{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T14:47:29Z","timestamp":1791298049311,"version":"4.1.0"},"reference-count":54,"publisher":"The Endocrine Society","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2010,2,1]]},"abstract":"<jats:p>Vinclozolin is an endocrine-disrupting chemical (EDC) that binds with high affinity to the androgen receptor (AR) and blocks the action of gonadal hormones on male reproductive organs. An alternative mechanism of action of Vinclozolin involves transgenerational effects on the male reproductive tract. We previously reported in utero Vinclozolin exposure-induced prostatitis (prostate inflammation) in postpubertal rats concurrent with down-regulation of AR and increased nuclear factor-\u03baB activation. We postulated the male reproductive abnormalities induced by in utero Vinclozolin exposure could be reversed by testosterone supplementation, in contrast to the permanent modifications involving DNA methyltransferases (Dnmts) described by others. To test this hypothesis, we administered high-dose testosterone at puberty to Vinclozolin-treated rats and determined the effect on anogenital distance (AGD); testicular germ cell apoptosis, concentration of elongated spermatids, and the onset of prostatitis. Concurrently we examined Dnmt1, \u22123A, \u22123B, and \u22123L mRNA expression. Consistent with previous reports, in utero exposure to Vinclozolin significantly reduced AGD, increased testicular germ cell apoptosis 3-fold, reduced elongated spermatid number by 40%, and induced postpubertal prostatitis in 100% of exposed males. Administration of high-dose testosterone (25 mg\/kg) at puberty normalized AGD, reduced germ cell apoptosis, and restored elongated spermatid number. Testosterone restored AR and nuclear factor-\u03baB expression in the prostate and abolished Vinclozolin-induced prostatitis. Altered Dnmt expression was evident with in utero Vinclozolin exposure and was not normalized after testosterone treatment. These data demonstrate in utero Vinclozolin-induced male reproductive tract abnormalities are AR mediated and reversible and involve a mechanism independent of Dnmt expression.<\/jats:p>","DOI":"10.1210\/en.2009-0982","type":"journal-article","created":{"date-parts":[[2010,1,7]],"date-time":"2010-01-07T23:36:16Z","timestamp":1262907376000},"page":"783-792","source":"Crossref","is-referenced-by-count":48,"title":["Vinclozolin Exposure in Utero Induces Postpubertal Prostatitis and Reduces Sperm Production via a Reversible Hormone-Regulated Mechanism"],"prefix":"10.1210","volume":"151","author":[{"given":"Prue A.","family":"Cowin","sequence":"first","affiliation":[{"name":"Monash Institute of Medical Research (P.A.C., E.G., J.A., G.P.R.),"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elspeth","family":"Gold","sequence":"first","affiliation":[{"name":"Monash Institute of Medical Research (P.A.C., E.G., J.A., G.P.R.),"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasna","family":"Aleksova","sequence":"first","affiliation":[{"name":"Monash Institute of Medical Research (P.A.C., E.G., J.A., G.P.R.),"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moira K.","family":"O'Bryan","sequence":"first","affiliation":[{"name":"Department of Anatomy and Developmental Biology (M.K.O.), Monash University, Clayton, Victoria 3168, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul M. D.","family":"Foster","sequence":"first","affiliation":[{"name":"National Institute of Environmental Health Sciences (P.M.D.F.), Research Triangle Park, North Carolina 27709;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hamish S.","family":"Scott","sequence":"first","affiliation":[{"name":"Division of Molecular Pathology (H.S.S.), Institute of Medical and Veterinary Science, Hanson Institute, and School of Medicine, University of Adelaide, South Australia 5000, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gail P.","family":"Risbridger","sequence":"first","affiliation":[{"name":"Monash Institute of Medical Research (P.A.C., E.G., J.A., G.P.R.),"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","reference":[{"key":"2020071612261573000_R1","volume-title":"A scientific detective