{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T03:28:52Z","timestamp":1790393332349,"version":"4.1.0"},"reference-count":56,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2020,12,22]],"date-time":"2020-12-22T00:00:00Z","timestamp":1608595200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"US Food and Drug Administration","award":["E0744301"],"award-info":[{"award-number":["E0744301"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Consumer products manufactured with antimicrobial silver nanoparticles (AgNPs) may affect the gastrointestinal (GI) system. The human GI-tract is complex and there are physiological and anatomical differences between human and animal models that limit comparisons between species. Thus, assessment of AgNP toxicity on the human GI-tract may require tools that allow for the examination of subtle changes in inflammatory markers and indicators of epithelial perturbation. Fresh tissues were excised from the GI-tract of human male and female subjects to evaluate the effects of AgNPs on the GI-system. The purpose of this study was to perform an assessment on the ability of the ex vivo model to evaluate changes in levels of pro-\/anti-inflammatory cytokines\/chemokines and mRNA expression of intestinal permeability related genes induced by AgNPs in ileal tissues. The ex vivo model preserved the structural and biological functions of the in-situ organ. Analysis of cytokine expression data indicated that intestinal tissue of male and female subjects responded differently to AgNP treatment, with male samples showing significantly elevated Granulocyte-macrophage colony-stimulating factor (GM-CSF) after treatment with 10 nm and 20 nm AgNPs for 2 h and significantly elevated RANTES after treatment with 20 nm AgNPs for 24 h. In contrast, tissues of female showed no significant effects of AgNP treatment at 2 h and significantly decreased RANTES (20 nm), TNF-\u03b1 (10 nm), and IFN-\u03b3 (10 nm) at 24 h. Smaller size AgNPs (10 nm) perturbed more permeability-related genes in samples of male subjects, than in samples from female subjects. In contrast, exposure to 20 nm AgNPs resulted in upregulation of a greater number of genes in female-derived samples (36 genes) than in male-derived samples (8 genes). The ex vivo tissue model can distinguish sex dependent effects of AgNP and could serve as a translational non-animal model to assess the impacts of xenobiotics on human intestinal mucosa.<\/jats:p>","DOI":"10.3390\/ijms22010009","type":"journal-article","created":{"date-parts":[[2020,12,22]],"date-time":"2020-12-22T20:39:29Z","timestamp":1608669569000},"page":"9","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Human Intestinal Tissue Explant Exposure to Silver Nanoparticles Reveals Sex Dependent Alterations in Inflammatory Responses and Epithelial Cell Permeability"],"prefix":"10.3390","volume":"22","author":[{"given":"Kuppan","family":"Gokulan","sequence":"first","affiliation":[{"name":"National Center for Toxicological Research, Division of Microbiology, US Food and Drug Administration, 3900 NCTR Rd, Jefferson, AR 72079, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Williams","sequence":"additional","affiliation":[{"name":"National Center for Toxicological Research, Division of Microbiology, US Food and Drug Administration, 3900 NCTR Rd, Jefferson, AR 72079, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Orr","sequence":"additional","affiliation":[{"name":"National Center for Toxicological Research, Division of Microbiology, US Food and Drug Administration, 3900 NCTR Rd, Jefferson, AR 72079, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9496-6636","authenticated-orcid":false,"given":"Sangeeta","family":"Khare","sequence":"additional","affiliation":[{"name":"National Center for Toxicological Research, Division of Microbiology, US Food and Drug Administration, 3900 NCTR Rd, Jefferson, AR 72079, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,12,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1089\/fpd.2015.2054","article-title":"Dose and Size-Dependent Antiviral Effects of Silver Nanoparticles on Feline Calicivirus, a Human Norovirus Surrogate","volume":"13","author":"Bekele","year":"2016","journal-title":"Foodborne Pathog. Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1831","DOI":"10.3389\/fmicb.2016.01831","article-title":"Mechanistic Basis of Antimicrobial Actions of Silver Nanoparticles","volume":"7","author":"Dakal","year":"2016","journal-title":"Front. Microbiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"6555","DOI":"10.1007\/s00253-016-7657-7","article-title":"Antimicrobial activity of biogenic silver nanoparticles, and silver chloride nanoparticles: An overview and comments","volume":"100","author":"Duran","year":"2016","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.nano.2006.12.001","article-title":"Antimicrobial effects of silver nanoparticles","volume":"3","author":"Kim","year":"2007","journal-title":"Nanomedicine"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1007\/s10534-013-9645-z","article-title":"Antimicrobial silver: Uses, toxicity and potential for resistance","volume":"26","author":"Mijnendonckx","year":"2013","journal-title":"Biometals"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/j.jviromet.2011.09.003","article-title":"Inhibitory effects of silver nanoparticles on H1N1 influenza A virus in vitro","volume":"178","author":"Xiang","year":"2011","journal-title":"J. Virol. Methods"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2857","DOI":"10.2147\/IJN.S161379","article-title":"Responses of intestinal virome to silver nanoparticles: Safety assessment by classical virology, whole-genome sequencing and bioinformatics approaches","volume":"13","author":"Gokulan","year":"2018","journal-title":"Int. J. Nanomed."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.fct.2013.08.014","article-title":"Nanoparticle release from nano-silver antimicrobial food containers","volume":"62","author":"Echegoyen","year":"2013","journal-title":"Food Chem. Toxicol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1080\/19440049.2012.762693","article-title":"Migration of silver from commercial plastic food containers and implications for consumer exposure assessment","volume":"30","author":"Fabricius","year":"2013","journal-title":"Food Addit. Contam. Part A"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/j.fct.2016.12.014","article-title":"Assessment of antimicrobial effects of food contact materials containing silver on growth of Salmonella Typhimurium","volume":"100","author":"Williams","year":"2017","journal-title":"Food Chem. Toxicol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4133","DOI":"10.1021\/es7032718","article-title":"Nanoparticle silver released into water from commercially available sock fabrics","volume":"42","author":"Benn","year":"2008","journal-title":"Environ. Sci. Technol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1016\/j.jhazmat.2016.03.067","article-title":"The release of silver nanoparticles from commercial toothbrushes","volume":"322","author":"Mackevica","year":"2017","journal-title":"J. Hazard. Mater."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1016\/S0168-6445(03)00047-0","article-title":"Bacterial silver resistance: Molecular biology and uses and misuses of silver compounds","volume":"27","author":"Silver","year":"2003","journal-title":"FEMS Microbiol. Rev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1061\/(ASCE)EE.1943-7870.0000330","article-title":"Ceramic Filters Impregnated with Silver Nanoparticles for Point-of-Use Water Treatment in Rural Guatemala","volume":"137","author":"Kallman","year":"2011","journal-title":"J. Environ. Eng."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"8515","DOI":"10.1021\/acs.est.5b01428","article-title":"Silver Dissolution and Release from Ceramic Water Filters","volume":"49","author":"Mittelman","year":"2015","journal-title":"Environ. Sci. Technol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1875","DOI":"10.2134\/jeq2009.0363","article-title":"The release of nanosilver from consumer products used in the home","volume":"39","author":"Benn","year":"2010","journal-title":"J. Environ. Qual."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"279","DOI":"10.3109\/17435390.2014.921346","article-title":"Effects of subchronic exposure of silver nanoparticles on intestinal microbiota and gut-associated immune responses in the ileum of Sprague-Dawley rats","volume":"9","author":"Williams","year":"2015","journal-title":"Nanotoxicology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1280","DOI":"10.1016\/j.tiv.2014.06.005","article-title":"Exposure to silver nanoparticles induces size- and dose-dependent oxidative stress and cytotoxicity in human colon carcinoma cells","volume":"28","author":"Rumpker","year":"2014","journal-title":"Toxicol. Vitr."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"852","DOI":"10.3109\/17435390.2014.980760","article-title":"Molecular mechanism of silver nanoparticles in human intestinal cells","volume":"9","author":"Niemann","year":"2015","journal-title":"Nanotoxicology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1793","DOI":"10.1016\/j.tiv.2015.07.017","article-title":"Oxidative stress-mediated inhibition of intestinal epithelial cell proliferation by silver nanoparticles","volume":"29","author":"McCracken","year":"2015","journal-title":"Toxicol. Vitr."