title: A single dose of enterolactone activates estrogen signaling and regulates expression of circadian clock genes in mice.
abstract: Enterolactone (EL) is an enterolignan produced by gut microbiota from dietary plant lignans. Epidemiological and experimental studies suggest that EL and plant lignans may reduce the risk of breast and prostate cancer as well as cardiovascular disease. These effects are thought to at least in part involve modulation of estrogen receptor activity. Surprisingly little is known about the in vivo estrogenicity of EL. In the present study, we investigated the target tissues of EL, the genes affected by EL treatment, and the response kinetics. Following a single dose of EL, luciferase was significantly induced in reproductive and nonreproductive tissues of male and female 3xERE-luciferase mice, indicating estrogen-like activity. Microarray analysis revealed that EL regulated the expression of only 1% of 17β-estradiol target genes in the uterus. The majority of these genes were traditional estrogen target genes, but also members of the circadian signaling pathway were affected. Kinetic analyses showed that EL undergoes rapid phase II metabolism and is efficiently excreted. In vivo imaging demonstrated that the estrogen response followed similar, fast kinetics. We conclude that EL activates estrogen signaling in both male and female mice and that the transient responses may be due to the fast metabolism of the compound. Lastly, EL may represent a link among diet, gut microbiota, and circadian signaling.
authors.affiliation: Department of Cell Biology and Anatomy, Institute of Biomedicine, University of Turku, Turku, Finland. pauliina.damdimopoulou@ki.se
authors.forename: Pauliina
authors.initials: P
authors.lastname: Damdimopoulou
authors.forename: Tarja
authors.initials: T
authors.lastname: Nurmi
authors.forename: Anu
authors.initials: A
authors.lastname: Salminen
authors.forename: Anastasios E
authors.initials: AE
authors.lastname: Damdimopoulos
authors.forename: Maria
authors.initials: M
authors.lastname: Kotka
authors.forename: Paul
authors.initials: P
authors.lastname: van der Saag
authors.forename: Leena
authors.initials: L
authors.lastname: Strauss
authors.forename: Matti
authors.initials: M
authors.lastname: Poutanen
authors.forename: Ingemar
authors.initials: I
authors.lastname: Pongratz
authors.forename: Sari
authors.initials: S
authors.lastname: Mäkelä
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology; D000818:Animals; D056926:CLOCK Proteins / Q000235:genetics / Q000378:metabolism*; D057906:Circadian Clocks / Q000187:drug effects / Q000235:genetics*; D004958:Estradiol / Q000494:pharmacology; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D017705:Lignans / Q000097:blood / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009919:Orchiectomy; D010052:Ovariectomy; D048789:Phytoestrogens / Q000494:pharmacology*; D040081:Protein Array Analysis; D011897:Random Allocation; D015398:Signal Transduction / Q000187:drug effects*; D014599:Uterus / Q000378:metabolism
chemical_list: D004967:Estrogens; D017705:Lignans; D048789:Phytoestrogens; D004958:Estradiol; D008156:Luciferases; D056926:CLOCK Proteins; D015107:4-Butyrolactone; C029497:2,3-bis(3'-hydroxybenzyl)butyrolactone