story","author":"Colborn","year":"1996"},{"key":"2020071612261573000_R2","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1136\/bmj.305.6854.609","article-title":"Evidence for decreasing quality of semen during past 50 years.","volume":"305","author":"Carlsen","year":"1992","journal-title":"Br Med J"},{"key":"2020071612261573000_R3","doi-asserted-by":"crossref","first-page":"1276","DOI":"10.1093\/jnci\/djg040","article-title":"Annual report to the nation on the status of cancer, 1975\u20132000, featuring the uses of surveillance data for cancer prevention and control.","volume":"95","author":"Weir","year":"2003","journal-title":"J Natl Cancer Inst"},{"key":"2020071612261573000_R4","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1071\/R98051","article-title":"Antiandrogens as environmental endocrine disruptors.","volume":"10","author":"Kelce","year":"1998","journal-title":"Reprod Fertil Dev"},{"key":"2020071612261573000_R5","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1006\/taap.1994.1117","article-title":"Environmental hormone disruptors: evidence that vinclozolin developmental toxicity is mediated by antiandrogenic metabolites.","volume":"126","author":"Kelce","year":"1994","journal-title":"Toxicol Appl Pharmacol"},{"key":"2020071612261573000_R6","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1007\/s001090050104","article-title":"Environmental antiandrogens: developmental effects, molecular mechanisms, and clinical implications.","volume":"75","author":"Kelce","year":"1997","journal-title":"J Mol Med"},{"key":"2020071612261573000_R7","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1191\/074823399678846664","article-title":"Administration of potentially antiandrogenic pesticides (procymidone, linuron, iprodione, chlozolinate, p,p\u2032-DDE, and ketoconazole) and toxic substances (dibutyl- and diethylhexyl phthalate, PCB 169, and ethane dimethane sulphonate) during sexual differentiation produces diverse profiles of reproductive malformations in the male rat.","volume":"15","author":"Gray Jr","year":"1999","journal-title":"Toxicol Ind Health"},{"key":"2020071612261573000_R8","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1093\/toxsci\/55.1.152","article-title":"Characterization of the period of sensitivity of fetal male sexual development to vinclozolin.","volume":"55","author":"Wolf","year":"2000","journal-title":"Toxicol Sci"},{"key":"2020071612261573000_R9","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1289\/ehp.11239","article-title":"Early onset endocrine disruptor induced prostatitis in the rat.","volume":"116","author":"Cowin","year":"2008","journal-title":"Environ Health Perspect"},{"key":"2020071612261573000_R10","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.ygeno.2007.10.002","article-title":"Transgenerational epigenetic programming of the embryonic testis transcriptome.","volume":"91","author":"Anway","year":"2008","journal-title":"Genomics"},{"key":"2020071612261573000_R11","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1002\/pros.20724","article-title":"Transgenerational effects of the endocrine disruptor vinclozolin on the prostate transcriptome and adult onset disease.","volume":"68","author":"Anway","year":"2008","journal-title":"Prostate"},{"key":"2020071612261573000_R12","doi-asserted-by":"crossref","first-page":"1466","DOI":"10.1126\/science.1108190","article-title":"Epigenetic transgenerational actions of endocrine disruptors and male fertility.","volume":"308","author":"Anway","year":"2005","journal-title":"Science"},{"key":"2020071612261573000_R13","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1016\/j.reprotox.2008.04.001","article-title":"Vinclozolin\u2014the lack of a transgenerational effect after oral maternal exposure during organogenesis.","volume":"25","author":"Schneider","year":"2008","journal-title":"Reprod Toxicol"},{"key":"2020071612261573000_R14","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/j.taap.2009.03.004","article-title":"Maternal exposure to anti-androgenic compounds, vinclozolin, flutamide and procymidone, has no effects on spermatogenesis and DNA methylation in male rats of subsequent