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/s12989-016-0117-9","article-title":"Effects of silver nanoparticles and ions on a co-culture model for the gastrointestinal epithelium","volume":"13","author":"Georgantzopoulou","year":"2016","journal-title":"Part. Fibre Toxicol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1186\/s12951-016-0214-9","article-title":"Size and dose dependent effects of silver nanoparticle exposure on intestinal permeability in an in vitro model of the human gut epithelium","volume":"14","author":"Williams","year":"2016","journal-title":"J. Nanobiotechnology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"327","DOI":"10.14573\/altex.1510051","article-title":"Non-animal models of epithelial barriers (skin, intestine and lung) in research, industrial applications and regulatory toxicology","volume":"32","author":"Gordon","year":"2015","journal-title":"ALTEX"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Verhoeckx, K., Cotter, P., L\u00f3pez-Exp\u00f3sito, I., Kleivel, C., Lea, T., Mackie, A., Requena, T., Swiatecka, D., and Wichers, H. (2015). HT29 Cell Line. The Impact of Food Bioactives on Health: In Vitro and Ex Vivo Models, Springer.","DOI":"10.1007\/978-3-319-16104-4"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1186\/s12951-019-0503-1","article-title":"Using 3D gastrointestinal tract in vitro models with microfold cells and mucus secreting ability to assess the hazard of copper oxide nanomaterials","volume":"17","author":"Ude","year":"2019","journal-title":"J. Nanobiotechnology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.addr.2015.02.003","article-title":"Studies and methodologies on vaginal drug permeation","volume":"92","author":"Machado","year":"2015","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1242\/dmm.027649","article-title":"Helicobacter pylori-induced gastric pathology: Insights from in vivo and ex vivo models","volume":"10","author":"Burkitt","year":"2017","journal-title":"Dis. Model Mech."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3535","DOI":"10.1038\/s41598-020-60521-5","article-title":"Intestinal ex vivo organoid culture reveals altered programmed crypt stem cells in patients with celiac disease","volume":"10","author":"Dieterich","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1136\/gutjnl-2014-307204","article-title":"Ex vivo culture of the intestinal epithelium: Strategies and applications","volume":"63","author":"Leushacke","year":"2014","journal-title":"Gut"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1038\/s41575-019-0255-2","article-title":"Organoid models of gastrointestinal cancers in basic and translational research","volume":"17","author":"Lau","year":"2020","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1016\/j.jcmgh.2017.12.010","article-title":"Microfluidic Organ-on-a-Chip Models of Human Intestine","volume":"5","author":"Bein","year":"2018","journal-title":"Cell. Mol. Gastroenterol. Hepatol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2264","DOI":"10.1039\/C7LC00155J","article-title":"Organs-on-chips with integrated electrodes for trans-epithelial electrical resistance (TEER) measurements of human epithelial barrier function","volume":"17","author":"Henry","year":"2017","journal-title":"Lab Chip"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2871","DOI":"10.1038\/s41598-018-21201-7","article-title":"Development of a primary human Small Intestine-on-a-Chip using biopsy-derived organoids","volume":"8","author":"Kasendra","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"442","DOI":"10.4161\/gmic.20885","article-title":"Should probiotics be tested on ex vivo organ culture models?","volume":"3","author":"Tsilingiri","year":"2012","journal-title":"Gut Microbes"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3768","DOI":"10.1007\/s11095-015-1738-7","article-title":"Pharmacodynamic Activity of Dapivirine and Maraviroc Single Entity and Combination Topical Gels for HIV-1 Prevention","volume":"32","author":"Dezzutti","year":"2015","journal-title":"Pharm. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1517\/17425255.2016.1125882","article-title":"Precision-cut intestinal slices: Alternative model for drug transport, metabolism, and toxicology research","volume":"12","author":"Li","year":"2016","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"434010","DOI":"10.1155\/2013\/434010","article-title":"Cytokine levels in the serum of healthy subjects","volume":"2013","author":"Kleiner","year":"2013","journal-title":"Mediat. Inflamm."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1038\/nri.2016.90","article-title":"Sex differences in immune responses","volume":"16","author":"Klein","year":"2016","journal-title":"Nat. Rev. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1016\/j.cell.2016.10.018","article-title":"Host and Environmental Factors Influencing Individual Human Cytokine Responses","volume":"167","author":"Jaeger","year":"2016","journal-title":"Cell"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/1743-8977-11-13","article-title":"Titanium dioxide nanoparticle impact and translocation through ex vivo, in vivo and in vitro gut epithelia","volume":"11","author":"Brun","year":"2014","journal-title":"Part. Fibre Toxicol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.colsurfb.2015.07.038","article-title":"The influence of small intestinal mucus structure on particle transport ex vivo","volume":"135","author":"Bajka","year":"2015","journal-title":"Colloids Surf. B