Endocrine disruption potentials of organophosphate flame retardants and related mechanisms in H295R and MVLN cell lines and in zebrafish

Organophosphate flame retardants (OPFRs) are frequently detected in environment and biota. However, knowledge on their potential toxicological effects is limited. Endocrine disrupting potentials of six OPFRs, i.e., tris-(2-chloroethyl) phosphate (TCEP), tris-(2-chloroisopropyl) phosphate (TCPP), tris-(1,3-dichloro-2-propyl) phosphate (TDCPP), tris-(2-butoxyethyl) phosphate (TBEP), triphenyl phosphate (TPP), and tricresyl phosphate (TCP), were investigated using human cell lines as well as zebrafish (Danio rerio). Sex hormone synthesis and steroidogenic gene transcriptions were measured using H295R cells. With MVLN cells, estrogen receptor binding activities of OPFRs were evaluated. In zebrafish, sex hormones and related gene transcriptions were determined for each sex after 14 d exposure to OPFRs. All six OPFRs increased both 17β-estradiol (E2) and testosterone (T) concentrations in H295R cells. In addition, transcription of four major steroidogenic genes was up-regulated and that of two sulfotransferase genes was down-regulated. In MVLN cells, no OPFRs acted as estrogen receptor agonists, while TDCPP, TPP, and TCP acted as antagonists inhibiting binding of E2 to estrogen receptor. After 14 d of zebrafish exposure, TCP, TDCPP, or TPP significantly increased plasma T and E2 concentrations, but did not change 11-ketotestosterone (11-KT) among female fish. Among males, both T and 11-KT decreased and E2 increased. In general, transcription of CYP17 and CYP19a genes was significantly up-regulated in both sexes, while vitellogenin (VTG) 1 gene was down- and up-regulated in female and male fish, respectively. The results of this study showed that OPFRs could alter sex hormone balance through several mechanisms including alterations of steroidogenesis or estrogen metabolism.