In vitro estrogen-disrupting effects of organophosphate flame retardants

Abstract

Organophosphate flame retardants (OPFRs), as substitutes for polybrominated diphenyl ethers (PBDEs), are frequently detected in the environment and biota due to their widespread use. Thus, there is a need to investigate their potential estrogen-disrupting effects and possible mechanisms of action in an effort to obtain a better risk assessment. In this study, we characterized the activities on estrogen receptor α (ERα) and the estrogen-disrupting potential of fourteen OPFRs, TMP, TEP, TPP, TnBP, TiBP, THP, TPhP, TCP, DPK, MDPP, IDPP, CDP, IPPDP and MPhP, using three in vitro assays representing different specific modes of action (MoAs). In the yeast two-hybrid assay, no OPFRs induced agonistic activity, but TiBP, DPK, TPhP, MDPP, CDP and IPPDP were shown to be hydrophobicity-dependent antagonists and to compete with E2 for binding to ERα. In the MVLN cell assay, TPhP was the only OPFR among the 14 tested that was able to activate ERα-estrogen responsive element (ERE) pathways. The results from the E-SCREEN assay showed that all tested OPFRs except TMP had estrogenic properties, and G protein-coupled receptor 30 (GPR30) was involved in the estrogenicity of eight OPFRs, TiBP, THP, TPhP, TCP, MDPP, IPPDP, CDP and MPhP. It was also found that in the E-SCREEN assay, the estrogenicity of alkyl-OPFRs but not aryl-OPFRs was closely correlated to hydrophobicity. Our research suggested that most OPFRs were estrogen disruptors, but their related mechanisms were complex and might involve ERα-mediated and/or ERα-independent pathways. Further in vitro studies concerning the estrogenic effects and involved mechanisms of OPFRs, as well as comprehensive evaluations of OPFRs including health and ecological assessments are needed to determine whether they are safe substitutes for PBDEs.