generations.","volume":"237","author":"Inawaka","year":"2009","journal-title":"Toxicol Appl Pharmacol"},{"key":"2020071612261573000_R15","doi-asserted-by":"crossref","first-page":"5524","DOI":"10.1210\/en.2006-0987","article-title":"Transgenerational epigenetic imprinting of the male germline by endocrine disruptor exposure during gonadal sex determination.","volume":"147","author":"Chang","year":"2006","journal-title":"Endocrinology"},{"key":"2020071612261573000_R16","doi-asserted-by":"crossref","first-page":"2976","DOI":"10.1210\/endo.150.6.9995","volume":"150","journal-title":"Endocrinology"},{"key":"2020071612261573000_R17","doi-asserted-by":"crossref","first-page":"5515","DOI":"10.1210\/en.2006-0640","article-title":"Endocrine disruptor vinclozolin induced epigenetic transgenerational adult-onset disease.","volume":"147","author":"Anway","year":"2006","journal-title":"Endocrinology"},{"key":"2020071612261573000_R18","doi-asserted-by":"crossref","first-page":"4068","DOI":"10.1073\/pnas.0500702102","article-title":"Meiotic and epigenetic defects in Dnmt3L-knockout mouse spermatogenesis.","volume":"102","author":"Webster","year":"2005","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071612261573000_R19","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1095\/biolreprod17.2.298","article-title":"Preputial separation as an external sign of pubertal development in the male rat.","volume":"17","author":"Korenbrot","year":"1977","journal-title":"Biol Reprod"},{"key":"2020071612261573000_R20","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1093\/toxsci\/58.1.50","article-title":"The effect of atrazine on puberty in male Wistar rats: an evaluation in the protocol for the assessment of pubertal development and thyroid function.","volume":"58","author":"Stoker","year":"2000","journal-title":"Toxicol Sci"},{"key":"2020071612261573000_R21","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1046\/j.1365-2605.1997.d01-121.x","article-title":"Androgen action on the restoration of spermatogenesis in adult rats: effects of human chorionic gonadotrophin, testosterone and flutamide administration on germ cell number.","volume":"20","author":"Meachem","year":"1997","journal-title":"Int J Androl"},{"key":"2020071612261573000_R22","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1677\/jme.0.0320055","article-title":"Epigenetic regulation of inhibin \u03b1-subunit gene in prostate cancer cell lines.","volume":"32","author":"Balanathan","year":"2004","journal-title":"J Mol Endocrinol"},{"key":"2020071612261573000_R23","doi-asserted-by":"crossref","first-page":"4922","DOI":"10.1210\/en.2002-220493","article-title":"Direct response of the murine prostate gland and seminal vesicles to estradiol.","volume":"143","author":"Bianco","year":"2002","journal-title":"Endocrinology"},{"key":"2020071612261573000_R24","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1002\/pros.20149","article-title":"Comparison of the zones of the human prostate with the seminal vesicle: morphology, immunohistochemistry, and cell kinetics.","volume":"62","author":"Laczko\u0301","year":"2005","journal-title":"Prostate"},{"key":"2020071612261573000_R25","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1046\/j.1432-0436.2001.680414.x","article-title":"Cell differentiation lineage in the prostate.","volume":"68","author":"Wang","year":"2001","journal-title":"Differentiation"},{"key":"2020071612261573000_R26","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1128\/MCB.25.2.751-766.2005","article-title":"DNA methyltransferase 3b regulates nerve growth factor-induced differentiation of PC12 cells by recruiting histone deacetylase 2.","volume":"25","author":"Bai","year":"2005","journal-title":"Mol Cell Biol"},{"key":"2020071612261573000_R27","doi-asserted-by":"crossref","first-page":"184","DOI":"10.2353\/ajpath.2009.080296","article-title":"Activin C antagonizes activin A in vitro and overexpression leads to pathologies in vivo.","volume":"174","author":"Gold","year":"2009","journal-title":"Am J Pathol"},{"key":"2020071612261573000_R28","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/S0074-7696(08)62497-3","article-title":"Analyzing renal glomeruli with the new