{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T17:12:26Z","timestamp":1776273146768,"version":"3.50.1"},"reference-count":22,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,11,4]],"date-time":"2020-11-04T00:00:00Z","timestamp":1604448000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,11,4]],"date-time":"2020-11-04T00:00:00Z","timestamp":1604448000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100004440","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["098522"],"award-info":[{"award-number":["098522"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Focal dysgenesis is a consistent feature of testicular dysgenesis syndrome (TDS) in humans. Rodent studies show that perturbation of androgens (e.g. following phthalate exposure) during a fetal masculinisation programming window (MPW) predisposes to a TDS phenotype. This study aimed to determine whether dissociation and reconstitution of rat fetal testis tissue during the MPW can be used to model and manipulate seminiferous cord development, including induction of focal dysgenesis, as described in TDS. Dissociated fetal rat testes were xenotransplanted subcutaneously into recipient mice for 4\u00a0weeks. Transplanted mice were treated with vehicle or di-<jats:italic>n<\/jats:italic>-butyl-phthalate (DBP, a plasticising chemical known to induce testicular dysgenesis in vivo in rats). Testosterone production by the transplants was measured in recipient mice and immunofluorescence was performed on the retrieved transplants to identify features consistent with focal testicular dysgenesis. Re-aggregation of rat fetal testis tissue xenotransplants during the MPW results in reconstitution of seminiferous cords. Features of focal testicular dysgenesis were present in re-aggregated testis, including ectopic Sertoli cells and intratubular Leydig cells (ITLCs). DBP exposure of recipient mice reduced androgen-dependent seminal vesicle weight (8.3 vs 26.7\u00a0mg; p\u2009&lt;\u20090.05), but did not enhance features of focal dysgenesis including number of ITLCs (0.07 vs 0.10 cells\/mm<jats:sup>2<\/jats:sup>; p\u2009&gt;\u20090.05). We conclude that\u00a0seminiferous cord reformation during the MPW results in development of focal dysgenesis. The system may be used to separate specific effects (e.g. androgen suppression) of individual chemical exposures from other mechanisms that may be conserved in TDS.<\/jats:p>","DOI":"10.1038\/s41598-020-75803-1","type":"journal-article","created":{"date-parts":[[2020,11,4]],"date-time":"2020-11-04T11:03:36Z","timestamp":1604487816000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Reconstitution of rat fetal testis during the masculinisation programming window induces focal dysgenesis consistent with testicular dysgenesis syndrome"],"prefix":"10.1038","volume":"10","author":[{"given":"Ellie","family":"Smart","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joni","family":"Macdonald","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lee B.","family":"Smith","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rod T.","family":"Mitchell","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2020,11,4]]},"reference":[{"key":"75803_CR1","doi-asserted-by":"publisher","first-page":"e33","DOI":"10.1016\/j.fertnstert.2007.12.026","volume":"89","author":"RM Sharpe","year":"2008","unstructured":"Sharpe, R. M. & Skakkebaek, N. E. Testicular dysgenesis syndrome: Mechanistic insights and potential new downstream effects. Fertil. Steril. 89, e33-38. https:\/\/doi.org\/10.1016\/j.fertnstert.2007.12.026 (2008).","journal-title":"Fertil. Steril."},{"key":"75803_CR2","doi-asserted-by":"publisher","unstructured":"Skakkebaek, N. E., Rajpert-De Meyts, E. & Main, K. M. Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects. Hum. Reprod. 16, 972\u2013978, https:\/\/doi.org\/10.1093\/humrep\/16.5.972 (2001).","DOI":"10.1093\/humrep\/16.5.972"},{"key":"75803_CR3","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1152\/physrev.00017.2015","volume":"96","author":"NE Skakkebaek","year":"2016","unstructured":"Skakkebaek, N. E. et al. Male reproductive disorders and fertility trends: Influences of environment and genetic susceptibility. Physiol. Rev. 96, 55\u201397. https:\/\/doi.org\/10.1152\/physrev.00017.2015 (2016).","journal-title":"Physiol. Rev."