Early-onset endocrine disruptor-induced prostatitis in the rat.
BACKGROUND
Androgens are critical for specifying prostate development, with the fetal prostate sensitive to altered hormone levels and endocrine-disrupting chemicals (EDCs) that exhibit estrogenic or antiandrogenic properties. Prostatic inflammation (prostatitis) affects 9% of men of all ages, and > 90% of cases are of unknown etiology.


OBJECTIVE
In this study we aimed to evaluate effects of in utero exposure to the antiandrogenic EDC vinclozolin, during the period of male reproductive tract development, on neonatal, prepubertal, and postpubertal prostate gland function of male offspring.


METHODS
Fetal rats were exposed to vinclozolin (100 mg/kg body weight) or vehicle control (2.5 mL/kg body weight) in utero from gestational day 14 (GD14) to GD19 via oral administration to pregnant dams. Tissue analysis was carried out when male offspring were 0, 4, or 8 weeks of age.


RESULTS
In utero exposure to vinclozolin was insufficient to perturb prostatic development and branching, although expression of androgen receptor and mesenchymal fibroblast growth factor-10 was down-regulated. Prostate histology remained normal until puberty, but 100% of animals displayed prostatitis postpubertally (56 days of age). Prostatic inflammation was associated with phosphorylation and nuclear translocation of nuclear factor-kappa B (NFkappaB) and postpubertal activation of proinflammatory NFkappaB-dependent genes, including the chemokine interleukin-8 and the cytokine transforming growth factor-beta1. Significantly, inflammation arising from vinclozolin exposure was not associated with the emergence of premalignant lesions, such as prostatic intra-epithelial neoplasia or proliferative inflammatory atrophy, and hence mimics nonbacterial early-onset prostatitis that commonly occurs in young men.


CONCLUSIONS
These data are the first to unequivocally implicate EDCs as a causative factor and fill an important knowledge gap on the etiology of prostatitis.
Cowin
Prue A
PA
Centre for Urological Research, Monash Institute of Medical Research, Monash University, Clayton, Victoria, Australia.
Foster
Paul
P
Pedersen
John
J
Hedwards
Shelley
S
McPherson
Stephen J
SJ
Risbridger
Gail P
GP
D021581:Active Transport, Cell Nucleus; D000726:Androgen Antagonists / Q000633:toxicity*; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D004848:Epithelium / Q000254:growth & development / Q000473:pathology; D005260:Female; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D008297:Male; D008431:Maternal-Fetal Exchange; D009024:Morphogenesis; D016328:NF-kappa B / Q000378:metabolism; D010080:Oxazoles / Q000633:toxicity*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011467:Prostate / Q000254:growth & development / Q000473:pathology; D011472:Prostatitis / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012741:Sexual Maturation; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
D000726:Androgen Antagonists; D016209:Interleukin-8; D016328:NF-kappa B; D010080:Oxazoles; D053773:Transforming Growth Factor beta1; C025643:vinclozolin