Developmental estrogen exposures predispose to prostate carcinogenesis with aging

Abstract

Prostate morphogenesis occurs in utero in humans and during the perinatal period in rodents. While largely driven by androgens, there is compelling evidence for a permanent influence of estrogens on prostatic development. If estrogenic exposures are abnormally high during the critical developmental period, permanent alterations in prostate morphology and function are observed, a process referred to as developmental estrogenization. Using the neonatal rodent as an animal model, it has been shown that early exposure to high doses of estradiol results in an increased incidence of prostatic lesions with aging which include hyperplasia, inflammatory cell infiltration and prostatic intraepithelial neoplasia or PIN, believed to be the precursor lesion for prostatic adenocarcinoma. The present review summarizes research performed in our laboratory to characterize developmental estrogenization and identify the molecular pathways involved in mediating this response. Furthermore, recent studies performed with low-dose estradiol exposures during development as well as exposures to environmentally relevant doses of the endocrine disruptor bisphenol A show increased susceptibility to PIN lesions with aging following additional adult exposure to estradiol. Gene methylation analysis revealed a potential epigenetic basis for the estrogen imprinting of the prostate gland. Taken together, our results suggest that a full range of estrogenic exposures during the postnatal critical period - from environmentally relevant bisphenol A exposure to low-dose and pharmacologic estradiol exposures - results in an increased incidence and susceptibility to neoplastic transformation of the prostate gland in the aging male which may provide a fetal basis for this adult disease.

Figure 1

Schematic representation of rat animal model for developmental estrogenization of the prostate gland. Day of birth (DOB) is considered day 0. Newborn male pups were given S.C. injections of high dose estradiol benzoate (25 μg) or oil as controls on day 1, 3 and 5. Rats are weaned on day 25. In young adulthood, significant differentiation defects and dysplasia are observed in the prostate gland as described in the text.

Figure 2

Schematic representation of “two-hit” rat animal model for low-dose exposure to estradiol or bisphenol A (BPA) followed by second exposure to T+E implants on day 90. Newborn rats were injected with oil, high-dose estradiol benzoate (EB, 2500 μg/kg BW), low-dose EB (0.1 μg/kg BW) or BPA (10 μg/kg BW) on days 1, 3 and 5. At day 90, they were implanted with empty capsules or T+E capsules for 16 weeks. Arrowheads indicate times for tissue collection.

Figure 3

Proposed model for epigenetic mechanism of developmental estrogenization of the prostate gland by exposures to estradiol, E₂ or environmental disruptors such as BPA. See text for description.