title: Estrogenicity of alkylphenols and alkylated non-phenolics in a rainbow trout (Oncorhynchus mykiss) primary hepatocyte culture.
abstract: Alkylphenols act as estrogen mimics by binding to and transactivating estrogen receptors (ERs) in fish. In the present study, activation of ER-mediated production of the estrogenic biomarker vitellogenin (vtg) in a primary culture of rainbow trout (Oncorhynchus mykiss) hepatocytes was used to construct a structure-activity relationship for this ubiquitous group of aquatic pollutants. The role of alkyl chain length and branching, substituent position, number of alkylated groups, and the requirement of a phenolic ring structure was assessed. The results showed that most alkylphenols were estrogenic, although with 3-300 thousand times lower affinity than the endogenous estrogen 17beta-estradiol. Mono-substituted tertiary alkylphenols with moderate (C4-C5) and long alkyl chain length (C8-C9) in the para position exhibited the highest estrogenic potency. Substitution with multiple alkyl groups, presence of substituents in the ortho- and meta-position and lack of a hydroxyl group on the benzene ring reduced the estrogenic activity, although several estrogenic alkylated non-phenolics were identified. Co-exposures with the natural estrogen 17beta-estradiol led to identification of additional estrogenic compounds as well as some anti-estrogens. A combination of low affinity for the ER and cytotoxicity was identified as factors rendering some of the alkylphenols non-estrogenic in the bioassay when tested alone.
authors.affiliation: Norwegian Institute for Water Research (NIVA), Gaustadallèen 21, N-0349 Oslo, Norway. knut.erik.tollefsen@niva.no
authors.forename: K-E
authors.initials: KE
authors.lastname: Tollefsen
authors.forename: Sissel
authors.initials: S
authors.lastname: Eikvar
authors.forename: Eivind Farmen
authors.initials: EF
authors.lastname: Finne
authors.forename: Oscar
authors.initials: O
authors.lastname: Fogelberg
authors.forename: Inger Katharina
authors.initials: IK
authors.lastname: Gregersen
mesh_terms: D000818:Animals; D015415:Biomarkers; D002478:Cells, Cultured; D004967:Estrogens / Q000633:toxicity*; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008967:Molecular Biology; D017686:Oncorhynchus mykiss; D010636:Phenols / Q000633:toxicity*; D011960:Receptors, Estrogen; D013329:Structure-Activity Relationship; D014819:Vitellogenins / Q000378:metabolism; D014874:Water Pollutants, Chemical / Q000633:toxicity
chemical_list: D015415:Biomarkers; D004967:Estrogens; D010636:Phenols; D011960:Receptors, Estrogen; D014819:Vitellogenins; D014874:Water Pollutants, Chemical