Document Detail

Developmental exposure to estradiol and bisphenol A increases susceptibility to prostate carcinogenesis and epigenetically regulates phosphodiesterase type 4 variant 4.
MedLine Citation:
PMID:  16740699     Owner:  NLM     Status:  MEDLINE    
Early developmental perturbations have been linked to adult-onset 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.
Shuk-Mei Ho; Wan-Yee Tang; Jessica Belmonte de Frausto; Gail S Prins
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.    
Journal Detail:
Title:  Cancer research     Volume:  66     ISSN:  0008-5472     ISO Abbreviation:  Cancer Res.     Publication Date:  2006 Jun 
Date Detail:
Created Date:  2006-06-02     Completed Date:  2006-07-27     Revised Date:  2014-09-21    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  5624-32     Citation Subset:  IM    
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MeSH Terms
3',5'-Cyclic-AMP Phosphodiesterases / genetics*
Animals, Newborn
Benzhydryl Compounds
Cyclic Nucleotide Phosphodiesterases, Type 4
DNA Methylation / drug effects*
Dose-Response Relationship, Drug
Epigenesis, Genetic
Estradiol / toxicity*
Genetic Predisposition to Disease
Genomic Imprinting / drug effects
Isoenzymes / genetics
Phenols / toxicity*
Precancerous Conditions / chemically induced,  enzymology,  genetics
Prostate / drug effects
Prostatic Neoplasms / chemically induced*,  enzymology,  genetics*
Rats, Sprague-Dawley
Grant Support
Reg. No./Substance:
0/Benzhydryl Compounds; 0/Isoenzymes; 0/Phenols; 4TI98Z838E/Estradiol; EC',5'-Cyclic-AMP Phosphodiesterases; EC Nucleotide Phosphodiesterases, Type 4; MLT3645I99/bisphenol A

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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