title: Vinclozolin exposure in utero induces postpubertal prostatitis and reduces sperm production via a reversible hormone-regulated mechanism.
abstract: 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-kappaB 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-kappaB 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.
authors.affiliation: Monash Institute of Medical Research, Monash University, Clayton, Victoria 3168, Australia.
authors.forename: Prue A
authors.initials: PA
authors.lastname: Cowin
authors.forename: Elspeth
authors.initials: E
authors.lastname: Gold
authors.forename: Jasna
authors.initials: J
authors.lastname: Aleksova
authors.forename: Moira K
authors.initials: MK
authors.lastname: O'Bryan
authors.forename: Paul M D
authors.initials: PM
authors.lastname: Foster
authors.forename: Hamish S
authors.initials: HS
authors.lastname: Scott
authors.forename: Gail P
authors.initials: GP
authors.lastname: Risbridger
mesh_terms: D001003:Anal Canal / Q000033:anatomy & histology; D000726:Androgen Antagonists / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics; D005260:Female; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010080:Oxazoles / Q000494:pharmacology*; D011247:Pregnancy; D011467:Prostate / Q000187:drug effects / Q000196:embryology / Q000473:pathology; D011472:Prostatitis / Q000139:chemically induced* / Q000517:prevention & control; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013087:Spermatids / Q000187:drug effects / Q000502:physiology; D013737:Testis / Q000033:anatomy & histology / Q000187:drug effects; D013739:Testosterone / Q000627:therapeutic use
chemical_list: D000726:Androgen Antagonists; D010080:Oxazoles; D013739:Testosterone; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619381:Dnmt1 protein, mouse; C000619382:Dnmt1 protein, rat; C025643:vinclozolin