stereology.","volume":"161","author":"Bertram","year":"1995","journal-title":"Int Rev Cytol"},{"key":"2020071612261573000_R29","doi-asserted-by":"crossref","first-page":"2458","DOI":"10.1210\/endo.142.6.8079","article-title":"Elevated androgens and prolactin in aromatase deficient (ArKO) mice cause enlargement but not malignancy of the prostate gland.","volume":"142","author":"McPherson","year":"2001","journal-title":"Endocrinology"},{"key":"2020071612261573000_R30","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1095\/biolreprod54.1.36","article-title":"Neonatal exposure of rats to recombinant follicle stimulating hormone increases adult Sertoli and spermatogenic cell numbers.","volume":"54","author":"Meachem","year":"1996","journal-title":"Biol Reprod"},{"key":"2020071612261573000_R31","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1677\/joe.0.1620039","article-title":"Morphometric studies of neonatal estrogen imprinting in the mature mouse prostate.","volume":"162","author":"Singh","year":"1999","journal-title":"J Endocrinol"},{"key":"2020071612261573000_R32","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1530\/jrf.0.0540103","article-title":"Daily sperm production and epididymal sperm reserves of pubertal and adult rats.","volume":"54","author":"Robb","year":"1978","journal-title":"J Reprod Fertil"},{"key":"2020071612261573000_R33","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1002\/j.1939-4640.2002.tb02607.x","article-title":"Hormonal regulation of spermatogenesis in primates and man: insights for development of the male hormonal contraceptive.","volume":"23","author":"McLachlan","year":"2002","journal-title":"J Androl"},{"key":"2020071612261573000_R34","doi-asserted-by":"crossref","first-page":"3962","DOI":"10.1210\/jc.2006-1145","article-title":"The relative roles of follicle-stimulating hormone and luteinizing hormone in maintaining spermatogonial maturation and spermiation in normal men.","volume":"91","author":"Matthiesson","year":"2006","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071612261573000_R35","doi-asserted-by":"crossref","first-page":"1140","DOI":"10.1248\/bpb.30.1140","article-title":"Dihydrotestosterone inhibits tumor necrosis factor \u03b1 induced interleukin-1\u03b1 mRNA expression in rheumatoid fibroblast-like synovial cells.","volume":"30","author":"Itoh","year":"2007","journal-title":"Biol Pharm Bull"},{"key":"2020071612261573000_R36","first-page":"435","article-title":"Molecular control of immune\/inflammatory responses: interactions between nuclear factor-\u03baB and steroid receptor-signaling pathways.","volume":"20","author":"McKay","year":"1999","journal-title":"Endocr Rev"},{"key":"2020071612261573000_R37","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1002\/jcb.10729","article-title":"NF-\u03baB activation in human prostate cancer: important mediator or epiphenomenon?","volume":"91","author":"Suh","year":"2004","journal-title":"J Cell Biochem"},{"key":"2020071612261573000_R38","author":"Litwin","year":"2007"},{"key":"2020071612261573000_R39","doi-asserted-by":"crossref","first-page":"6868","DOI":"10.1038\/sj.onc.1209935","article-title":"Cross-talk between nuclear receptors and nuclear factor \u03baB.","volume":"25","author":"De Bosscher","year":"2006","journal-title":"Oncogene"},{"key":"2020071612261573000_R40","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1172\/JCI11991","article-title":"Control of oncogenesis and cancer therapy resistance by the transcription factor NF-\u03baB.","volume":"107","author":"Baldwin","year":"2001","journal-title":"J Clin Invest"},{"key":"2020071612261573000_R41","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1038\/nrc780","article-title":"NF-\u03baB in cancer: from innocent bystander to major culprit.","volume":"2","author":"Karin","year":"2002","journal-title":"Nat Rev Cancer"},{"key":"2020071612261573000_R42","doi-asserted-by":"crossref","first-page":"6938","DOI":"10.1038\/sj.onc.1203221","article-title":"Aberrant rel\/nfkb genes and activity in human cancer.","volume":"18","author":"Rayet","year":"1999","journal-title":"Oncogene"},{"key":"2020071612261573000_R43","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1242\/jcs.115.1.141","article-title":"The