Although estrogen levels are low or undetectable in adult male mice, administration of exogenous estrogens during development48 dramatically affects prostate growth and function.49-54 The effects of estrogens vary according to timing and duration of exposure, in addition to the type and dose of estrogen administered. Furthermore, the individual lobes of the prostate exhibit varied degrees of response to estrogens and androgens.
The neonatal period after birth is very fundamental for the rodent prostate development in which the prostate involves branching morphogenesis followed by functional differentiation. In this period, brief exposure of male rats or mice to high-level estrogens will cause irreversible alterations in development and function of the prostate gland and a reduced responsiveness to androgens during adulthood.50'55-57 The estrogen imprinting effect is associated with an aging-related prostatic lesion, which includes the hyperplasia of prostatic epithelial cells or severe dysplasia similar to high grade prostatic intra-epithelial neoplasia (PIN) and extensive immune cell infiltrate.51'58-61
As early as 1978, Rajfer and Coffey reported that if high dose of 17^-estradiol at 500 pg per day, or estradiol benzoate at 250 pg per day, or estradiol dipropionate at 100 pg per day, is administered to intact male rats for 2 days during the 1st week after birth, the prostate, at adulthood, is diminutive in size and is inert to the action of exogenous androgens. If immature rodents are exposed to exogenous estrogen before puberty, the aging animals develop prostatic epithelial hyperplasia50 or even dysplasia if androgen is given together with estrogen.61 A series of studies by McLachlan et al. demonstrated that perinatal exposure to the synthetic estrogen, DES, results in an assortment of apparently direct defects in the murine male reproductive tract, including undescended testes, epididymal cysts, aberrant expression of estrogen inducible genes, adenocarcinoma, and sterility.61-65
In addition to morphological and histological changes, several groups characterized the other hallmarks of neonatal estrogen imprinting in the rat model as well as in different mouse strains. These included transient up-regulation of ERa, down-regulation of androgen receptor (AR), decreased ERp levels in adult prostate epithelium, lack of dorsal lateral prostate (DLP) secretory protein, up-regulated proto-oncogene c-fos, reduced TGFp type I receptor levels in the prostate epithelium, but not in stroma, whereas there was no effect on TGFp type II receptor. p21 (cip-1/waf-1) is a cyclin-dependent kinase inhibitor, and is known to be inducible by TGF^1 in the prostate. Neonatal estrogenization prevented this transient expression of p21 (cip-1/waf-1) in the prostate epithelium cells. Those changes in molecular levels suggested they could be good markers for estrogenization in the prostate.66-72
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