{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,21]],"date-time":"2026-02-21T08:55:42Z","timestamp":1771664142842,"version":"3.50.1"},"reference-count":43,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2022,5,9]],"date-time":"2022-05-09T00:00:00Z","timestamp":1652054400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100008143","name":"ONPRC","doi-asserted-by":"publisher","award":["P51 OD011092"],"award-info":[{"award-number":["P51 OD011092"]}],"id":[{"id":"10.13039\/100008143","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["R01 - HL146736P"],"award-info":[{"award-number":["R01 - HL146736P"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["U54 HD055744"],"award-info":[{"award-number":["U54 HD055744"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000071","name":"NICHD","doi-asserted-by":"publisher","award":["K12 HD000849"],"award-info":[{"award-number":["K12 HD000849"]}],"id":[{"id":"10.13039\/100000071","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,9,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The cystic fibrosis transmembrane conductance regulator (CFTR) is an apical membrane chloride\/bicarbonate ion channel in epithelial cells. Mutations in CFTR cause cystic fibrosis, a disease characterized by thickened mucus secretions and is associated with subfertility and infertility. CFTR function has been well characterized in vitro and in vivo in airway and other epithelia studies. However, little is known about CFTR function in the cervix in health and its contribution to cyclic regulation of fertility from endocervical mucus changes. Contributing to this research gap is the lack of information on the effect of sex steroid hormones on CFTR expression in cervical epithelial cells across the menstrual cycle. Herein, we demonstrate the hormonal regulation of CFTR expression in endocervical cells both in vitro and in vivo, and that conditionally reprogrammed endocervical epithelial cells can be used to interrogate CFTR ion channel function. CFTR activity was demonstrated in vitro using electrophysiological methods and functionally inhibited by the CFTR-specific inhibitors inh-172 and GlyH-101. We also report that CFTR expression is increased by estradiol in the macaque cervix both in vitro and in vivo in Rhesus macaques treated with artificial menstrual cycles. Estrogen upregulation of CFTR is blocked in vivo by cotreatment with progesterone. Our findings provide the most comprehensive evidence to date that steroid hormones drive changes in CFTR expression. These data are integral to understanding the role of CFTR as a fertility regulator in the endocervix.<\/jats:p>","DOI":"10.1093\/biolre\/ioac090","type":"journal-article","created":{"date-parts":[[2022,5,9]],"date-time":"2022-05-09T12:31:12Z","timestamp":1652099472000},"page":"732-740","source":"Crossref","is-referenced-by-count":10,"title":["Functional evaluation of the cystic fibrosis transmembrane conductance regulator in the endocervix"],"prefix":"10.1093","volume":"107","author":[{"given":"Leo","family":"Han","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology , Oregon Health & Science University, Portland, OR, USA"},{"name":"Division of Reproductive and Developmental Sciences , Oregon National Primate Research Center, Portland, OR, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mackenzie","family":"Roberts","sequence":"additional","affiliation":[{"name":"Division of Reproductive and Developmental Sciences , Oregon National Primate Research Center, Portland, OR, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Addie","family":"Luo","sequence":"additional","affiliation":[{"name":"Division of Reproductive and Developmental Sciences , Oregon National Primate Research Center, Portland, OR, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuhao","family":"Wei","sequence":"additional","affiliation":[{"name":"Division of Reproductive and Developmental Sciences , Oregon National Primate Research Center, Portland, OR, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ov D","family":"Slayden","sequence":"additional","affiliation":[{"name":"Division of Reproductive and Developmental Sciences , Oregon National Primate Research Center, Portland, OR, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kelvin D","family":"Macdonald","sequence":"additional","affiliation":[{"name":"Department of Pediatrics , Oregon Health & Science