},{"key":"75803_CR4","doi-asserted-by":"publisher","unstructured":"Hoei-Hansen, C. E., Holm, M., Rajpert-De Meyts, E. & Skakkebaek, N. E. Histological evidence of testicular dysgenesis in contralateral biopsies from 218 patients with testicular germ cell cancer. J. Pathol. 200, 370\u2013374, https:\/\/doi.org\/10.1002\/path.1372 (2003).","DOI":"10.1002\/path.1372"},{"key":"75803_CR5","doi-asserted-by":"publisher","unstructured":"Holm, M., Rajpert-De Meyts, E., Andersson, A. M. & Skakkebaek, N. E. Leydig cell micronodules are a common finding in testicular biopsies from men with impaired spermatogenesis and are associated with decreased testosterone\/LH ratio. J. Pathol. 199, 378\u2013386, https:\/\/doi.org\/10.1002\/path.1309 (2003).","DOI":"10.1002\/path.1309"},{"key":"75803_CR6","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1016\/s0378-4274(01)00298-3","volume":"120","author":"RM Sharpe","year":"2001","unstructured":"Sharpe, R. M. Hormones and testis development and the possible adverse effects of environmental chemicals. Toxicol. Lett. 120, 221\u2013232. https:\/\/doi.org\/10.1016\/s0378-4274(01)00298-3 (2001).","journal-title":"Toxicol. Lett."},{"key":"75803_CR7","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1111\/j.1365-2605.2009.01005.x","volume":"33","author":"DJ Macleod","year":"2010","unstructured":"Macleod, D. J. et al. Androgen action in the masculinization programming window and development of male reproductive organs. Int. J. Androl. 33, 279\u2013287. https:\/\/doi.org\/10.1111\/j.1365-2605.2009.01005.x (2010).","journal-title":"Int. J. Androl."},{"key":"75803_CR8","doi-asserted-by":"publisher","unstructured":"van den Driesche, S. et al. Experimentally induced testicular dysgenesis syndrome originates in the masculinization programming window. JCI Insight 2, e91204, https:\/\/doi.org\/10.1172\/jci.insight.91204 (2017).","DOI":"10.1172\/jci.insight.91204"},{"key":"75803_CR9","doi-asserted-by":"publisher","first-page":"1479","DOI":"10.1172\/JCI34241","volume":"118","author":"M Welsh","year":"2008","unstructured":"Welsh, M. et al. Identification in rats of a programming window for reproductive tract masculinization, disruption of which leads to hypospadias and cryptorchidism. J. Clin. Invest. 118, 1479\u20131490. https:\/\/doi.org\/10.1172\/JCI34241 (2008).","journal-title":"J. Clin. Invest."},{"key":"75803_CR10","doi-asserted-by":"publisher","first-page":"E1502","DOI":"10.1210\/jc.2011-1100","volume":"96","author":"PA Fowler","year":"2011","unstructured":"Fowler, P. A., Bhattacharya, S., Flannigan, S., Drake, A. J. & O\u2019Shaughnessy, P. J. Maternal cigarette smoking and effects on androgen action in male offspring: Unexpected effects on second-trimester anogenital distance. J. Clin. Endocrinol. Metab. 96, E1502-1506. https:\/\/doi.org\/10.1210\/jc.2011-1100 (2011).","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"75803_CR11","doi-asserted-by":"publisher","unstructured":"van den Driesche, S., Kolovos, P., Platts, S., Drake, A. J. & Sharpe, R. M. Inter-relationship between testicular dysgenesis and Leydig cell function in the masculinization programming window in the rat. PLoS One 7, e30111, https:\/\/doi.org\/10.1371\/journal.pone.0030111 (2012).","DOI":"10.1371\/journal.pone.0030111"},{"key":"75803_CR12","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1080\/01926230490265894","volume":"32","author":"NJ Barlow","year":"2004","unstructured":"Barlow, N. J., McIntyre, B. S. & Foster, P. M. Male reproductive tract lesions at 6, 12, and 18 months of age following in utero exposure to di(n-butyl) phthalate. Toxicol. Pathol. 32, 79\u201390. https:\/\/doi.org\/10.1080\/01926230490265894 (2004).","journal-title":"Toxicol. Pathol."},{"key":"75803_CR13","doi-asserted-by":"publisher","first-page":"1383","DOI":"10.1093\/humrep\/deg273","volume":"18","author":"JS Fisher","year":"2003","unstructured":"Fisher, J. S., Macpherson, S., Marchetti, N. & Sharpe, R. M. Human \u201ctesticular dysgenesis syndrome\u201d: A possible model using in-utero exposure of the rat to dibutyl phthalate. Hum. Reprod. 18, 1383\u20131394. https:\/\/doi.org\/10.1093\/humrep\/deg273 (2003).","journal-title":"Hum. Reprod."},{"key":"75803_CR14","doi-asserted-by":"publisher","first-page":"2521","DOI":"10.1038\/s41598-017-02684-2","volume":"7","author":"NLM Lara","year":"2017","unstructured":"Lara, N. L. M., van den Driesche, S., Macpherson, S., Franca, L. R. & Sharpe, R. M. Dibutyl phthalate induced testicular dysgenesis originates after seminiferous cord formation in rats. Sci. Rep. 7, 2521. https:\/\/doi.org\/10.1038\/s41598-017-02684-2 (2017).","journal-title":"Sci. Rep."