Biointerfaces"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"6922","DOI":"10.1016\/j.biomaterials.2013.05.039","article-title":"Enhanced vaginal drug delivery through the use of hypotonic formulations that induce fluid uptake","volume":"34","author":"Ensign","year":"2013","journal-title":"Biomaterials"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.ejpb.2006.07.016","article-title":"Nanoparticles based on N-trimethylchitosan: Evaluation of absorption properties using in vitro (Caco-2 cells) and ex vivo (excised rat jejunum) models","volume":"65","author":"Sandri","year":"2007","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1007\/s00428-012-1195-1","article-title":"Comparative tight junction protein expressions in colonic Crohn\u2019s disease, ulcerative colitis, and tuberculosis: A new perspective","volume":"460","author":"Das","year":"2012","journal-title":"Virchows Arch."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1007\/s00418-008-0424-9","article-title":"Tight junctions and the modulation of barrier function in disease","volume":"130","author":"Forster","year":"2008","journal-title":"Histochem. Cell Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/S0889-8553(05)70004-2","article-title":"Intestinal epithelial hyperpermeability. Mechanisms and relevance to disease","volume":"27","author":"Unno","year":"1998","journal-title":"Gastroenterol. Clin. N. Am."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/j.envpol.2017.11.074","article-title":"Dysbiosis of gut microbiota by chronic coexposure to titanium dioxide nanoparticles and bisphenol A: Implications for host health in zebrafish","volume":"234","author":"Chen","year":"2018","journal-title":"Environ. Pollut."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1186\/s12951-019-0499-6","article-title":"Alteration in the mRNA expression of genes associated with gastrointestinal permeability and ileal TNF-alpha secretion due to the exposure of silver nanoparticles in Sprague-Dawley rats","volume":"17","author":"Orr","year":"2019","journal-title":"J. Nanobiotechnol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1007\/s12031-016-0803-y","article-title":"Regulation and the Mechanism of Estrogen on Cav1.2 Gene in Rat-Cultured Cortical Astrocytes","volume":"60","author":"He","year":"2016","journal-title":"J. Mol. Neurosci."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Mukherjee, R., Kim, S.W., Choi, M.S., and Yun, J.W. (2014). Sex-dependent expression of caveolin 1 in response to sex steroid hormones is closely associated with development of obesity in rats. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0090918"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Weiss, C.R., Guan, Q., Ma, Y., Qing, G., Bernstein, C.N., Warrington, R.J., and Peng, Z. (2015). The potential protective role of caveolin-1 in intestinal inflammation in TNBS-induced murine colitis. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0119004"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"6665","DOI":"10.1128\/IAI.00949-06","article-title":"Caveolin-1-deficient mice show defects in innate immunity and inflammatory immune response during Salmonella enterica serovar Typhimurium infection","volume":"74","author":"Medina","year":"2006","journal-title":"Infect. Immun."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1038\/s12276-020-0386-0","article-title":"Gastrointestinal tract modeling using organoids engineered with cellular and microbiota niches","volume":"52","author":"Min","year":"2020","journal-title":"Exp. Mol. Med."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1093\/toxsci\/kfv318","article-title":"Differential Effects of Silver Nanoparticles and Silver Ions on Tissue Accumulation, Distribution, and Toxicity in the Sprague Dawley Rat Following Daily Oral Gavage Administration for 13 Weeks","volume":"150","author":"Boudreau","year":"2016","journal-title":"Toxicol. Sci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1354\/vp.08-VP-0187-G-FL","article-title":"Early phase morphological lesions and transcriptional responses of bovine ileum infected with Mycobacterium avium subsparatuberculosis","volume":"46","author":"Khare","year":"2009","journal-title":"Vet. Pathol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/j.fct.2017.09.004","article-title":"Effects of residual levels of tetracycline on the barrier functions of human intestinal epithelial cells","volume":"109","author":"Gokulan","year":"2017","journal-title":"Food Chem. Toxicol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/1\/9\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:48:15Z","timestamp":1760179695000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/1\/9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,22]]},"references-count":56,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,1]]}},"alternative-id":["ijms22010009"],"URL":"https:\/\/doi.org\/10.3390\/ijms22010009","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,12,22]]}}}