University, Portland, OR, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2022,5,9]]},"reference":[{"key":"2022091511311840000_ref1","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1016\/S0140-6736(03)12567-6","article-title":"Cystic fibrosis","volume":"361","author":"Ratjen","year":"2003","journal-title":"Lancet"},{"key":"2022091511311840000_ref2","doi-asserted-by":"crossref","first-page":"1638","DOI":"10.1001\/jama.1996.03540200024023","article-title":"Hypofertility with thick cervical mucus: another mild form of cystic fibrosis?","volume":"276","year":"1996","journal-title":"JAMA"},{"key":"2022091511311840000_ref3","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1016\/0002-9378(70)90254-1","article-title":"Cervical mucus in cystic fibrosis: a possible cause of infertility","volume":"108","author":"Oppenheimer","year":"1970","journal-title":"Am J Obstet Gynecol"},{"key":"2022091511311840000_ref4","doi-asserted-by":"crossref","first-page":"1201.e19","DOI":"10.1016\/j.fertnstert.2007.08.063","article-title":"Infertility and abnormal cervical mucus in two sisters who are compound heterozygotes for the cystic fibrosis (CF) \u0394F508 and R117H\/7T mutations","volume":"90","author":"Schoyer","year":"2008","journal-title":"Fertil Steril"},{"key":"2022091511311840000_ref5","doi-asserted-by":"crossref","first-page":"2790","DOI":"10.1210\/en.2007-1581","article-title":"Infertility in females with cystic fibrosis is multifactorial: evidence from mouse models","volume":"149","author":"Hodges","year":"2008","journal-title":"Endocrinology"},{"key":"2022091511311840000_ref6","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1016\/S0015-0282(16)39790-4","article-title":"Water and electrolytes in cervical mucus from patients with cystic fibrosis","volume":"24","author":"Kopito","year":"1973","journal-title":"Fertil Steril"},{"key":"2022091511311840000_ref7","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1007\/s00018-016-2391-y","article-title":"Role of CFTR in epithelial physiology","volume":"74","author":"Saint-Criq","year":"2017","journal-title":"Cell Mol Life Sci"},{"key":"2022091511311840000_ref8","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/j.molmed.2007.05.001","article-title":"Cystic fibrosis: a disease of vulnerability to airway surface dehydration","volume":"13","author":"Boucher","year":"2007","journal-title":"Trends Mol Med"},{"key":"2022091511311840000_ref9","doi-asserted-by":"crossref","first-page":"1263","DOI":"10.1084\/jem.20120562","article-title":"Bicarbonate and functional CFTR channel are required for proper mucin secretion and link cystic fibrosis with its mucus phenotype","volume":"209","author":"Gustafsson","year":"2012","journal-title":"J Exp Med"},{"key":"2022091511311840000_ref10","doi-asserted-by":"crossref","first-page":"2329","DOI":"10.1113\/jphysiol.2010.187237","article-title":"A new role for bicarbonate secretion in cervico-uterine mucus release","volume":"588","author":"Muchekehu","year":"2010","journal-title":"J Physiol"},{"key":"2022091511311840000_ref11","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1016\/0002-9378(72)90617-5","article-title":"A composite picture of the menstrual cycle","volume":"114","author":"Moghissi","year":"1972","journal-title":"Am J Obstet Gynecol"},{"key":"2022091511311840000_ref12","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1095\/biolreprod60.1.58","article-title":"MUC4 and MUC5B transcripts are the prevalent Mucin messenger ribonucleic acids of the human endocervix","volume":"60","author":"Gipson","year":"1999","journal-title":"Biol Reprod"},{"key":"2022091511311840000_ref13","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1074\/mcp.M600439-MCP200","article-title":"Large scale identification of proteins, Mucins, and their O-glycosylation in the endocervical mucus during the menstrual cycle","volume":"6","author":"Andersch-Bj\u00f6rkman","year":"2007","journal-title":"Mol Cell Proteomics"},{"key":"2022091511311840000_ref14","first-page":"347","article-title":"Cyclic changes of cervical mucus enzymes related to the time of ovulation II. Amino peptidase and esterase","volume":"48","author":"Moghissi","year":"1976","journal-title":"Obstet Gynecol"},{"key":"2022091511311840000_ref15","doi-asserted-by":"crossref","first-page":"10260","DOI":"10.1073\/pnas.1106695108","article-title":"Human cystic fibrosis airway epithelia have reduced Cl\u2212 conductance but not increased Na+ conductance","volume":"108","author":"Itani","year":"2011","journal-title":"PNAS"},{"key":"2022091511311840000_ref16","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1038\/nm.3201","article-title":"A