Vinclozolin exposure in utero induces postpubertal prostatitis and reduces sperm production via a reversible hormone-regulated mechanism

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dc.contributor.authorCowin, P.
dc.contributor.authorGold, E.
dc.contributor.authorAleksova, J.
dc.contributor.authorO'Bryan, M.
dc.contributor.authorFoster, P.
dc.contributor.authorScott, H.
dc.contributor.authorRisbridger, G.
dc.date.issued2010
dc.description.abstractVinclozolin 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-{kappa}B 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, –3A, –3B, and –3L 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-{kappa}B 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.
dc.description.statementofresponsibilityPrue A. Cowin, Elspeth Gold, Jasna Aleksova, Moira K. O'Bryan, Paul M. D. Foster, Hamish S. Scott and Gail P. Risbridger
dc.identifier.citationEndocrinology, 2010; 151(2):783-792
dc.identifier.doi10.1210/en.2009-0982
dc.identifier.issn0013-7227
dc.identifier.issn0013-7227
dc.identifier.orcidO'Bryan, M. [0000-0001-7298-4940]
dc.identifier.orcidScott, H. [0000-0002-5813-631X]
dc.identifier.urihttp://hdl.handle.net/2440/59746
dc.language.isoen
dc.publisherEndocrine Soc
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/171601
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/461204
dc.rightsCopyright © 2010 by The Endocrine Society
dc.source.urihttps://doi.org/10.1210/en.2009-0982
dc.subjectProstate
dc.subjectTestis
dc.subjectSpermatids
dc.subjectAnimals
dc.subjectMice, Knockout
dc.subjectMice
dc.subjectRats
dc.subjectProstatitis
dc.subjectOxazoles
dc.subjectTestosterone
dc.subjectAndrogen Antagonists
dc.subjectReverse Transcriptase Polymerase Chain Reaction
dc.subjectApoptosis
dc.subjectPregnancy
dc.subjectAnal Canal
dc.subjectFemale
dc.subjectMale
dc.subjectDNA (Cytosine-5-)-Methyltransferase 1
dc.subjectDNA (Cytosine-5-)-Methyltransferases
dc.titleVinclozolin exposure in utero induces postpubertal prostatitis and reduces sperm production via a reversible hormone-regulated mechanism
dc.typeJournal article
pubs.publication-statusPublished

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