Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.1 (phosphodiesterase)
 18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Developmental exposure to estradiol and bisphenol A increases susceptibility to prostate carcinogenesis and epigenetically regulates phosphodiesterase type 4 variant 4. 1674 Jun 99

An important and controversial health concern is whether low-dose exposures to hormonally active environmental oestrogens such as bisphenol A can promote human diseases including prostate cancer. Our studies in rats have shown that pharmacological doses of oestradiol administered during the critical window of prostate development result in marked prostate pathology in adulthood that progress to neoplastic lesions with ageing. Our recent studies have also demonstrated that transient developmental exposure of rats to low, environmentally relevant doses of bisphenol A or oestradiol increases prostate gland susceptibility to adult-onset precancerous lesions and hormonal carcinogenesis. These findings indicate that a wide range of oestrogenic exposures during development can predispose to prostatic neoplasia that suggests a potential developmental basis for this adult disease. To identify a molecular basis for oestrogen imprinting, we screened for DNA methylation changes over time in the exposed prostate glands. We found permanent alterations in DNA methylation patterns of multiple cell signalling genes suggesting an epigenetic mechanism of action. For phosphodiesterase type 4 variant 4 (PDE4D4), an enzyme responsible for intracellular cyclic adenosine monophosphate breakdown, a specific methylation cluster was identified in the 5'-flanking CpG island that was gradually hypermethylated with ageing in normal prostates resulting in loss of gene expression. However, in prostates exposed to neonatal oestradiol or bisphenol A, this region became hypomethylated with ageing resulting in persistent and elevated PDE4D4 expression. In total, these findings indicate that low-dose exposures to ubiquitous environmental oestrogens impact the prostate epigenome during development and in so doing, promote prostate disease with ageing.
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PMID:Perinatal exposure to oestradiol and bisphenol A alters the prostate epigenome and increases susceptibility to carcinogenesis. 1822 66

Lower urinary tract symptoms (LUTS) are extremely common in men and, in addition to causing considerable bother, can lead to the development of complications, such as acute urinary retention. Over the past couple of decades, developments in the medical management of LUTS in men have led to a substantial decline in the number of surgical procedures being performed to treat associated disorders, such as prostatectomy for benign prostatic enlargement. In this Review we summarize the available treatments and discuss the latest data on the use of anticholinergics and phosphodiesterase type-5 inhibitors for this indication. We also review the various combinations of medical therapies that have been reported in the literature to optimize the management of LUTS in men. In addition, there is a growing realization that LUTS in men are not synonymous with prostatic disease, and in many patients overactive bladder syndrome is the cause or a component of the LUTS experienced; we have, therefore, taken the opportunity to try to clarify the terminology used in LUTS in men, since there is the potential for considerable confusion with the terms that are currently in common usage in any discussion of this disorder.
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PMID:Medical management of lower urinary tract symptoms in men: current treatment and future approaches. 1830 17

Androgen replacement therapy (ART) is a widely accepted form of treatment worldwide for aging men with late-onset hypogonadism (LOH) syndrome. Concurrent with the progressive decline in testosterone from middle age, there is a gradual increase in prostate volume, reflecting the development of benign prostatic hyperplasia (BPH). Prostate growth is dependent on the presence of androgens, and conversely, antiandrogen agents or orchidectomy can decrease prostate volume in patients with BPH. Thus, it is important to investigate whether ART could have any negative effects on prostatic disease or lower urinary tract symptoms (LUTS). Although only limited amounts of information on the correlations between androgen levels in aging men and clinical manifestations of LUTS are available, a few recent studies have suggested that testosterone levels may have some beneficial effects on various urinary functions in men. Androgen receptors are found in the urothelium, urinary bladder, prostate, and urethra, and testosterone could have an impact on the autonomic nervous system, bladder smooth muscle differentiation, nitric oxide synthase, phosphodiesterase-5 and Rho/Rho-kinase activities, and pelvic blood flow. In addition, some previous studies demonstrated that ART had little effect on LUTS or urinary function in aging men with LOH syndrome. Furthermore, some recent randomized controlled trials indicated that short-term ART may be effective in the improvement of LUTS in hypogonadal men with mild BPH. However, only limited information is available regarding the effects of longer-term ART or the safety of ART in men with severe BPH and LUTS, and further studies are required to reach more definitive conclusions.
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PMID:Late-onset hypogonadism syndrome and lower urinary tract symptoms. 2208 58