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Alterations in the sperm histone-retained epigenome are associated with unexplained male factor infertility and poor blastocyst development in donor oocyte IVF cycles.
Hum Reprod. 2017 Dec 01; 32(12):2443-2455.HR

Abstract

STUDY QUESTION

Is there a distinct sperm histone-retained epigenetic signature in unexplained male factor infertility patients resulting in compromised blastocyst development?

SUMMARY ANSWER

Using only donor oocyte IVF cycles, sperm DNA methylation patterns and miRNA profiles were significantly altered in normozoospermic patients resulting in poor blastocyst development, reflecting a subset of unexplained male factor infertility.

WHAT IS KNOWN ALREADY

Aberrant sperm DNA methylation has been associated with known male factor infertility, particularly noted in oligozoospermic patients. Unexplained male factor infertility remains a significant proportion of in vitro fertilization failures having unknown underlying physiology.

STUDY DESIGN, SIZE, DURATION

Sperm samples (n = 40) and blastocysts (n = 48) were obtained during fertile donor oocyte IVF cycles with normozoospermic parameters, thereby excluding known female and male infertility factors. Samples were divided into two groups based on blastocyst development (Good Group = ≥20% embryos with D5 grade 'AA' blastocysts, and ≥60% embryos of transferable quality on D5 and D6; Poor Group = ≤10% embryos with D5 grade 'AA' blastocysts, and ≤40% embryos of transferable quality on D5 and D6).

PARTICIPANTS/MATERIALS, SETTING, METHODS

Samples were obtained from patients undergoing IVF treatments with informed consent and institutional review board approval. The Infinium HumanMethylation450 BeadChip microarray was used to identify histone-retained CpG island genes and genomic regions showing differences in sperm DNA methylation between the Good Group and the Poor Group. Pathway and gene network analysis for the significantly altered genes was performed, and targeted DNA methylation validation was completed for 23 genes and two imprinting control regions. Sperm miRNA profiles were assessed using the TaqMan® Human MicroRNA Array Card, with corresponding blastocyst mRNA gene expression examined by qRT-PCR.

MAIN RESULTS AND THE ROLE OF CHANCE

Our study is the first to investigate unexplained male factor infertility while significantly eliminating confounding female factors from our sample population by using only young fertile donor oocytes. We identified 1634 CpG sites located at retained histone CpG island regions that had significant sperm DNA methylation differentials between the two embryogenesis groups (P < 0.05). A largely hypermethylated profile was evident in the Good Group, with a small but distinct and statistically significant shift (P < 0.05) observed in the Poor Group. Genes involved in embryonic development were highly represented among histone-retained CpG sites with decreased methylation in the Poor Group (P < 0.05). Ten significantly altered sperm miRNAs (P < 0.05), correlated with altered target gene mRNA expression in the blastocysts from the Poor Group (P < 0.05). Taken together, significantly impacted sperm miRNA and target transcript levels in blastocysts from the Poor Group may contribute alongside aberrant sperm DNA methylation to the compromised blastocyst development observed.

LIMITATIONS, REASONS FOR CAUTION

Our examination of CpG island regions restricted to retained histones represents only a small part of the sperm epigenome. The results observed are descriptive and further studies are needed to elucidate the functional effects of differential sperm DNA methylation on unexplained male factor infertility and blastocyst development.

WIDER IMPLICATIONS OF THE FINDINGS

Slight epigenetic changes in sperm may have a cumulative effect on fertility and embryonic developmental competence. Knowledge of sperm epigenetics and inheritance has important implications for future generations, while providing evidence for potential causes of unexplained male factor infertility.

STUDY FUNDING/COMPETING INTEREST(S)

No external funding was used for this study. None of the authors have any competing interest.

Authors+Show Affiliations

Fertility Labs of Colorado, 10290 Ridgegate Circle, Lone Tree CO, 80124, USA.Fertility Labs of Colorado, 10290 Ridgegate Circle, Lone Tree CO, 80124, USA.Fertility Labs of Colorado, 10290 Ridgegate Circle, Lone Tree CO, 80124, USA.Colorado Center for Reproductive Medicine, 10290 Ridgegate Circle, Lone Tree CO, 80124, USA.Fertility Labs of Colorado, 10290 Ridgegate Circle, Lone Tree CO, 80124, USA. Colorado Center for Reproductive Medicine, 10290 Ridgegate Circle, Lone Tree CO, 80124, USA.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29087470

