title: Excess cholesterol induces mouse egg activation and may cause female infertility.
abstract: The HDL receptor scavenger receptor, class B type I (SR-BI) controls the structure and fate of plasma HDL. Female SR-BI KO mice are infertile, apparently because of their abnormal cholesterol-enriched HDL particles. We examined the growth and meiotic progression of SR-BI KO oocytes and found that they underwent normal germinal vesicle breakdown; however, SR-BI KO eggs, which had accumulated excess cholesterol in vivo, spontaneously activated, and they escaped metaphase II (MII) arrest and progressed to pronuclear, MIII, and anaphase/telophase III stages. Eggs from fertile WT mice were activated when loaded in vitro with excess cholesterol by a cholesterol/methyl-β-cyclodextrin complex, phenocopying SR-BI KO oocytes. In vitro cholesterol loading of eggs induced reduction in maturation promoting factor and MAPK activities, elevation of intracellular calcium, extrusion of a second polar body, and progression to meiotic stages beyond MII. These results suggest that the infertility of SR-BI KO females is caused, at least in part, by excess cholesterol in eggs inducing premature activation and that cholesterol can activate WT mouse eggs to escape from MII arrest. Analysis of SR-BI KO female infertility raises the possibility that abnormalities in cholesterol metabolism might underlie some cases of human female infertility of unknown etiology.
authors.affiliation: Departments of Biology and.
authors.forename: Ayce
authors.initials: A
authors.lastname: Yesilaltay
authors.affiliation: Departments of Biology and Howard Hughes Medical Institute, Whitehead Institute, Cambridge, MA 02142;
authors.forename: Gregoriy A
authors.initials: GA
authors.lastname: Dokshin
authors.affiliation: Departamento de Nutrición, Diabetes y Metabolismo and.
authors.forename: Dolores
authors.initials: D
authors.lastname: Busso
authors.affiliation: Departments of Biology and.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel;
authors.forename: Dalia
authors.initials: D
authors.lastname: Galiani
authors.affiliation: Comparative Medicine and.
authors.forename: Tony
authors.initials: T
authors.lastname: Chavarria
authors.affiliation: The Koch Institute, Massachusetts Institute of Technology, Cambridge, MA 02139;
authors.forename: Eliza
authors.initials: E
authors.lastname: Vasile
authors.affiliation: Departamento de Nutrición, Diabetes y Metabolismo and.
authors.forename: Linda
authors.initials: L
authors.lastname: Quilaqueo
authors.affiliation: Departamento de Neurología, Pontificia Universidad Católica de Chile, 8330024 Santiago, Chile;
authors.forename: Juan Andrés
authors.initials: JA
authors.lastname: Orellana
authors.affiliation: Departments of Biology and.
authors.forename: Dalia
authors.initials: D
authors.lastname: Walzer
authors.affiliation: Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; and.
authors.forename: Ruth
authors.initials: R
authors.lastname: Shalgi
authors.affiliation: Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel;
authors.forename: Nava
authors.initials: N
authors.lastname: Dekel
authors.affiliation: Department of Molecular and Integrative Physiology, Institute for Reproductive Health and Regenerative Medicine, University of Kansas Medical Center, Kansas City, KS 66160.
authors.forename: David F
authors.initials: DF
authors.lastname: Albertini
authors.affiliation: Departamento de Nutrición, Diabetes y Metabolismo and.
authors.forename: Attilio
authors.initials: A
authors.lastname: Rigotti
authors.affiliation: Departments of Biology and Howard Hughes Medical Institute, Whitehead Institute, Cambridge, MA 02142;
authors.forename: David C
authors.initials: DC
authors.lastname: Page
authors.affiliation: Departments of Biology and krieger@mit.edu.
authors.forename: Monty
authors.initials: M
authors.lastname: Krieger
mesh_terms: D000818:Animals; D002470:Cell Survival; D002784:Cholesterol / Q000633:toxicity*; D008076:Cholesterol, HDL / Q000378:metabolism*; D004533:Egtazic Acid / Q000494:pharmacology; D005260:Female; D007247:Infertility, Female / Q000209:etiology*; D020935:MAP Kinase Signaling System; D008540:Meiosis / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009865:Oocytes / Q000166:cytology / Q000187:drug effects*; D059705:Polar Bodies; D051122:Scavenger Receptors, Class B / Q000172:deficiency* / Q000502:physiology; D013324:Strontium / Q000494:pharmacology; D047392:beta-Cyclodextrins / Q000494:pharmacology
chemical_list: D008076:Cholesterol, HDL; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D047392:beta-Cyclodextrins; C108732:methyl-beta-cyclodextrin; D004533:Egtazic Acid; D002784:Cholesterol; C025700:strontium chloride; D013324:Strontium
keywords: HDL; cholesterol; egg; fertility; meiosis