Elevated peritoneal fluid ceramides in human endometriosis-associated infertility and their effects on mouse oocyte maturation

Sphingolipidomics and multivariate statistics identified elevated peritoneal fluid ceramides in infertile women with endometriosis. Functional studies revealed that the ceramides affect oocyte maturation by modulating mitochondrial superoxide production.

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Volume 110, Issue 4, Pages 767–777.e5

Authors:

Yie Hou Lee, Ph.D., Joan Xiaohui Yang, Ph.D., John Carson Allen, Ph.D., Chuen Seng Tan, Ph.D., Bernard Su Min Chern, M.B., Tse Yeun Tan, M.B., Heng Hao Tan, M.B., Citra Nurafah Zaini Mattar, M.B., Ph.D., Jerry Kok Yen Chan, M.B., Ph.D.

Abstract:

Objective

To characterize the peritoneal fluid (PF) sphingolipid profile in endometriosis-associated infertility (EAI), and to assess the plausible functional role(s) of ceramides in oocyte maturation potential.

Design

Retrospective case-control study and in vitro mouse oocyte study.

Setting

University-affiliated hospital and university laboratory.

Subjects

Twenty-seven infertile patients diagnosed with endometriosis and 20 infertile patients who did not have endometriosis; BALB/c female mice.

Intervention(s)

None.

Main Outcome Measure(s)

PF sphingolipid concentrations. Number of metaphase II (MII) mouse oocytes.

Result(s)

Liquid chromatography–tandem mass spectrometry revealed 11 significantly elevated PF sphingolipids in infertile women with severe endometriosis compared with infertile women without endometriosis (change >50%, false discovery rate ≤10%). Logistic regression analysis identified three very-long-chain ceramides potentially associated with EAI. Functional studies revealed that very-long-chain ceramides may compromise or induce murine MII oocyte maturation. The oocyte maturation effects induced by the very long-chain ceramides were triggered by alterations in mitochondrial superoxide production in a concentration-dependent manner. Scavenging of mitochondrial superoxide reversed the maturation effects of C24:0 ceramide.

Conclusion(s)

EAI is associated with accumulation of PF very-long-chain ceramides. Mouse studies demonstrated how ceramides affect MII oocyte maturation, mediating through mitochondrial superoxide. These results provide an opportunity for direct functional readout of pathophysiology in EAI, and future therapies targeted at this sphingolipid metabolism may be harnessed for improved oocyte maturation.


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Fertility and Sterility

Editorial Office, American Society for Reproductive Medicine

Fertility and Sterility® is an international journal for obstetricians, gynecologists, reproductive endocrinologists, urologists, basic scientists and others who treat and investigate problems of infertility and human reproductive disorders. The journal publishes juried original scientific articles in clinical and laboratory research relevant to reproductive endocrinology, urology, andrology, physiology, immunology, genetics, contraception, and menopause. Fertility and Sterility® encourages and supports meaningful basic and clinical research, and facilitates and promotes excellence in professional education, in the field of reproductive medicine.

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