The effects of six organophosphate flame retardants on endocrine receptor targets in mammalian cancer cell lines

The effects of six selected organophosphate flame retardants (OPFRs) tris(2-butoxyethyl) phosphate (TBOEP), tris(2-chloroethyl) phosphate (TCEP), tris(1-chloro-2-propyl) phosphate (TCIPP), tris(methylphenyl) phosphate (TMPP), tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) and triethyl phosphate (TEP) on the activities of the androgen-, estrogen- and aryl hydrocarbon receptors were assessed in human prostate cancer cells (LNCaP) and endometrial cancer cells (ECC-1 cells). Binding affinity for the estrogen receptor (ER) of the selected OPFRs appeared limited in ECC-1 cells, as no profound changes in ER inducible target gene expression were observed. Furthermore, the six selected OPFRs exerted few effects on the aryl hydrocarbon receptor-inducible CYP1A1 expression, although at high concentrations TMPP mildly induced gene expression. Messenger RNA and protein accumulation of androgen receptor (AR) target genes were examined for TDCIPP. Additionally, secretory PSA detection, chromatin immunoprecipitation and a ligand binding assay were performed using TDCIPP and the synthetic androgen methyltrienolone. AR inducible target gene and protein expression were significantly altered by TDCIPP exposure, as well as excreted prostate specific antigen. For the first time it was demonstrated that TDCIPP does not have binding affinity for the AR-ligand binding domain and appears to exert its anti-androgenic effects in LNCaP cells in a non-competitive fashion. Furthermore, TDCIPP exposure could adversely influence clinical outcomes for prostate cancer screenings, resulting in false negatives. Prolonged TDCIPP exposure could also carry the risk of exacerbating the progression of prostate cancer into a metastatic androgen-independent sub-type by simulating androgen deprivation.