{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T17:05:44Z","timestamp":1790701544279,"version":"4.1.0"},"reference-count":37,"publisher":"American Chemical Society (ACS)","issue":"3","license":[{"start":{"date-parts":[[2017,12,29]],"date-time":"2017-12-29T00:00:00Z","timestamp":1514505600000},"content-version":"vor","delay-in-days":4028,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2007,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Certain phthalates can impair Leydig cell distribution and steroidogenesis in the fetal rat in utero, but it is unknown whether similar effects might occur in the human.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>Our aim in this study was to investigate the effects of di(n-butyl) phthalate (DBP), or its metabolite monobutyl phthalate (MBP), on testosterone production and Leydig cell aggregation (LCA) in fetal testis explants from the rat and human, and to compare the results with in vivo findings for DBP-exposed rats. We also wanted to determine if DBP\/MBP affects testosterone production in vivo in the neonatal male marmoset.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Fetal testis explants obtained from the rat [gestation day (GD)19.5] and from the human (15\u201319 weeks of gestation) were cultured for 24\u201348 hr with or without human chorionic gonadotropin (hCG) or 22R-hydroxycholesterol (22R-OH), and with or without DBP\/MBP. Pregnant rats and neonatal male marmosets were dosed with 500 mg\/kg\/day DBP or MBP.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Exposure of rats in utero to DBP (500 mg\/kg\/day) for 48 hr before GD21.5 induced major suppression of intratesticular testosterone levels and cytochrome P450 side chain cleavage enzyme (P450scc) expression; this short-term treatment induced LCA, but was less marked than longer term (GD13.5\u201320.5) DBP treatment. In vitro, MBP (10\u22123 M) did not affect basal or 22R-OH-stimulated testosterone production by fetal rat testis explants but slightly attenuated hCG-stimulated steroidogenesis; MBP induced minor LCA in vitro. None of these parameters were affected in human fetal testis explants cultured with 10\u22123 M MBP for up to 48 hr. Because the in vivo effects of DBP\/MBP were not reproduced in vitro in the rat, the absence of MBP effects in vitro on fetal human testes is inconclusive. In newborn (Day 2\u20137) marmosets, administration of a single dose of 500 mg\/kg MBP significantly (p = 0.019) suppressed blood testosterone levels 5 hr later. Similar treatment of newborn co-twin male marmosets for 14 days resulted in increased Leydig cell volume per testis (p = 0.011), compared with co-twin controls; this is consistent with MBP-induced inhibition of steroidogenesis followed by compensatory Leydig cell hyperplasia\/hypertrophy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings suggest that MBP\/DBP suppresses steroidogenesis by fetal-type Leydig cells in primates as in rodents, but this cannot be studied in vitro.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1289\/ehp.9490","type":"journal-article","created":{"date-parts":[[2006,12,19]],"date-time":"2006-12-19T11:53:48Z","timestamp":1166529228000},"page":"390-396","source":"Crossref","is-referenced-by-count":171,"title":["Effects of Monobutyl and Di(\n                    <i>n<\/i>\n                    -butyl) Phthalate\n                    <i>in Vitro<\/i>\n                    on Steroidogenesis and Leydig Cell Aggregation in Fetal Testis Explants from the Rat: Comparison with Effects\n                    <i>in Vivo<\/i>\n                    in the Fetal Rat and Neonatal Marmoset and\n                    <i>in Vitro<\/i>\n                    in the Human"],"prefix":"10.1021","volume":"115","author":[{"given":"Nina","family":"Hallmark","sequence":"first","affiliation":[{"name":"MRC Human Reproductive Sciences Unit, Centre for Reproductive Biology, Queen\u2019s Medical Research Institute, Edinburgh, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marion","family":"Walker","sequence":"additional","affiliation":[{"name":"MRC Human Reproductive Sciences Unit, Centre for Reproductive Biology, Queen\u2019s Medical Research Institute, Edinburgh, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris","family":"McKinnell","sequence":"additional","affiliation":[{"name":"MRC Human Reproductive Sciences Unit, Centre for Reproductive Biology, Queen\u2019s Medical Research Institute, Edinburgh, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I. Kim","family":"Mahood","sequence":"additional","affiliation":[{"name":"MRC Human Reproductive Sciences Unit, Centre for Reproductive Biology, Queen\u2019s Medical Research