title: Effects of primary metabolites of organophosphate flame retardants on transcriptional activity via human nuclear receptors.
abstract: Organophosphate flame retardants (OPFRs) have been used in a wide variety of applications and detected in several environmental matrices, including indoor air and dust. Continuous human exposure to these chemicals is of growing concern. In this study, the agonistic and/or antagonistic activities of 12 primary OPFR-metabolites against ten human nuclear receptors were examined using cell-based transcriptional assays, and compared to those of their parent compounds. As a result, 3-hydroxylphenyl diphenyl phosphate and 4-hydroxylphenyl diphenyl phosphate showed more potent estrogen receptor α (ERα) and ERβ agonistic activity than did their parent, triphenyl phosphate (TPHP). In addition, these hydroxylated TPHP-metabolites also showed ERβ antagonistic activity at higher concentrations and exhibited pregnane X receptor (PXR) agonistic activity as well as androgen receptor (AR) and glucocorticoid receptor (GR) antagonistic activities at similar levels to those of TPHP. Bis(2-butoxyethyl) 3'-hydroxy-2-butoxyethyl phosphate and 2-hydroxyethyl bis(2-butoxyethyl) phosphate act as PXR agonists at similar levels to their parent, tris(2-butoxyethyl) phosphate. On the other hand, seven diester OPFR-metabolites and 1-hydroxy-2-propyl bis(1-chloro-2-propyl) phosphate did not show any receptor activity. Taken together, these results suggest that hydroxylated TPHP-metabolites show increased estrogenicity compared to the parent compound, whereas the diester OPFR-metabolites may have limited nuclear receptor activity compared to their parent triester OPFRs.
authors.affiliation: Hokkaido Institute of Public Health, Kita-19, Nishi-12, Kita-ku, Sapporo 060-0819, Japan. Electronic address: kojima@iph.pref.hokkaido.jp.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kojima
authors.affiliation: Hokkaido Institute of Public Health, Kita-19, Nishi-12, Kita-ku, Sapporo 060-0819, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Takeuchi
authors.affiliation: Toxicological Center, Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Antwerp, Belgium.
authors.forename: Nele
authors.initials: N
authors.lastname: Van den Eede
authors.affiliation: Toxicological Center, Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Antwerp, Belgium.
authors.forename: Adrian
authors.initials: A
authors.lastname: Covaci
mesh_terms: D000818:Animals; D001711:Biotransformation; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D047629:Estrogen Receptor beta / Q000037:antagonists & inhibitors; D005411:Flame Retardants / Q000633:toxicity*; D017930:Genes, Reporter / Q000187:drug effects; D006801:Humans; D009943:Organophosphorus Compounds / Q000493:pharmacokinetics / Q000633:toxicity* / Q000652:urine; D010957:Plasmids / Q000235:genetics; D000077297:Pregnane X Receptor; D011944:Receptors, Androgen / Q000187:drug effects; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects*; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors; D011987:Receptors, Steroid / Q000819:agonists; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation / Q000187:drug effects*; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D047629:Estrogen Receptor beta; D005411:Flame Retardants; D009943:Organophosphorus Compounds; D000077297:Pregnane X Receptor; D011944:Receptors, Androgen; D018160:Receptors, Cytoplasmic and Nuclear; D011965:Receptors, Glucocorticoid; D011987:Receptors, Steroid; D001616:beta-Galactosidase
keywords: Flame retardants; Human; Nuclear receptor; Organophosphate; Reporter gene assay; Urinary metabolite