{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T00:25:08Z","timestamp":1789431908462,"version":"build-2803163510"},"reference-count":36,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2024,2,29]],"date-time":"2024-02-29T00:00:00Z","timestamp":1709164800000},"content-version":"vor","delay-in-days":59,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Whitehall Foundation Research","award":["2020-12-107"],"award-info":[{"award-number":["2020-12-107"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Many common chemotherapeutics produce disruptions in the sense of taste which can lead to loss of appetite, nutritional imbalance, and reduced quality of life, especially if taste loss persists after treatment ends. Cyclophosphamide (CYP), an alkylating chemotherapeutic agent, affects taste sensitivity through its cytotoxic effects on mature taste receptor cells (TRCs) and on taste progenitor cell populations, retarding the capacity to replace TRCs. Mechanistic studies have focused primarily on taste cells, however, taste signaling requires communication between TRCs and the gustatory nerve fibers that innervate them. Here, we evaluate cyclophosphamide\u2019s effects on the peripheral gustatory nerve fibers that innervate the taste buds. Following histological analysis of tongue tissues, we find that CYP reduces innervation within the fungiform and circumvallates taste buds within 4 days after administration. To better understand the dynamics of the denervation process, we used 2-photon intravital imaging to visualize the peripheral gustatory nerve fibers within individual fungiform taste buds up to 20 days after CYP treatment. We find that gustatory fibers retract from the taste bud properly but are maintained within the central papilla core. These data indicate that in addition to TRCs, gustatory nerve fibers are also affected by CYP treatment. Because the connectivity between TRCs and gustatory neurons must be re-established for proper function, gustatory fibers should continue to be included in future studies to understand the mechanisms leading to chemotherapy-induced persistent taste loss.<\/jats:p>","DOI":"10.1093\/chemse\/bjae010","type":"journal-article","created":{"date-parts":[[2024,2,29]],"date-time":"2024-02-29T10:41:44Z","timestamp":1709203304000},"source":"Crossref","is-referenced-by-count":6,"title":["Cyclophosphamide induces the loss of taste bud innervation in mice"],"prefix":"10.1093","volume":"49","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-7099-320X","authenticated-orcid":false,"given":"Ryan M","family":"Wood","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Developmental and Regenerative Biology, The University of Texas at San Antonio , One UTSA Circle, San Antonio, TX , USA"},{"name":"The Graduate Program in Neuroscience, The University of Texas at San Antonio , San Antonio, TX , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin L","family":"Vasquez","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Developmental and Regenerative Biology, The University of Texas at San Antonio , One UTSA Circle, San Antonio, TX , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-4013-4958","authenticated-orcid":false,"given":"Krystal A","family":"Goyins","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Developmental and Regenerative Biology, The University of Texas at San Antonio , One UTSA Circle, San Antonio, TX , USA"},{"name":"The Graduate Program in Developmental and Regenerative Sciences, The University of Texas at San Antonio , San Antonio, TX , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-8405-6612","authenticated-orcid":false,"given":"Eduardo","family":"Gutierrez Kuri","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Developmental and Regenerative Biology, The University of Texas at San Antonio , One UTSA Circle, San Antonio, TX , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-8858-9161","authenticated-orcid":false,"given":"Kevin","family":"Connelly","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Developmental and Regenerative Biology, The University of Texas at San Antonio , One UTSA Circle, San Antonio, TX , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-7935-1450","authenticated-orcid":false,"given":"Saima","family":"Humayun","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Developmental and Regenerative Biology, The University of Texas at San Antonio , One UTSA Circle, San Antonio, TX , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1089-3733","authenticated-orcid":false,"given":"Lindsey J","family":"Macpherson","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Developmental and Regenerative Biology, The University of Texas at San Antonio , One UTSA Circle, San Antonio, TX , USA"},{"name":"Brain Health Consortium, The University of Texas at San Antonio , San Antonio, TX , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,2,29]]},"reference":[{"issue":"3","key":"2024031213173683900_CIT0001","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1007\/s00520-007-0319-7","article-title":"Self-reported taste and smell changes during cancer chemotherapy","volume":"16","author":"Bernhardson","year":"2008","journal-title":"Support Care Cancer"},{"issue":"1-2","key":"2024031213173683900_CIT0002","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.pain.2005.02.010","article-title":"Peripheral inflammation selectively increases trpv1 function in ib4-positive sensory neurons from adult mouse","volume":"115","author":"Breese","year":"2005","journal-title":"Pain"},{"issue":"17","key":"2024031213173683900_CIT0003","first-page":"3054","article-title":"Sonic hedgehog from both nerves and epithelium is a key trophic factor for taste bud maintenance","volume":"144","author":"Castillo-Azofeifa","year":"2017","journal-title":"Development"},{"issue":"14","key":"2024031213173683900_CIT0004","doi-asserted-by":"crossref","first-page":"dev164889","DOI":"10.1242\/dev.164889","article-title":"Sox2 regulation by hedgehog signaling controls adult lingual epithelium homeostasis","volume":"145","author":"Castillo-Azofeifa","year":"2018","journal-title":"Development"},{"issue":"4","key":"2024031213173683900_CIT0005","doi-asserted-by":"crossref","first-page":"e0214890","DOI":"10.1371\/journal.pone.0214890","article-title":"Cyclophosphamide and the taste system: effects of dose fractionation and amifostine on taste cell renewal","volume":"14","author":"Delay","year":"2019","journal-title":"PLoS One"},{"issue":"2","key":"2024031213173683900_CIT0006","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1007\/s00441-021-03561-1","article-title":"Probing the multimodal fungiform papilla: complex peripheral nerve endings of chorda tympani taste and mechanosensitive fibers before and after hedgehog pathway inhibition","volume":"387","author":"Donnelly","year":"2022","journal-title":"Cell Tissue Res"},{"key":"2024031213173683900_CIT0007","doi-asserted-by":"crossref","first-page":"bjab011","DOI":"10.1093\/chemse\/bjab011","article-title":"A mechanistic overview of taste bud maintenance and impairment in cancer therapies","volume":"46","author":"Gaillard","year":"2021","journal-title":"Chem Senses"},{"issue":"1","key":"2024031213173683900_CIT0008","doi-asserted-by":"crossref","first-page":"17934","DOI":"10.1038\/s41598-019-54216-9","article-title":"Fractionated head and neck irradiation impacts taste progenitors, differentiated taste cells, and wnt\/beta-catenin signaling in adult mice","volume":"9","author":"Gaillard","year":"2019","journal-title":"Sci Rep"},{"issue":"4","key":"2024031213173683900_CIT0009","doi-asserted-by":"crossref","first-page":"490","DOI":"10.3109\/0284186X.2011.633554","article-title":"Taste alterations in breast and gynaecological cancer patients receiving chemotherapy: prevalence, course of severity, and quality of life correlates","volume":"51","author":"Gamper","year":"2012","journal-title":"Acta Oncol"},{"issue":"6","key":"2024031213173683900_CIT0010","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1016\/j.jpainsymman.2011.11.011","article-title":"Coming to your senses: detecting taste and smell alterations in chemotherapy patients. a systematic review","volume":"44","author":"Gamper","year":"2012","journal-title":"J Pain Symptom Manage"},{"issue":"2","key":"2024031213173683900_CIT0011","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/j.jpainsymman.2006.07.017","article-title":"Chemosensory dysfunction is a primary factor in the evolution of declining nutritional status and quality of life in patients with advanced cancer","volume":"33","author":"Hutton","year":"2007","journal-title":"J Pain Symptom Manage"},{"issue":"3","key":"2024031213173683900_CIT0012","doi-asserted-by":"crossref","first-page":"1034","DOI":"10.1152\/jn.00822.2014","article-title":"Hedgehog pathway blockade with the cancer drug lde225 disrupts taste organs and taste