Transient neonatal estrogen exposure to estrogen-deficient mice (aromatase knockout) reduces prostate weight and induces inflammation in late life.
Exposure of newborn male mice to estrogens is associated with age-related changes in prostate size and induction of epithelial hyperplasia and dysplasia. Whether these changes directly result from systemic estrogen administration or indirect effects of estrogens on systemic testosterone levels is unclear. We have addressed this question using aromatase-knockout (ArKO) mice that are estrogen-deficient during their lifespan but have elevated androgen levels and develop prostate enlargement and hyperplasia (McPherson SJ, Wang H, Jones ME, Pedersen J, Iismaa TP, Wreford N, Simpson ER, Risbridger GP: Endocrinology 2001, 142:2458-2467). Circulating testosterone and dihydrotestosterone levels were significantly decreased by neonatal diethylstilbestrol treatment, remained suppressed in adult wild-type mice, but rapidly returned to control levels in ArKO animals. However, adult prostate weight and luminal size were reduced in both wild-type and ArKO animals. Because both wild-type and ArKO mice developed epithelial hyperplasia and inflammation following neonatal diethylstilbestrol treatment, this validates that estrogens directly cause prostatic inflammation and epithelial hyperplasia. Furthermore, because ArKO mice are estrogen-deficient, this study demonstrates the sensitivity of the neonatal period to estrogen exposure and the long range and permanent nature of the prostatic responses that occur. Finally, this study establishes the ArKO mouse model of estrogen deficiency as a unique approach to study the effects of estrogens, estrogenic factors, and endocrine disruptors on prostate development.
Bianco
Joseph John
JJ
Monash Institute of Reproduction and Development, Monash University, Clayton, Victoria 3168, Australia.
McPherson
Stephen John
SJ
Wang
Hong
H
Prins
Gail S
GS
Risbridger
Gail Petuna
GP
D000818:Animals; D001141:Aromatase / Q000235:genetics*; D001835:Body Weight / Q000187:drug effects; D004054:Diethylstilbestrol / Q000494:pharmacology*; D004967:Estrogens / Q000378:metabolism; D004968:Estrogens, Non-Steroidal / Q000494:pharmacology*; D005260:Female; D007249:Inflammation; D008297:Male; D018811:Maternal Exposure; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009929:Organ Size; D011467:Prostate / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*
D004967:Estrogens; D004968:Estrogens, Non-Steroidal; D004054:Diethylstilbestrol; D001141:Aromatase