Institute, Edinburgh, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hayley","family":"Scott","sequence":"additional","affiliation":[{"name":"MRC Human Reproductive Sciences Unit, Centre for Reproductive Biology, Queen\u2019s Medical Research Institute, Edinburgh, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosemary","family":"Bayne","sequence":"additional","affiliation":[{"name":"MRC Human Reproductive Sciences Unit, Centre for Reproductive Biology, Queen\u2019s Medical Research Institute, Edinburgh, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiona","family":"Coutts","sequence":"additional","affiliation":[{"name":"MRC Human Reproductive Sciences Unit, Centre for Reproductive Biology, Queen\u2019s Medical Research Institute, Edinburgh, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard A.","family":"Anderson","sequence":"additional","affiliation":[{"name":"MRC Human Reproductive Sciences Unit, Centre for Reproductive Biology, Queen\u2019s Medical Research Institute, Edinburgh, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Greig","sequence":"additional","affiliation":[{"name":"MRC Human Reproductive Sciences Unit, Centre for Reproductive Biology, Queen\u2019s Medical Research Institute, Edinburgh, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith","family":"Morris","sequence":"additional","affiliation":[{"name":"MRC Human Reproductive Sciences Unit, Centre for Reproductive Biology, Queen\u2019s Medical Research Institute, Edinburgh, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard M.","family":"Sharpe","sequence":"additional","affiliation":[{"name":"MRC Human Reproductive Sciences Unit, Centre for Reproductive Biology, Queen\u2019s Medical Research Institute, Edinburgh, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2006,12,19]]},"reference":[{"key":"2026080503030949100_micit1","author":"Animal (Scientific Procedures) Act"},{"key":"2026080503030949100_micit2","first-page":"397","article-title":"Pathogenesis of male reproductive tract lesions from gestation through adulthood following in utero exposure to di(n-butyl) phthalate","volume":"31","author":"Barlow","year":"2003","journal-title":"Toxicol Pathol"},{"key":"2026080503030949100_micit3","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1093\/toxsci\/kfg087","article-title":"Quantitative changes in gene expression in fetal rat testes following exposure to di(n-butyl) phthalate","volume":"73","author":"Barlow","year":"2003","journal-title":"Toxicol Sci"},{"key":"2026080503030949100_micit4","doi-asserted-by":"crossref","first-page":"3158","DOI":"10.1210\/jc.2004-0741","article-title":"Is spermatogenic damage associated with Leydig cell dysfunction? [Editorial]","volume":"89","author":"de Krester","year":"2004","journal-title":"J Clin Endocrinol Metab"},{"key":"2026080503030949100_micit5","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1095\/biolreprod58.1.116","article-title":"Gonadotropin-independent regulation of steroidogenesis in the fetal rat testis","volume":"58","author":"El-Gehani","year":"1998","journal-title":"Biol Reprod"},{"key":"2026080503030949100_micit6","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/S0378-4274(99)00192-7","article-title":"Critical period for adverse effects on development of reproductive system in male offspring of rats given di-n-butyl phthalate during late pregnancy","volume":"111","author":"Ema","year":"2000","journal-title":"Toxicol Lett"},{"key":"2026080503030949100_micit7","first-page":"599","article-title":"Leydig cell structure and steroidogenic function","volume":"39","author":"Ewing","year":"1983","journal-title":"Recent Prog Horm Res"},{"key":"2026080503030949100_micit8","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1093\/humrep\/deg273","article-title":"Human \u2018testicular dysgenesis syndrome\u2019: a possible model using in-utero exposure of the rat to dibutyl phthalate","volume":"18","author":"Fisher","year":"2003","journal-title":"Hum Reprod"},{"key":"2026080503030949100_micit9","doi-asserted-by":"crossref","first-page":"3122","DOI":"10.1210\/jc.2004-2465","article-title":"A window of opportunity: the diagnosis of gonadotropin deficiency in the male infant","volume":"90","author":"Grumbach","year":"2005","journal-title":"J Clin Endocrinol Metab"},{"key":"2026080503030949100_micit10","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/S0303-7207(01)00461-0","article-title":"Origin, differentiation and regulation of fetal and adult Leydig cells","volume":"179","author":"Habert","year":"2001","journal-title":"Mol Cell Endocrinol"},{"key":"2026080503030949100_micit11","first-page":"466","article-title":"Control of testicular steroidogenesis in foetal rat: effect of decapitation on testosterone