Excess cholesterol induces mouse egg activation and may cause female infertility

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.National Institutes of Health (U.S.)National Institutes of Health (U.S.) (Pre-doctoral Training Grant T32GM007287)Massachusetts Institute of Technology (International Science and Technology Initiatives Chile Cooperative Grant

Additional file 1: Figure S1. of A-to-I RNA editing in the rat brain is age-dependent, region-specific and sensitive to environmental stress across generations

A Flow chart of sample preparation using the Illumina-based Htr2c-direcetd NGS. (PDF 92 kb

Additional file 4: Figure S3. of A-to-I RNA editing in the rat brain is age-dependent, region-specific and sensitive to environmental stress across generations

A-to-I RNA editing in oocytes, AMY and PFC of adult female rats. Editing sites where % editing are high are presented in the top part of the figure; sites where % editing are low (0–4%) are presented in the bottom part. N’s, PFC, 11, AMY 12, Oocytes 5–12. (TIFF 584 kb

Additional file 2: Table S1. of A-to-I RNA editing in the rat brain is age-dependent, region-specific and sensitive to environmental stress across generations

RNA editing sites detected with mmPCR-seq. Table S2. Primer sequences used for mmPCR-seq, Real-Time PCR and Htr2c-directed NGS. Table S3. % RNA editing in PFC and AMY of neonatal (P0) vs. adult (P60) rats. Table S4. Age-dependent changes in Htr2c isoform prevalence in PFC and AMY. Table S5. % RNA editing in neonatal (P0) and adult (P60) PFC vs. AMY. Table S6. Htr2c and ADARs correlations with significant non-synonymous editing sites. Table S7. Changes in Htr2c isoform prevalence in PFC vs. AMY at P0 and P60. Table S8. The effects of PRS on RNA editing at learning- and stress-related genes in F0, F1 and F2. Table S9. Statistical analysis of editing differences between oocytes, PFC and AMY. (XLSX 92 kb