Cross-talk between 2,3,7,8-tetrachlorodibenzo-p-dioxin and testosterone signal transduction pathways in LNCaP prostate cancer cells

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and related compounds modulate v arious endocrine functions by enhancing ligand metabolism, altering hormone synthesis, down regulating receptor levels, and interfering with gene tran scription. In the present study, we investigated the effects of TCDD on tes tosterone signal transduction pathways and vice versa in the androgen recep tor (AR) positive LNCaP prostate cancer cell line. TCDD induced CYP1A1 mRMA and related enzyme activity in these cells, with dose and time-dependence. Both normal and testosterone-stimulated cell growth was inhibited by TCDD. The expression levels of the aryl hydrocarbon receptor (AhR), the aryl hyd rocarbon receptor nuclear translocator (ARNT), and AR were not affected by exposure to TCDD at a dose of 10 nM for a 24 hr time period. Testosterone t reatment dose-dependently inhibited the TCDD-induced CYP1A1 mRNA accumulati on and related enzyme activity, Reciprocally, TCDD also dose-dependently in hibited testosterone-dependent transcriptional activity and testosterone-re gulated prostate specific antigen (PSA) expression. Taken together, these r esults demonstrate antiandrogenic functions of TCDD and a specific ligand-i nduced bilateral transcriptional interference between TCDD and testosterone mediated signal transduction pathways. (C) 1999 Academic Press.