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Inheritance of epigenetic dysregulation from male factor infertility has a direct impact on reproductive potential
Michelle M Denomme1, Blair R McCallie1, Jason C Parks1
1Fertility Labs of Colorado, Lone Tree, Colorado.
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.
Insights
Male-factor infertility leads to epigenetic changes in blastocysts, affecting gene expression and embryo development. These methylation and transcription alterations explain reduced reproductive success even with euploid embryo transfers.
Area of Science:
- Reproductive Biology
- Epigenetics
- Genomics
Background:
- Male-factor infertility (MF) affects a significant portion of couples seeking fertility treatment.
- Epigenetic modifications, such as DNA methylation, play a crucial role in embryonic development.
- Previous studies have not fully elucidated the epigenetic landscape of blastocysts from patients with MF infertility.
Purpose of the Study:
- To investigate the impact of male-factor infertility on the methylome and transcriptome of euploid blastocysts.
- To identify specific epigenetic alterations and their correlation with embryonic developmental competence.
Main Methods:
- Genome-wide DNA methylation analysis using Methyl Maxi-Seq.
- Global transcriptome profiling using small cell number RNA-Seq.
- Analysis of 72 blastocysts from male-factor infertility patients and controls, with validation via pyrosequencing and qPCR.
Main Results:
- Despite similar clinical pregnancy rates, male-factor infertility patients had a significantly higher miscarriage rate (14.7% vs. 2.2%).
- Significant alterations were observed in 1,111 CpG sites and 469 transcripts in blastocysts from male-factor infertility patients.
- Genes involved in cellular metabolic processes were universally affected, indicating widespread epigenetic dysregulation.
Conclusions:
- Epigenetic aberrations in blastocysts are a consequence of male-factor infertility, impacting embryogenesis.
- Altered methylation and transcription patterns affect key developmental genes, reducing embryonic competence.
- This epigenetic dysregulation offers a molecular explanation for diminished reproductive potential in male-factor infertility patients.
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