\/Objectives: Manganese is an essential nutrient involved in various biological processes, including reproductive health, yet the mechanisms regulating its homeostasis in the testis remain poorly understood. Methods and Results: In this study, we investigated the expression and regulation of key manganese transporters\u2014ZIP8, ZIP14, and ZnT10\u2014in mouse testes. Immunoblotting analyses revealed that ZIP8 is expressed in the testes, while ZIP14 and ZnT10 were undetectable. Using Zip14 knockout (Zip14-\/-) mice, which exhibit systemic manganese overload, we discovered a significant increase in manganese levels in the testis, accompanied by an upregulation of ZIP8. Importantly, the levels of other essential metals, such as iron, zinc, and copper, remained unchanged. Conclusions: Our findings suggest that ZIP8 plays a critical role in manganese transport in the testis, and its increased expression may contribute to manganese accumulation in the absence of ZIP14. This study advances our understanding of manganese homeostasis in the testis and its potential impact on male reproductive health.<\/jats:p>","DOI":"10.3390\/nu16213575","type":"journal-article","created":{"date-parts":[[2024,10,22]],"date-time":"2024-10-22T04:10:14Z","timestamp":1729570214000},"page":"3575","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["ZIP8 Is Upregulated in the Testis of Zip14-\/- Mice"],"prefix":"10.3390","volume":"16","author":[{"given":"Varalakshmi","family":"Vungutur","sequence":"first","affiliation":[{"name":"School of Nutritional Sciences and Wellness, The University of Arizona, Tucson, AZ 85721, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9230-7477","authenticated-orcid":false,"given":"Shannon M.","family":"McCabe","sequence":"additional","affiliation":[{"name":"School of Nutritional Sciences and Wellness, The University of Arizona, Tucson, AZ 85721, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ningning","family":"Zhao","sequence":"additional","affiliation":[{"name":"School of Nutritional Sciences and Wellness, The University of Arizona, Tucson, AZ 85721, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1016\/j.mam.2005.07.003","article-title":"Nutritional aspects of manganese homeostasis","volume":"26","author":"Aschner","year":"2005","journal-title":"Mol. Aspects Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"7580707","DOI":"10.1155\/2018\/7580707","article-title":"The Essential Element Manganese, Oxidative Stress, and Metabolic Diseases: Links and Interactions","volume":"2018","author":"Li","year":"2018","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1111\/j.1476-5381.2009.00291.x","article-title":"Arginase: An emerging key player in the mammalian immune system","volume":"158","author":"Munder","year":"2009","journal-title":"Br. J. Pharmacol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1016\/j.tips.2015.03.006","article-title":"Arginase: An old enzyme with new tricks","volume":"36","author":"Caldwell","year":"2015","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"257","DOI":"10.3109\/10409238509113606","article-title":"Galactosyltransferases: Physical, chemical, and biological aspects","volume":"17","author":"Ram","year":"1985","journal-title":"CRC Crit. Rev. Biochem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1007\/s00249-009-0459-4","article-title":"Identifying the structure of the active sites of human recombinant prolidase","volume":"39","author":"Besio","year":"2010","journal-title":"Eur. Biophys. J."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1023\/A:1005427323835","article-title":"The role of manganese superoxide dismutase in health and disease","volume":"21","author":"Robinson","year":"1998","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"520","DOI":"10.3945\/an.117.015305","article-title":"Manganese","volume":"8","author":"Aschner","year":"2017","journal-title":"Adv. Nutr."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Winslow, J.W.W., Limesand, K.H., and Zhao, N. (2020). The Functions of ZIP8, ZIP14, and ZnT10 in the Regulation of Systemic Manganese Homeostasis. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21093304"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.2741\/4665","article-title":"Manganese metabolism in humans","volume":"23","author":"Chen","year":"2018","journal-title":"Front. Biosci. (Landmark Ed.)"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Fung, C.K., and Zhao, N. (2022). The Combined Inactivation of Intestinal and Hepatic ZIP14 Exacerbates Manganese Overload in Mice. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23126495"},{"key":"ref_12","first-page":"199","article-title":"Manganese in health and disease","volume":"13","author":"Avila","year":"2013","journal-title":"Met. Ions Life Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"106924","DOI":"10.1016\/j.anireprosci.2022.106924","article-title":"Functions of manganese in reproduction","volume":"238","author":"Studer","year":"2022","journal-title":"Anim. Reprod. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1093\/toxsci\/kfg112","article-title":"The road to elucidating the mechanism of manganese-bilirubin-induced cholestasis","volume":"73","author":"Goering","year":"2003","journal-title":"Toxicol. Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1111\/and.12069","article-title":"Antioxidant effect of manganese on the testis structure and sperm parameters of formalin-treated mice","volume":"46","author":"Tajaddini","year":"2014","journal-title":"Andrologia"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"152","DOI":"10.4161\/oxim.2.3.8804","article-title":"Manganese provides antioxidant protection for sperm cryopreservation that may offer new consideration for clinical fertility","volume":"2","author":"Cheema","year":"2009","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Li, Y., Wu, J., Zhou, W., and Gao, E. (2012). Effects of manganese on routine semen quality parameters: Results from a population-based study in China. BMC Public Health, 12.","DOI":"10.1186\/1471-2458-12-919"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"108447","DOI":"10.1016\/j.reprotox.2023.108447","article-title":"Exposure to manganese during sertoli cell formation and proliferation disturbs early testicular development in rats","volume":"120","author":"Silva","year":"2023","journal-title":"Reprod. Toxicol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s12011-012-9335-7","article-title":"Seminal plasma metals concentration with respect to semen quality","volume":"148","author":"Li","year":"2012","journal-title":"Biol. Trace Elem. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1124\/mol.106.024521","article-title":"ZIP8, member of the solute-carrier-39 (SLC39) metal-transporter family: Characterization of transporter properties","volume":"70","author":"He","year":"2006","journal-title":"Mol. Pharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1039\/c2mt20024d","article-title":"Roles of ZIP8, ZIP14, and DMT1 in transport of cadmium and manganese in mouse kidney proximal tubule cells","volume":"4","author":"Fujishiro","year":"2012","journal-title":"Metallomics"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1124\/mol.107.043588","article-title":"Slc39a14 gene encodes ZIP14, a metal\/bicarbonate symporter: Similarities to the ZIP8 transporter","volume":"73","author":"Girijashanker","year":"2008","journal-title":"Mol. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"14079","DOI":"10.1523\/JNEUROSCI.2329-14.2014","article-title":"SLC30A10 is a cell surface-localized manganese efflux transporter, and parkinsonism-causing mutations block its intracellular trafficking and efflux activity","volume":"34","author":"Chen","year":"2014","journal-title":"J. Neurosci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"14773","DOI":"10.1074\/jbc.M116.728014","article-title":"Direct Comparison of Manganese Detoxification\/Efflux Proteins and Molecular Characterization of ZnT10 Protein as a Manganese Transporter","volume":"291","author":"Nishito","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Wei, G., Wu, Y., and Zhao, N. (2021). Generation of a Polyclonal Antibody against the Mouse Metal Transporter ZIP8. Antibodies, 10.","DOI":"10.3390\/antib10020016"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Yu, S., and Zhao, N. (2023). The Regulation of ZIP8 by Dietary Manganese in Mice. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24065962"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1016\/j.febslet.2004.12.006","article-title":"Structure-function analysis of a novel member of the LIV-1 subfamily of zinc transporters, ZIP14","volume":"579","author":"Taylor","year":"2005","journal-title":"FEBS Lett."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"34032","DOI":"10.1074\/jbc.M112.367284","article-title":"ZIP8 is an iron and zinc transporter whose cell-surface expression is up-regulated by cellular iron loading","volume":"287","author":"Wang","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1016\/j.ajhg.2012.01.017","article-title":"Mutations in SLC30A10 cause parkinsonism and dystonia with hypermanganesemia, polycythemia, and chronic liver disease","volume":"90","author":"Quadri","year":"2012","journal-title":"Am. J. Hum. Genet."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"5442","DOI":"10.1172\/JCI129710","article-title":"Manganese transporter Slc30a10 controls physiological manganese excretion and toxicity","volume":"129","author":"Mercadante","year":"2019","journal-title":"J. Clin. Investig."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"E1769","DOI":"10.1073\/pnas.1720739115","article-title":"SLC39A14 deficiency alters manganese homeostasis and excretion resulting in brain manganese accumulation and motor deficits in mice","volume":"115","author":"Jenkitkasemwong","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"17025","DOI":"10.1038\/celldisc.2017.25","article-title":"Manganese transporter Slc39a14 deficiency revealed its key role in maintaining manganese homeostasis in mice","volume":"3","author":"Xin","year":"2017","journal-title":"Cell Discov."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"5996","DOI":"10.1523\/JNEUROSCI.0285-17.2017","article-title":"Metal Transporter Zip14 (Slc39a14) Deletion in Mice Increases Manganese Deposition and Produces Neurotoxic Signatures and Diminished Motor Activity","volume":"37","author":"Aydemir","year":"2017","journal-title":"J. Neurosci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"13612","DOI":"10.1073\/pnas.0606424103","article-title":"Zip14 (Slc39a14) mediates non-transferrin-bound iron uptake into cells","volume":"103","author":"Liuzzi","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"6843","DOI":"10.1073\/pnas.0502257102","article-title":"Interleukin-6 regulates the zinc transporter Zip14 in liver and contributes to the hypozincemia of the acute-phase response","volume":"102","author":"Liuzzi","year":"2005","journal-title":"Proc. Natl. Acad. Sci. 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