role of IKK in constitutive activation of NF-\u03baB transcription factor in prostate carcinoma cells.","volume":"115","author":"Gasparian","year":"2002","journal-title":"J Cell Sci"},{"key":"2020071612261573000_R44","doi-asserted-by":"crossref","first-page":"S81","DOI":"10.1016\/S0092-8674(02)00703-1","article-title":"Missing pieces in the NF-\u03baB puzzle","volume":"109","author":"Ghosh","year":"2002","journal-title":"Cell"},{"key":"2020071612261573000_R45","first-page":"7106","article-title":"Interruption of nuclear factor \u03baB signaling by the androgen receptor facilitates 12-O-tetradecanoylphorbolacetate-induced apoptosis in androgen-sensitive prostate cancer LNCaP cells.","volume":"63","author":"Altuwaijri","year":"2003","journal-title":"Cancer Res"},{"key":"2020071612261573000_R46","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1002\/pros.20217","article-title":"Constitutive activation of PI3K-Akt and NF-\u03baB during prostate cancer progression in autochthonous transgenic mouse model.","volume":"64","author":"Shukla","year":"2005","journal-title":"Prostate"},{"key":"2020071612261573000_R47","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1074\/jbc.270.2.837","article-title":"Nuclear factor-\u03baB functions as a negative regulator for the rat androgen receptor gene and NF-\u03baB activity increases during the age-dependent desensitization of the liver.","volume":"270","author":"Supakar","year":"1995","journal-title":"J Biol Chem"},{"key":"2020071612261573000_R48","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1210\/mend.12.1.0044","article-title":"Cross-talk between nuclear factor-\u03baB and the steroid hormone receptors: mechanisms of mutual antagonism.","volume":"12","author":"McKay","year":"1998","journal-title":"Mol Endocrinol"},{"key":"2020071612261573000_R49","doi-asserted-by":"crossref","first-page":"5258","DOI":"10.1073\/pnas.92.12.5258","article-title":"The causes and prevention of cancer.","volume":"92","author":"Ames","year":"1995","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071612261573000_R50","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1038\/nature01322","article-title":"Inflammation and cancer.","volume":"420","author":"Coussens","year":"2002","journal-title":"Nature"},{"key":"2020071612261573000_R51","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1038\/nature07205","article-title":"Cancer-related inflammation.","volume":"454","author":"Mantovani","year":"2008","journal-title":"Nature"},{"key":"2020071612261573000_R52","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1038\/448547a","article-title":"Cancer: an infernal triangle.","volume":"448","author":"Mantovani","year":"2007","journal-title":"Nature"},{"key":"2020071612261573000_R53","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1146\/annurev.pharmtox.45.120403.095832","article-title":"Aberrant DNA methylation as a cancer-inducing mechanism.","volume":"45","author":"Esteller","year":"2005","journal-title":"Annu Rev Pharmacol Toxicol"},{"key":"2020071612261573000_R54","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1038\/nrg1748","article-title":"The epigenetic progenitor origin of human cancer.","volume":"7","author":"Feinberg","year":"2006","journal-title":"Nat Rev Genet"}],"container-title":["Endocrinology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/151\/2\/783\/10724120\/endo0783.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/151\/2\/783\/10724120\/endo0783.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,22]],"date-time":"2024-03-22T12:00:59Z","timestamp":1711108859000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/endo\/article\/151\/2\/783\/2456509"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2010,2,1]]},"references-count":54,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2010,2,1]]}},"URL":"https:\/\/doi.org\/10.1210\/en.2009-0982","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.3611958.3324072","asserted-by":"object"}]},"ISSN":["0013-7227","1945-7170"],"issn-type":[{"value":"0013-7227","type":"print"},{"value":"1945-7170","type":"electronic"}],"subject":[],"published":{"date-parts":[[2010,2,1]]}}}