Structural properties of estrogen receptor ligand obtained by study of hydroxylated phthalate ester derivatives

Phthalate esters (PEs), a group of plasticizers, are suspected to be endocrine-disrupting chemicals. Here, PE derivatives were used as probes for elucidating the structural properties of estrogen receptor (ER) ligands. A comprehensive study was performed using more than 40 PE derivatives including ring-/alkyl-hydroxylated and nonsymmetrical diesters possessing independently altered alkyls of C1–C8. Estrogenic activity of these derivatives is determined with three assays for ER-binding, coactivator-recruiting and transactivation. Phenolic hydroxylation increased activity, while hydroxylation of the ester alkyl group had no distinct effect on ER binding or transcription coactivator recruitment. Ring-hydroxylated PE derivatives harboring different ester alkyls revealed that the length of both alkyls independently affects transactivation of ER. These comprehensive data would be useful for the better understanding of structure–activity relationship of endocrine-disrupting chemicals.