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.

Epigenetic reprogramming and imprinting in origins of disease

“…The fact that the epigenetic "memory" can be transmitted to daughter cells and across several generations, influence sexual behavior, and thus impact Darwinian evolution makes this a field of investigation that should be highly valuable for generating new insights into the basis of disease development. The pioneer research examining a few epigenetic targets at a time are the proof-of-principle studies (McLachan [75,76], New-bold [61,80], Prins [94], Ho [41,79], Soto [82], Skinner [17,85] and Hilakivi-Clarke [46,52]). To attain the next level of excellence, research in this area should focus on high-throughput comprehensive characterization of an entire epigenome susceptible to specific or multifaceted developmental reprogramming.…”

Prospects for Epigenetic Epidemiology

“…Such exposure also decreases methylation of the cancer-causing oncogene c-fos (121) and the estrogen-responsive gene lactoferrin in mice (122). In animals, in utero or neonatal exposure to bisphenol A is associated with higher body mass, altered reproductive function, increasing cancer risk, and specific DNA methylation changes (123)(124)(125).…”

Prostate-Specific Antigen Levels in Relation to Background Factors: Are there Links to Endocrine Disrupting Chemicals and AhR Expression?

“…Out of these wide range of factors a great deal of interest is being directed towards the supposition that excessive exposure to endocrine disruptors or modulators and elevated polycyclic aromatic hydrocarbon-DNA adducts in benign prostate hyperplasia (Tang et al, 2013) as certain environmental chemicals may act as inducers of PCa (Golden et al, 1998;Prins et al, 2007;Medjakovic et al, 2013). Their effects may be due to mimicking the endogenous hormones such as estrogens and androgens, antagonizing their effects, changing their pattern of synthesis and metabolism and modifying the hormone receptors levels (Muir, 2005).…”