and plasma luteinizing hormone-like activity","volume":"99","author":"Habert","year":"1982","journal-title":"Acta Endocrinol"},{"key":"2026080503030949100_micit12","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1136\/oem.2004.017590","article-title":"Phthalates and human health","volume":"62","author":"Hauser","year":"2005","journal-title":"Occup Environ Med"},{"key":"2026080503030949100_micit13","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1002\/path.1372","article-title":"Histological evidence of testsicular dysgenesis in contralateral biopsies from 218 patients with testicular germ cell cancer","volume":"200","author":"Hoei-Hansen","year":"2003","journal-title":"J Pathol"},{"key":"2026080503030949100_micit14","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1007\/978-1-4899-0952-7_3","article-title":"Endocrine, paracrine and autocrine regulation of testicular steroidogenesis","volume":"377","author":"Huhtaniemi","year":"1995","journal-title":"Adv Exp Med Biol"},{"key":"2026080503030949100_micit15","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1111\/j.1365-2605.2005.00607.x","article-title":"Di(2-ethyhexyl)phthalate (DEHP): human metabolism and internal exposure\u2014an update and latest results","volume":"29","author":"Koch","year":"2006","journal-title":"Int J Androl"},{"key":"2026080503030949100_micit16","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1093\/toxsci\/kfh169","article-title":"Dose-dependent alterations in gene expression and testosterone synthesis in the fetal testes of male rats exposed to di (n-butyl) phthalate","volume":"81","author":"Lehmann","year":"2004","journal-title":"Toxicol Sci"},{"key":"2026080503030949100_micit17","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1210\/en.2004-0671","article-title":"Abnormal Leydig cell aggregation in the fetal testis of rats exposed to di (n-butyl) phthalate and its possible role in testicular dysgenesis","volume":"146","author":"Mahood","year":"2005","journal-title":"Endocrinology"},{"key":"2026080503030949100_micit18","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1111\/j.1365-2605.2005.00574.x","article-title":"Cellular origins of testicular dysgenesis in rats exposed in utero to di(n-butyl) phthalate","volume":"29","author":"Mahood","year":"2006","journal-title":"Int J Androl"},{"key":"2026080503030949100_micit19","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1677\/joe.0.1490191","article-title":"The neonatal period: a critical interval in primate development","volume":"149","author":"Mann","year":"1996","journal-title":"J Endocrinol"},{"key":"2026080503030949100_micit20","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1530\/rep.0.1220419","article-title":"Comparison of androgen receptor and oestrogen receptor beta immunoexpression in the testes of the common marmoset (Callithrix jacchus) from birth to adulthood: low androgen receptor immunoexpression in Sertoli cells during the neonatal increase in testosterone concentrations","volume":"122","author":"McKinnell","year":"2001","journal-title":"Reproduction"},{"key":"2026080503030949100_micit21","doi-asserted-by":"crossref","first-page":"4536","DOI":"10.1210\/en.2005-0676","article-title":"Expression of insulin-like factor 3 (Insl3) protein in the rat testis during fetal and postnatal development and in relation to cyptorchidism induced by in utero exposure to di (n-butyl) phthalate","volume":"146","author":"McKinnell","year":"2005","journal-title":"Endocrinology"},{"key":"2026080503030949100_micit22","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1093\/toxsci\/55.1.143","article-title":"Dose-dependent alterations in androgen-regulated male reproductive development in rats exposed to di(n-butyl) phthalate during late gestation","volume":"55","author":"Mylchreest","year":"2000","journal-title":"Toxicol Sci"},{"key":"2026080503030949100_micit23","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1046\/j.1365-2605.2003.00381.x","article-title":"The contributions of deficient androgenic action in spermatogenic disorders","volume":"26","author":"Ochsenkuhn","year":"2003","journal-title":"Int J Androl"},{"key":"2026080503030949100_micit24","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1093\/toxsci\/58.2.339","article-title":"The plasticizer diethylhexyl phthalate induces malformations by decreasing fetal testosterone synthesis during sexual differentiation in the male rat","volume":"58","author":"Parks","year":"2000","journal-title":"Toxicol Sci"},{"key":"2026080503030949100_micit25","author":"Polkinghorne"},{"key":"2026080503030949100_micit26","first-page":"579","article-title":"The disposition of 14C-di-2-ethylhexylphthalate (DEHP) in the