Mechanisms of aromatic hydrocarbon (AH) receptor-mediated disruption of androgen receptor function

The mechanism by which TODD, through an aromatic hydrocarbon receptor (AHR) mediated pathway, blocks androgen receptor (AR) function has yet to be fully characterized. Several mechanisms derived from studies of cross-talk between the AHR and several steroid hormone receptors, particularly the estrogen receptor, have been proposed. These mechanisms include enhancing steroid metabolism and/or decreasing steroid biosynthesis through induction of xenobiotic metabolizing enzymes, downregulating hormone receptor levels, and interfering with steroid receptor-mediated gene induction. In utero and lactational exposure to low maternal doses of 2, 3, 7, 8-Tetrachlorodibenzo-p-dioxin, (TCDD, or dioxin), reduces the size of the testis, epididymis, seminal vesicle, and the prostate in male rodent offspring. Adult male animals also show decreases in accessory sex organ weights, testicular functions, and reduced fertility, but are more resistant to TCDD toxicity than developing rodents. Consequently, the effects of maternal TCDD exposure on male offspring do not correlate with decreases in androgen receptor mRNA or protein levels, or in circulating androgens.;To characterize the mechanism(s) by which activated AHR blocks AR-mediated transcriptional activity, transient transfections studies were conducted in AHR-positive LNCaP and African green monkey CV-1 cells, which lack endogenous AHR. Results show that activation of AHR can block the androgen-dependent activity of the human PSA (prostate specific antigen) and rat probasin gene promoters in LNCaP as well as in African green monkey CV-1 cells. Over-expression of ARNT showed no effect. AHR blocked the activity of both wild-type and LNCaP-derived mutant AR expressed in CV-1 cells. Functional studies showed that TCDD did not decrease the levels of nuclear AR or compete for binding to AR in a whole cell-based binding assay.;In conclusion, these data point to at least three mechanisms whereby TCDD blocks AR function in LNCaP cells: (1) by blocking androgen-induced cell proliferation in LNCaP cells through modulating the activity of cell cycle regulatory proteins, (2) through interfering with AR-mediated transcriptional activity, and/or (3) through cross-talk of AR- and AHR-mediated signal transduction pathways, possibly involving competition for coregulators or through direct protein interaction. (Abstract shortened by UMI.).