Perinatal Estrogen Exposure Hormonal Imprinting

Perinatal estrogen exposure of mice resulted in epithelial dysplasia of the peri-urethral proximal parts of the dorsolateral and anterior prostate and seminal vesicles [214,215], as well as in carcinomas in these areas [212], as summarized earlier. In addition, mice that were neonatally estrogenized hyper-responded to secondary estrogen treatment [214]. These very same tissue areas contain estrogen receptors which indicates their estrogen sensitivity [214]. However, the activity of 17^-estradiol hydroxysteroid oxidoreductase, believed to be a mar ker of estrogen sensitivity, and incorporation of tritiated thymidine in epithelial compartments of these tissues were not changed in response to secondary treatments with estrogen in neonatally estrogenized mice [214, 215]. In response to secondary androgen treatment, tritiated thymidine incorporation was markedly increased selectively only in the stromal cells of the anterior and ventral prostate, indicating a lasting effect of neonatal estrogen exposure on the androgen-responsiveness of the stromal component of the mouse prostate [214]. These observations suggest that perinatal estrogen exposure of mice imprints lasting alterations in estrogen as well as androgen responsiveness of the male accessory sex glands.

The precise mechanism of these complex imprinting effects is not clear. Perinatal estrogen treatment may act indirectly on the male accessory sex glands by imprinting permanent alterations in the secretion of pituitary hormones and testicular androgen, or directly by imprinting altered expression of androgen, estrogen, and prolactin receptors or changes in steroid metabolism in the accessory sex gland [260-263]. For example, in neonatally estrogenized mice, the plasma levels of luteinizing hormone and follicle stimulating hormone were elevated [261], while circulating testosterone levels were decreased [260,263] or unchanged [261]. Prostatic DHT formation via 5a-reductase was impaired in adult mice neonatally treated with DES [246]. Nuclear androgen receptor levels in these mice were decreased in dorsal and ventral prostate but not affected in the lateral lobe, and the numbers of androgen receptor-positive stromal cells was increased in all three lobes [263]. However, although the exact mechanisms of the carcinogenic effects of perinatal estrogen exposure for the prostate remain unclear, there appear to be lasting direct and indirect effects of this treatment on the mouse prostate. No abnormalities in circulating estrogen and androgen levels were found in boys that had been exposed to DES in utero [264]. Thus, the human relevance of the effects of perinatal estrogen exposure in mice remains uncertain at present.

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