functional CFTR assay using primary cystic fibrosis intestinal organoids","volume":"19","author":"Dekkers","year":"2013","journal-title":"Nat Med"},{"key":"2022091511311840000_ref17","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.1093\/biolre\/ioaa039","article-title":"Conditionally reprogrammed macaque endocervical cells retain steroid receptor expression and produce mucus","volume":"102","author":"Han","year":"2020","journal-title":"Biol Reprod"},{"key":"2022091511311840000_ref18","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1679\/aohc.67.393","article-title":"Hormonal regulation and localization of estrogen, progestin and androgen receptors in the endometrium of nonhuman primates: effects of progesterone receptor antagonists","volume":"67","author":"Slayden","year":"2004","journal-title":"Arch Histol Cytol"},{"key":"2022091511311840000_ref19","doi-asserted-by":"crossref","first-page":"S6","DOI":"10.1186\/1477-7827-4-S1-S6","article-title":"A critical period of progesterone withdrawal precedes menstruation in macaques","volume":"4","author":"Slayden","year":"2006","journal-title":"Reprod Biol Endocrinol"},{"key":"2022091511311840000_ref20","doi-asserted-by":"crossref","first-page":"1723","DOI":"10.1093\/humrep\/des086","article-title":"Localization and hormonal regulation of endometrial matrix metalloproteinase-26 in the rhesus macaque","volume":"27","author":"Almeida-Francia","year":"2012","journal-title":"Hum Reprod"},{"key":"2022091511311840000_ref21","author":"Tissue Distribution Program | OHSU"},{"key":"2022091511311840000_ref22","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1038\/nprot.2016.174","article-title":"Conditional reprogramming and long-term expansion of normal and tumor cells from human biospecimens","volume":"12","author":"Liu","year":"2017","journal-title":"Nat Protoc"},{"key":"2022091511311840000_ref23","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.jri.2011.08.002","article-title":"Innate immune mediator profiles and their regulation in a novel polarized immortalized epithelial cell model derived from human endocervix","volume":"92","author":"Buckner","year":"2011","journal-title":"J Reprod Immunol"},{"key":"2022091511311840000_ref24","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1677\/jme.1.01550","article-title":"Regulation of functional steroid receptors and ligand-induced responses in telomerase-immortalized human endometrial epithelial cells","volume":"34","author":"Hombach-Klonisch","year":"2005","journal-title":"J Mol Endocrinol"},{"key":"2022091511311840000_ref25","doi-asserted-by":"crossref","first-page":"3529","DOI":"10.2174\/13816128113199990321","article-title":"CFTR inhibitors","volume":"19","author":"Verkman","year":"2013","journal-title":"Curr Pharm Des"},{"key":"2022091511311840000_ref26","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1111\/jmp.12357","article-title":"Hormonal regulation of oviductal glycoprotein 1 (OVGP1; MUC9) in the rhesus macaque cervix","volume":"47","author":"Slayden","year":"2018","journal-title":"J Med Primatol"},{"key":"2022091511311840000_ref27","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1016\/S0015-0282(97)81358-1","article-title":"The cystic fibrosis transmembrane regulator gene is expressed in the human endocervix throughout the menstrual cycle","volume":"67","author":"Hayslip","year":"1997","journal-title":"Fertil Steril"},{"key":"2022091511311840000_ref28","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1002\/dc.22842","article-title":"Gynecologic cytology on conventional and liquid-based preparations: a comprehensive review of similarities and differences","volume":"41","author":"Hoda","year":"2013","journal-title":"Diagn Cytopathol"},{"key":"2022091511311840000_ref29","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1002\/mrd.22496","article-title":"Estrogen and progesterone differentially regulate the levels of cystic fibrosis transmembrane regulator (CFTR), adenylate cyclase (AC), and cyclic adenosine mono-phosphate (cAMP) in the rat cervix","volume":"82","author":"Ismail","year":"2015","journal-title":"Mol Reprod Dev"},{"key":"2022091511311840000_ref30","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.diff.2019.07.004","article-title":"Reproductive tract biology: of mice and men","volume":"110","author":"Cunha","year":"2019","journal-title":"Differentiation"},{"key":"2022091511311840000_ref31","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1007\/BF01730575","article-title":"Comparative