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Prue A. Cowin,¹ Paul Foster,² John Pedersen,³ Shelley Hedwards,¹ Stephen J. McPherson,¹ and Gail P. Risbridger¹

¹Centre for Urological Research, Monash Institute of Medical Research, Monash University, Clayton, Victoria, Australia; ²National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA; ³Tissupath Laboratories, Hawthorn, Victoria, Australia

Abstract
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.

Objectives: 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 (NFκB) and postpubertal activation of proinflammatory NFκB-dependent genes, including the chemokine interleukin-8 and the cytokine transforming growth factor-β1. Significantly, inflammation arising from vinclozolin exposure was not associated with the emergence of premalignant lesions, such as prostatic intraepithelial 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.

Key words: antiandrogen, endocrine disruptors, inflammation, prostate, prostatitis, vinclozolin. Environ Health Perspect 116:923–929 (2008) . doi:10.1289/ehp.11239 available via http://dx.doi.org/ [Online 26 March 2008]

Address correspondence to G.P. Risbridger, Monash Institute of Medical Research, Monash Medical Centre, 246 Clayton Rd., Clayton, Victoria, Australia 3168. Telephone: 61-3-9594-7408. Fax: 61-3-9594-7420. E-mail: Gail.Risbridger@med.monash.edu.au

We thank A. Mansell for insightful discussions and M. Richards for skilled technical assistance.

This research was funded by U.S. Department of Defense Prostate Cancer Research Program Exploration-Hypothesis Development Award (W81XWH-07-1-0126) (G.P.R.) and supported in part by the Intramural Research Program of the National Institute of Environmental Health Sciences (P.F.) .

The authors declare they have no competing financial interests.

Received 6 January 2008 ; accepted 26 March 2008.