Inheritance of epigenetic dysregulation from male factor infertility has a direct impact on reproductive potential

Epigenetic dysregulation in oligoasthenoteratozoospermia male factor blastocysts may directly affect embryonic competence and provide an explanation for the increased miscarriage rate observed in this population despite euploid blastocyst transfer.

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Volume 110, Issue 3, Pages 419–428.e1

Authors:

Michelle M. Denomme, Ph.D., Blair R. McCallie, B.Sc., Jason C. Parks, B.Sc., Keith Booher, Ph.D., William B. Schoolcraft, M.D., Mandy G. Katz-Jaffe, Ph.D.

Abstract:

Objective

To evaluate the epigenetic consequence on the methylome and subsequent transcriptome in euploid blastocysts of male-factor (MF) infertility patients.

Design

Methylome and transcriptome analysis on individual oligoasthenoteratozoospermia (OAT [MF]) blastocysts.

Setting

Infertility clinic.

Patient(s)

Clinical data from 128 couples presenting with OAT (MF) and 118 maternal age–matched control (no MF) subjects undergoing infertility treatment from 2010 to 2014, along with 72 surplus cryopreserved blastocysts donated from 33 couples with their informed consents.

Intervention(s)

None.

Main Outcome Measure(s)

Methyl Maxi-Seq (Zymo Research) was used to determine genome-wide DNA methylation, and small cell number RNA-Seq was used to examine the global transcriptome. Validation experiments were performed with the use of pyrosequencing or quantitative real-time polymerase chain reaction. Statistical analysis used Student t test, analysis of variance in R, Fisher exact test, and pairwise fixed reallocation randomization test where appropriate, with significance at P<.05.

Result(s)

Clinical pregnancy rates were similar between OAT (MF) patients and control (no MF) subjects after euploid embryo transfer. However, the miscarriage rate for OAT (MF) patients was significantly higher (14.7% vs. 2.2%; P<.05). Methylome and transcriptome analyses of individual blastocysts revealed significant alterations in 1,111 CpG sites and 469 transcripts, respectively (P<.05). Pathway analysis elucidated genes involved in “regulation of cellular metabolic process” as universally affected. Validation of the genome-wide approaches was performed for SBF1 and SLC6A9 (P<.05).

Conclusion(s)

Methylation and transcription aberrations in individual OAT (MF) blastocysts illustrate an epigenetic consequence of MF infertility on embryogenesis, significantly altering key developmental genes and affecting embryonic competence. This epigenetic dysregulation provides an explanation for the reduced reproductive potential in OAT (MF) patients despite euploid blastocyst transfers.


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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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