anatomy and histology of the cervix uteri in non-human primates","volume":"13","author":"Hafez","year":"1972","journal-title":"Primates"},{"key":"2022091511311840000_ref32","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1093\/humrep\/11.suppl_2.150","article-title":"Non-human primate models: artificial menstrual cycles, endometrial matrix metalloproteinases and s.c. endometrial grafts","volume":"11","author":"Brenner","year":"1996","journal-title":"Hum Reprod"},{"key":"2022091511311840000_ref33","article-title":"Comparing endocervical mucus proteome of humans and rhesus macaques","volume":"15","author":"Han","journal-title":"Proteomics Clin Appl"},{"key":"2022091511311840000_ref34","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1016\/S0022-3476(86)80825-3","article-title":"Increased nasal potential difference and amiloride sensitivity in neonates with cystic fibrosis","volume":"108","author":"Gowen","year":"1986","journal-title":"J Pediatr"},{"key":"2022091511311840000_ref35","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1016\/j.yexmp.2009.09.018","article-title":"CFTR and tight junctions in cultured bronchial epithelial cells","volume":"88","author":"Nilsson","year":"2010","journal-title":"Exp Mol Pathol"},{"key":"2022091511311840000_ref36","author":"Measurement of Transepithelial Electrical Resistance (TEER)"},{"key":"2022091511311840000_ref37","doi-asserted-by":"crossref","first-page":"2365","DOI":"10.1074\/jbc.M110.175109","article-title":"TMEM16A inhibitors reveal TMEM16A as a minor component of calcium-activated chloride channel conductance in airway and intestinal epithelial cells","volume":"286","author":"Namkung","year":"2011","journal-title":"J Biol Chem"},{"key":"2022091511311840000_ref38","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.coph.2018.09.007","article-title":"The epithelial sodium channel (ENaC) as a therapeutic target for cystic fibrosis","volume":"43","author":"Shei","year":"2018","journal-title":"Curr Opin Pharmacol"},{"key":"2022091511311840000_ref39","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1016\/S0015-0282(16)49230-7","article-title":"Intrauterine insemination for infertility due to cystic fibrosis","volume":"45","author":"Kredentser","year":"1986","journal-title":"Fertil Steril"},{"key":"2022091511311840000_ref40","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1016\/S0015-0282(16)44773-4","article-title":"Sodium bicarbonate douching for improvement of the postcoital test","volume":"33","author":"Ansari","year":"1980","journal-title":"Fertil Steril"},{"key":"2022091511311840000_ref41","first-page":"195","article-title":"Estrogen inhibition of cystic fibrosis transmembrane conductance regulator-mediated chloride secretion","volume":"295","author":"Singh","year":"2000","journal-title":"J Pharmacol Exp Ther"},{"key":"2022091511311840000_ref42","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1016\/j.jcf.2015.06.002","article-title":"Targeting ion channels in cystic fibrosis","volume":"14","author":"Mall","year":"2015","journal-title":"J Cyst Fibros"},{"key":"2022091511311840000_ref43","doi-asserted-by":"crossref","first-page":"2557","DOI":"10.3390\/ijms21072557","article-title":"Pharmacological inhibition and activation of the Ca2+ activated Cl\u2212 channel TMEM16A","volume":"21","author":"Centeio","year":"2020","journal-title":"IJMS"}],"container-title":["Biology of Reproduction"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/biolreprod\/advance-article-pdf\/doi\/10.1093\/biolre\/ioac090\/43962945\/ioac090.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/biolreprod\/article-pdf\/107\/3\/732\/45798818\/ioac090.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/biolreprod\/article-pdf\/107\/3\/732\/45798818\/ioac090.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,9,15]],"date-time":"2022-09-15T11:32:14Z","timestamp":1663241534000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/biolreprod\/article\/107\/3\/732\/6582490"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,9]]},"references-count":43,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2022,5,9]]},"published-print":{"date-parts":[[2022,9,12]]}},"URL":"https:\/\/doi.org\/10.1093\/biolre\/ioac090","relation":{},"ISSN":["0006-3363","1529-7268"],"issn-type":[{"value":"0006-3363","type":"print"},{"value":"1529-7268","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,9]]},"published":{"date-parts":[[2022,5,9]]}}}