Developmental Exposure to Estradiol and Bisphenol A Increases Susceptibility to Prostate Carcinogenesis and Epigenetically Regulates Phosphodiesterase Type 4 Variant 4

Abstract

Early developmental perturbations have been linked to adultonset prostate pathology, including excessive exposure to estrogenic compounds; however, the molecular basis for this imprinting event is not known. An important and controversial health concern is whether low-dose exposures to hormonally active environmental estrogens, such as bisphenol A, can promote human diseases, including prostate cancer. Here, we show that transient developmental exposure of rats to low, environmentally relevant doses of bisphenol A or estradiol increases prostate gland susceptibility to adult-onset precancerous lesions and hormonal carcinogenesis. We found permanent alterations in the DNA methylation patterns of multiple cell signaling genes, suggesting an epigenetic basis for estrogen imprinting. For phosphodiesterase type 4 variant 4 (PDE4D4), an enzyme responsible for cyclic AMP breakdown, a specific methylation cluster was identified in the 5 ¶-flanking CpG island that was gradually hypermethylated with aging in normal prostates, resulting in loss of gene expression. Early and prolonged hypomethylation at this site following neonatal estradiol or bisphenol A exposure resulted in continued, elevated PDE4D4 expression. Cell line studies confirmed that site-specific methylation is involved in transcriptional silencing of the PDE4D4 gene and showed hypomethylation of this gene in prostate cancer cells. Importantly, the PDE4D4 alterations in the estrogen-exposed prostates were distinguishable before histopathologic changes of the gland, making PDE4D4 a candidate molecular marker for prostate cancer risk assessment as a result of endocrine disruptors. In total, these findings indicate that low-dose exposures to ubiquitous environmental estrogens affect the prostate epigenome during development and, in so doing, promote prostate disease with aging. (Cancer Res 2006; 66(11): 5624-32)

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).…”

AP-2 regulates the transcription of estrogen receptor (ER)-β by acting through a methylation hotspot of the 0N promoter in prostate cancer cells

“…Developmental perturbations of estrogen homeostasis increase the risk of prostate carcinogenesis (Ho et al, 2006b). The beneficial actions of phytoestrogens in ameliorating symptoms of benign prostatic hyperplasia and in chemoprevention of prostate cancer (PCa) are well documented (Comhaire and Mahmoud, 2004).…”

Profils de méthylation de l’ADN dans les cellules normales et cancéreuses

“…Une autre piste de recherche très prometteuse est la possible influence de l'environnement sur les profils de méthylation. Par exemple, une étude récente montre qu'une exposition à de faibles doses de polluants (bisphénol A) au cours du développement peut induire des anomalies épigénétiques liées à une augmentation de la fréquence de certains cancers chez la souris [17].…”