Excess cholesterol induces mouse egg activation and may cause female infertility

• Published in: Proceedings of the National Academy of Sciences - PNAS 2014-11, Vol.111 (46), p.E4972-E4980
• Main Authors: Yesilaltay, Ayce, Dokshin, Gregoriy A, Busso, Dolores, Wang, Li, Galiani, Dalia, Chavarria, Tony, Vasile, Eliza, Quilaqueo, Linda, Orellana, Juan Andrés, Walzer, Dalia, Shalgi, Ruth, Dekel, Nava, Albertini, David F, Rigotti, Attilio, Page, David C, Krieger, Monty
• Format: Article
• Language: English
• Subjects: Animals; beta-Cyclodextrins - pharmacology; Biological Sciences; Cell division; Cell Survival; Cholesterol; Cholesterol - toxicity; Cholesterol, HDL - metabolism; Eggs; Egtazic Acid - pharmacology; Female; Infertility; Infertility, Female - etiology; MAP Kinase Signaling System; Meiosis - drug effects; Meiosis - physiology; Mice; Mice, Inbred C57BL; Mice, Knockout; Oocytes - cytology; Oocytes - drug effects; PNAS Plus; Polar Bodies; Rodents; Scavenger Receptors, Class B - deficiency; Scavenger Receptors, Class B - physiology; Strontium - pharmacology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1418954111

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. Significance Production of functional sperm and eggs requires a complex process called meiosis. Meiosis in mouse and human eggs pauses at a stage called metaphase II (MII) arrest until fertilization by sperm. After fertilization, eggs released from MII arrest complete meiosis and develop into new individuals. In analyzing the female infertility of genetically altered mice, we discovered that excess cholesterol can trick mouse eggs into behaving as though they were fertilized (released from arrest), thus disrupting the normal synchrony between fertilization and completion of meiosis and rendering them dysfunctional. These findings suggest that abnormal cholesterol metabolism may contribute to some forms of human female infertility.