sensation","volume":"113","author":"Kumari","year":"2015","journal-title":"J Neurophysiol"},{"issue":"48","key":"2024031213173683900_CIT0013","doi-asserted-by":"crossref","first-page":"E10369","DOI":"10.1073\/pnas.1712881114","article-title":"Recovery of taste organs and sensory function after severe loss from hedgehog\/smoothened inhibition with cancer drug sonidegib","volume":"114","author":"Kumari","year":"2017","journal-title":"Proc Natl Acad Sci USA"},{"key":"2024031213173683900_CIT0014","doi-asserted-by":"crossref","first-page":"16150","DOI":"10.1038\/s41598-018-34399-3","article-title":"Species generalization and differences in hedgehog pathway regulation of fungiform and circumvallate papilla taste function and somatosensation demonstrated with sonidegib","volume":"8","author":"Kumari","year":"2018","journal-title":"Sci Rep-Uk"},{"issue":"2","key":"2024031213173683900_CIT0015","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1073\/pnas.2001833118","article-title":"R-spondin substitutes for neuronal input for taste cell regeneration in adult mice","volume":"118","author":"Lin","year":"2021","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"2","key":"2024031213173683900_CIT0016","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/j.stemcr.2021.12.002","article-title":"Rnf43\/znrf3 negatively regulates taste tissue homeostasis and positively regulates dorsal lingual epithelial tissue homeostasis","volume":"17","author":"Lu","year":"2022","journal-title":"Stem Cell Rep"},{"issue":"2","key":"2024031213173683900_CIT0017","doi-asserted-by":"crossref","first-page":"E200","DOI":"10.1073\/pnas.1719109115","article-title":"Neuronal delivery of hedgehog directs spatial patterning of taste organ regeneration","volume":"115","author":"Lu","year":"2018","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"2","key":"2024031213173683900_CIT0018","first-page":"107","article-title":"Taste bud regeneration and the search for taste progenitor cells","volume":"148","author":"Miura","year":"2010","journal-title":"Arch Ital Biol"},{"issue":"4","key":"2024031213173683900_CIT0019","doi-asserted-by":"crossref","first-page":"e61607","DOI":"10.1371\/journal.pone.0061607","article-title":"Pre-treatment with amifostine protects against cyclophosphamide-induced disruption of taste in mice","volume":"8","author":"Mukherjee","year":"2013","journal-title":"PLoS One"},{"key":"2024031213173683900_CIT0020","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1016\/j.neuroscience.2011.07.006","article-title":"Cyclophosphamide-induced disruption of umami taste functions and taste epithelium","volume":"192","author":"Mukherjee","year":"2011","journal-title":"Neuroscience"},{"issue":"9","key":"2024031213173683900_CIT0021","doi-asserted-by":"crossref","first-page":"e0185473","DOI":"10.1371\/journal.pone.0185473","article-title":"Cellular mechanisms of cyclophosphamide-induced taste loss in mice","volume":"12","author":"Mukherjee","year":"2017","journal-title":"PLoS One"},{"key":"2024031213173683900_CIT0022","doi-asserted-by":"crossref","first-page":"134","DOI":"10.3389\/fphys.2017.00134","article-title":"Alteration in taste perception in cancer: causes and strategies of treatment","volume":"8","author":"Murtaza","year":"2017","journal-title":"Front Physiol"},{"issue":"10","key":"2024031213173683900_CIT0023","doi-asserted-by":"crossref","first-page":"3474","DOI":"10.1523\/JNEUROSCI.4167-11.2012","article-title":"Mechanisms of taste bud cell loss after head and neck irradiation","volume":"32","author":"Nguyen","year":"2012","journal-title":"J Neurosci"},{"issue":"18","key":"2024031213173683900_CIT0024","doi-asserted-by":"crossref","first-page":"3935","DOI":"10.1002\/cne.24312","article-title":"The transcription factor phox2b distinguishes between oral and non-oral sensory neurons in the geniculate ganglion","volume":"525","author":"Ohman-Gault","year":"2017","journal-title":"J Comp Neurol"},{"issue":"5479","key":"2024031213173683900_CIT0025","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1126\/science.289.5479.628","article-title":"Altered nociceptive neuronal circuits after neonatal peripheral inflammation","volume":"289","author":"Ruda","year":"2000","journal-title":"Science"},{"key":"2024031213173683900_CIT0026","doi-asserted-by":"crossref","first-page":"bjab031","DOI":"10.1093\/chemse\/bjab031","article-title":"Cyclophosphamide-induced inflammation of taste buds and cytoprotection by