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Disruption of androgen regulation in the prostate by environmental contaminants and dietary factors Ralph, Jody Love

Abstract

There is a growing concern that many of the environmental and dietary chemicals, that are ingested by humans but have not been thoroughly tested for endocrine activity, may pose a significant health threat. These chemicals have the potential to mimic or antagonize hormone action through binding to intracellular receptors. This thesis examines the hypothesis that environmental contaminants and dietary factors can influence the function of androgen receptor (AR) in the prostate in a direct manner by binding it, or indirectly through the aryl hydrocarbon receptor (AhR), and thereby may influence prostate development and growth. We have characterized a subclass of androgen response elements in the probasin promoter and we have used a number of methods to investigate known and putative ligands of AhR that may impact androgen receptor function. Our in vitro experimental approach utilizes androgen- and aryl hydrocarbon-responsive DNA constructs connected to a firefly luciferase reporter gene. The degree to which the chemicals bind AR and displace androgen was also evaluated. The results indicate that several AhR ligands, including resveratrol, indole 3 carbinol, curcumin and hexachlorobenzene (HCB) antagonize androgen-initiated transcriptional activity without binding to the androgen receptor. Three AhR ligands have also been tested for in vivo effects using transgenic mice in which the prostate-specific androgen-responsive promoter is linked to a chloramphenicol acetyl transferase (CAT) reporter gene. In four-week-old mice, exposure to either 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD) or resveratrol decreased CAT activity and testis weight. In the eight-week-old mice, there was a significant decrease in both CAT activity and prostate weight upon exposure to either HCB or TCDD. Therefore, all three of the AhR ligands studied can suppress androgen-sensitive parameters both in vitro and in vivo. The latest project was designed to investigate the endocrine disrupting properties of 27 environmental compounds identified in an epidemiological study correlating agricultural occupational exposure to increased risk of prostate cancer. Eleven of the compounds bound AR while 22 caused a statistically significant alteration in androgen activity. Environmental contaminants have been implicated in the rising incidence of prostate cancer and insight into the mechanisms of endocrine disruption will clarify their potential role in this disease.

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