marmoset","volume":"11","author":"Rhodes","year":"1983","journal-title":"Dev Toxicol Environ Sci"},{"key":"2026080503030949100_micit27","first-page":"299","article-title":"Comparative pharmacokinetics and subacute toxicity of di(2-ethylhexyl) phthalate (DEHP) in rats and marmosets: extrapolation of effects in rodents to man","volume":"65","author":"Rhodes","year":"1986","journal-title":"Environ Health Perspect"},{"key":"2026080503030949100_micit28","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.beem.2005.09.005","article-title":"Pathways of endocrine disruption during male sexual differentiation and masculinisation","volume":"20","author":"Sharpe","year":"2006","journal-title":"Best Pract Res Clin Endocrinol Metab"},{"key":"2026080503030949100_micit29","doi-asserted-by":"crossref","first-page":"1692","DOI":"10.1093\/humrep\/17.7.1692","article-title":"Infant feeding with soy formula milk: effects on the testis and on blood testosterone levels in marmoset monkeys during the period of neonatal testicular activity","volume":"17","author":"Sharpe","year":"2002","journal-title":"Hum Reprod"},{"key":"2026080503030949100_micit30","doi-asserted-by":"crossref","first-page":"2023","DOI":"10.1351\/pac200375112023","article-title":"Male reproductive disorders and the role of endocrine disruption: advances in understanding and identification of areas for future research","volume":"75","author":"Sharpe","year":"2003","journal-title":"Pure Appl Chem"},{"key":"2026080503030949100_micit31","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1289\/ehp.6723","article-title":"Urinary levels of seven phthalate metabolites in the U.S. population from the National Health and Nutrition Examination Survey (NHANES) 1999\u20132000","volume":"112","author":"Silva","year":"2004","journal-title":"Environ Health Perspect"},{"key":"2026080503030949100_micit32","doi-asserted-by":"crossref","first-page":"972","DOI":"10.1093\/humrep\/16.5.972","article-title":"Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects","volume":"16","author":"Skakkebaek","year":"2001","journal-title":"Hum Reprod"},{"key":"2026080503030949100_micit33","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.1289\/ehp.8100","article-title":"Decrease in anogenital distance among male infants with prenatal phthalate exposure","volume":"113","author":"Swan","year":"2005","journal-title":"Environ Health Perspect"},{"key":"2026080503030949100_micit34","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1093\/humrep\/dei421","article-title":"Infant feeding with soy formula milk: effects on puberty progression, reproductive function and testicular cell numbers in marmoset monkeys in adulthood","volume":"21","author":"Tan","year":"2006","journal-title":"Hum Reprod"},{"key":"2026080503030949100_micit35","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1210\/en.2003-1475","article-title":"Di(n-butyl) phthalate impairs cholesterol transport and steroidogenesis in the fetal rat testis through a rapid and reversible mechanism","volume":"145","author":"Thompson","year":"2004","journal-title":"Endocrinology"},{"key":"2026080503030949100_micit36","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1095\/biolreprod.105.042382","article-title":"Differential steroidogenic gene expression in the fetal adrenal versus the testis and rapid and dynamic response of the fetal testis to di(n-butyl) phthalate","volume":"73","author":"Thompson","year":"2005","journal-title":"Biol Reprod"},{"key":"2026080503030949100_micit37","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/j.toxlet.2003.09.012","article-title":"Phthalate ester-induced gubernacular lesions are associated with reduced Insl3 gene expression in the fetal rat testis","volume":"146","author":"Wilson","year":"2004","journal-title":"Toxicol Lett"}],"container-title":["Environmental Health Perspectives"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/evhpaz\/article-pdf\/115\/3\/390\/66397426\/ehp.9490.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/evhpaz\/article-pdf\/115\/3\/390\/66397426\/ehp.9490.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T13:56:12Z","timestamp":1786629372000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/evhpaz\/article-lookup\/doi\/10.1289\/ehp.9490"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2006,12,19]]},"references-count":37,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2006,12,19]]},"published-print":{"date-parts":[[2007,3,1]]}},"URL":"https:\/\/doi.org\/10.1289\/ehp.9490","relation":{},"ISSN":["0091-6765","1552-9924"],"issn-type":[{"value":"0091-6765","type":"print"},{"value":"1552-9924","type":"electronic"}],"subject":[],"published":{"date-parts":[[2006,12,19]]}}}