amifostine","volume":"46","author":"Sarkar","year":"2021","journal-title":"Chem Senses"},{"issue":"23","key":"2024031213173683900_CIT0027","doi-asserted-by":"crossref","first-page":"2171","DOI":"10.1056\/NEJMoa1113713","article-title":"Efficacy and safety of vismodegib in advanced basal-cell carcinoma","volume":"366","author":"Sekulic","year":"2012","journal-title":"N Engl J Med"},{"issue":"1-3","key":"2024031213173683900_CIT0028","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/j.neulet.2003.12.007","article-title":"Recent findings on how proinflammatory cytokines cause pain: peripheral mechanisms in inflammatory and neuropathic hyperalgesia","volume":"361","author":"Sommer","year":"2004","journal-title":"Neurosci Lett"},{"issue":"1-2","key":"2024031213173683900_CIT0029","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.pain.2006.10.007","article-title":"Enhanced excitability of nociceptive trigeminal ganglion neurons by satellite glial cytokine following peripheral inflammation","volume":"129","author":"Takeda","year":"2007","journal-title":"Pain"},{"issue":"23","key":"2024031213173683900_CIT0030","doi-asserted-by":"crossref","first-page":"2180","DOI":"10.1056\/NEJMoa1113538","article-title":"Inhibiting the hedgehog pathway in patients with the basal-cell nevus syndrome","volume":"366","author":"Tang","year":"2012","journal-title":"N Engl J Med"},{"issue":"12","key":"2024031213173683900_CIT0031","doi-asserted-by":"crossref","first-page":"1164","DOI":"10.1056\/NEJMoa0905360","article-title":"Inhibition of the hedgehog pathway in advanced basal-cell carcinoma","volume":"361","author":"Von Hoff","year":"2009","journal-title":"N Engl J Med"},{"issue":"8","key":"2024031213173683900_CIT0032","doi-asserted-by":"crossref","first-page":"e3002271","DOI":"10.1371\/journal.pbio.3002271","article-title":"Rapid structural remodeling of peripheral taste neurons is independent of taste cell turnover","volume":"21","author":"Whiddon","year":"2023","journal-title":"PLoS Biol"},{"issue":"6","key":"2024031213173683900_CIT0033","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1016\/S1470-2045(19)30163-9","article-title":"Estimates of global chemotherapy demands and corresponding physician workforce requirements for 2018 and 2040: a population-based study","volume":"20","author":"Wilson","year":"2019","journal-title":"Lancet Oncol"},{"issue":"1","key":"2024031213173683900_CIT0034","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1523\/JNEUROSCI.22-01-00093.2002","article-title":"Peripheral inflammation sensitizes p2x receptor-mediated responses in rat dorsal root ganglion neurons","volume":"22","author":"Xu","year":"2002","journal-title":"J Neurosci"},{"issue":"8","key":"2024031213173683900_CIT0035","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1634\/theoncologist.2009-0333","article-title":"Taste alterations in cancer patients receiving chemotherapy: a neglected side effect","volume":"15","author":"Zabernigg","year":"2010","journal-title":"Oncologist"},{"issue":"7","key":"2024031213173683900_CIT0036","doi-asserted-by":"crossref","first-page":"2331","DOI":"10.1073\/pnas.0805159106","article-title":"R-spondin1 protects mice from chemotherapy or radiation-induced oral mucositis through the canonical wnt\/beta-catenin pathway","volume":"106","author":"Zhao","year":"2009","journal-title":"Proc Natl Acad Sci U S A"}],"container-title":["Chemical Senses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/chemse\/advance-article-pdf\/doi\/10.1093\/chemse\/bjae010\/56796706\/bjae010.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/chemse\/article-pdf\/doi\/10.1093\/chemse\/bjae010\/56945990\/bjae010.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/chemse\/article-pdf\/doi\/10.1093\/chemse\/bjae010\/56945990\/bjae010.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,12]],"date-time":"2024-03-12T09:20:01Z","timestamp":1710235201000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/chemse\/article\/doi\/10.1093\/chemse\/bjae010\/7616296"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,1]]},"references-count":36,"URL":"https:\/\/doi.org\/10.1093\/chemse\/bjae010","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2023.06.14.544942","asserted-by":"object"}]},"ISSN":["0379-864X","1464-3553"],"issn-type":[{"value":"0379-864X","type":"print"},{"value":"1464-3553","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2024,1,1]]},"published":{"date-parts":[[2024,1,1]]},"article-number":"bjae010"}}