Genetic, environmental and life-style effects on androgen receptor function

Detta är en avhandling från Lund University

Sammanfattning: Androgens regulate male reproductive function and their effects are mediated through the androgen receptor (AR). The AR gene contains a polymorphic CAG repeat, encoding a stretch of glutamines, affecting the transcriptional activity of the AR. Prostate specific antigen (PSA) is a downstream target and is commonly used in the screening of prostate cancer. The relationship between CAG number and male reproductive health has been suggested to be modulated by persistent organic pollutants (POPs). Humans are exposed mainly through food intake, but also from industrial processes and cigarette smoking. The dioxin-like POPs exert their effect through the aryl hydrocarbon receptor (AhR), shown to interact with the AR. The aims were to study the role of the CAG polymorphism on; AR activity and expression in the absence or presence of POPs; PSA concentration in serum and tissue; and reproductive parameters and hormones in men. It was also elucidated whether the CAG number could modify the effect of cigarette smoking on reproductive characteristics in men. The transactivation assay included a reporter gene with a human androgen responsive promoter. Cells were transfected with vectors having CAG numbers of 16, 22 or 28, representative of the human range. To explore the association between CAG number and reproductive outcome, an unprejudiced spline regression model with CAG number as a continuous variable was used, as well as a stratified model and in case of linear pattern, CAG number was investigated in a linear regression model. We found that the CAG variant with the median length had the highest AR activity, shown both in cell lines and prostate tissue, and as highest PSA concentration in younger and older men. The unprejudiced statistical analysis gave a better picture of the relationship between CAG number and reproductive outcomes, demonstrating a CAG-dependent effect on hormone levels. The CAG repeat also had a cell line- and dose-dependent modulating effect of POPs on AR activity and was negatively associated with semen volume in smoking men. To conclude, the median AR CAG number had the highest activity in vivo and in vitro. This pattern consisted even in the presence of POPs, indicating a stronger resistance for the median CAG length to these compounds compared to less common variants. The CAG number was also associated with reproductive hormone regulation and might modify the susceptibility of current cigarette smoking on semen volume in young men.