},{"key":"75803_CR15","doi-asserted-by":"publisher","first-page":"E341","DOI":"10.1210\/jc.2011-2411","volume":"97","author":"RT Mitchell","year":"2012","unstructured":"Mitchell, R. T. et al. Do phthalates affect steroidogenesis by the human fetal testis? Exposure of human fetal testis xenografts to di-n-butyl phthalate. J. Clin. Endocrinol. Metab. 97, E341-348. https:\/\/doi.org\/10.1210\/jc.2011-2411 (2012).","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"75803_CR16","doi-asserted-by":"publisher","first-page":"e386","DOI":"10.1111\/j.1365-2605.2010.01140.x","volume":"34","author":"MS Jobling","year":"2011","unstructured":"Jobling, M. S., Hutchison, G. R., van den Driesche, S. & Sharpe, R. M. Effects of di(n-butyl) phthalate exposure on foetal rat germ-cell number and differentiation: Identification of age-specific windows of vulnerability. Int. J. Androl. 34, e386-396. https:\/\/doi.org\/10.1111\/j.1365-2605.2010.01140.x (2011).","journal-title":"Int. J. Androl."},{"key":"75803_CR17","doi-asserted-by":"publisher","first-page":"611","DOI":"10.2164\/jandrol.05207","volume":"27","author":"K Gassei","year":"2006","unstructured":"Gassei, K., Schlatt, S. & Ehmcke, J. D. novo morphogenesis of seminiferous tubules from dissociated immature rat testicular cells in xenografts. J. Androl. 27, 611\u2013618. https:\/\/doi.org\/10.2164\/jandrol.05207 (2006).","journal-title":"J. Androl."},{"key":"75803_CR18","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1095\/biolreprod.106.056895","volume":"76","author":"K Kita","year":"2007","unstructured":"Kita, K. et al. Production of functional spermatids from mouse germline stem cells in ectopically reconstituted seminiferous tubules. Biol. Reprod. 76, 211\u2013217. https:\/\/doi.org\/10.1095\/biolreprod.106.056895 (2007).","journal-title":"Biol. Reprod."},{"key":"75803_CR19","doi-asserted-by":"publisher","unstructured":"Mahood, I. K. et al. Cellular origins of testicular dysgenesis in rats exposed in utero to di(n-butyl) phthalate. Int. J. Androl. 29, 148\u2013154; discussion 181\u2013145, https:\/\/doi.org\/10.1111\/j.1365-2605.2005.00574.x (2006).","DOI":"10.1111\/j.1365-2605.2005.00574.x"},{"key":"75803_CR20","doi-asserted-by":"publisher","unstructured":"van den Driesche, S. et al. Prolonged exposure to acetaminophen reduces testosterone production by the human fetal testis in a xenograft model. Sci. Transl. Med. 7, 288ra280, https:\/\/doi.org\/10.1126\/scitranslmed.aaa4097 (2015).","DOI":"10.1126\/scitranslmed.aaa4097"},{"key":"75803_CR21","doi-asserted-by":"publisher","first-page":"390","DOI":"10.1289\/ehp.9490","volume":"115","author":"N Hallmark","year":"2007","unstructured":"Hallmark, N. et al. Effects of monobutyl and di(n-butyl) phthalate in vitro on steroidogenesis and Leydig cell aggregation in fetal testis explants from the rat: Comparison with effects in vivo in the fetal rat and neonatal marmoset and in vitro in the human. Environ. Health Perspect. 115, 390\u2013396. https:\/\/doi.org\/10.1289\/ehp.9490 (2007).","journal-title":"Environ. Health Perspect."},{"key":"75803_CR22","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1093\/humupd\/7.3.231","volume":"7","author":"PM Foster","year":"2001","unstructured":"Foster, P. M., Mylchreest, E., Gaido, K. W. & Sar, M. Effects of phthalate esters on the developing reproductive tract of male rats. Hum. Reprod. Update 7, 231\u2013235. https:\/\/doi.org\/10.1093\/humupd\/7.3.231 (2001).","journal-title":"Hum. Reprod. Update"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-75803-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-75803-1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-75803-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,6]],"date-time":"2022-12-06T22:19:02Z","timestamp":1670365142000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-75803-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,4]]},"references-count":22,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["75803"],"URL":"https:\/\/doi.org\/10.1038\/s41598-020-75803-1","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,4]]},"assertion":[{"value":"21 August 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 October 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 November 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"19022"}}