Citation

Denomme, Michelle M., et al. "Alterations in the Sperm Histone-retained Epigenome Are Associated With Unexplained Male Factor Infertility and Poor Blastocyst Development in Donor Oocyte IVF Cycles." Human Reproduction (Oxford, England), vol. 32, no. 12, 2017, pp. 2443-2455.
Denomme MM, McCallie BR, Parks JC, et al. Alterations in the sperm histone-retained epigenome are associated with unexplained male factor infertility and poor blastocyst development in donor oocyte IVF cycles. Hum Reprod. 2017;32(12):2443-2455.
Denomme, M. M., McCallie, B. R., Parks, J. C., Schoolcraft, W. B., & Katz-Jaffe, M. G. (2017). Alterations in the sperm histone-retained epigenome are associated with unexplained male factor infertility and poor blastocyst development in donor oocyte IVF cycles. Human Reproduction (Oxford, England), 32(12), 2443-2455. https://doi.org/10.1093/humrep/dex317
Denomme MM, et al. Alterations in the Sperm Histone-retained Epigenome Are Associated With Unexplained Male Factor Infertility and Poor Blastocyst Development in Donor Oocyte IVF Cycles. Hum Reprod. 2017 Dec 1;32(12):2443-2455. PubMed PMID: 29087470.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Alterations in the sperm histone-retained epigenome are associated with unexplained male factor infertility and poor blastocyst development in donor oocyte IVF cycles. AU - Denomme,Michelle M, AU - McCallie,Blair R, AU - Parks,Jason C, AU - Schoolcraft,William B, AU - Katz-Jaffe,Mandy G, PY - 2017/05/17/received PY - 2017/10/02/accepted PY - 2017/11/1/pubmed PY - 2018/10/12/medline PY - 2017/11/1/entrez KW - DNA methylation KW - blastocyst KW - epigenetics KW - sperm KW - unexplained infertility SP - 2443 EP - 2455 JF - Human reproduction (Oxford, England) JO - Hum. Reprod. VL - 32 IS - 12 N2 - STUDY QUESTION: Is there a distinct sperm histone-retained epigenetic signature in unexplained male factor infertility patients resulting in compromised blastocyst development? SUMMARY ANSWER: Using only donor oocyte IVF cycles, sperm DNA methylation patterns and miRNA profiles were significantly altered in normozoospermic patients resulting in poor blastocyst development, reflecting a subset of unexplained male factor infertility. WHAT IS KNOWN ALREADY: Aberrant sperm DNA methylation has been associated with known male factor infertility, particularly noted in oligozoospermic patients. Unexplained male factor infertility remains a significant proportion of in vitro fertilization failures having unknown underlying physiology. STUDY DESIGN, SIZE, DURATION: Sperm samples (n = 40) and blastocysts (n = 48) were obtained during fertile donor oocyte IVF cycles with normozoospermic parameters, thereby excluding known female and male infertility factors. Samples were divided into two groups based on blastocyst development (Good Group = ≥20% embryos with D5 grade 'AA' blastocysts, and ≥60% embryos of transferable quality on D5 and D6; Poor Group = ≤10% embryos with D5 grade 'AA' blastocysts, and ≤40% embryos of transferable quality on D5 and D6). PARTICIPANTS/MATERIALS, SETTING, METHODS: Samples were obtained from patients undergoing IVF treatments with informed consent and institutional review board approval. The Infinium HumanMethylation450 BeadChip microarray was used to identify histone-retained CpG island genes and genomic regions showing differences in sperm DNA methylation between the Good Group and the Poor Group. Pathway and gene network analysis for the significantly altered genes was performed, and targeted DNA methylation validation was completed for 23 genes and two imprinting control regions. Sperm miRNA profiles were assessed using the TaqMan® Human MicroRNA Array Card, with corresponding blastocyst mRNA gene expression examined by qRT-PCR. MAIN RESULTS AND THE ROLE OF CHANCE: Our study is the first to investigate unexplained male factor infertility while significantly eliminating confounding female factors from our sample population by using only young fertile donor oocytes. We identified 1634 CpG sites located at retained histone CpG island regions that had significant sperm DNA methylation differentials between the two embryogenesis groups (P < 0.05). A largely hypermethylated profile was evident in the Good Group, with a small but distinct and statistically significant shift (P < 0.05) observed in the Poor Group. Genes involved in embryonic development were highly represented among histone-retained CpG sites with decreased methylation in the Poor Group (P < 0.05). Ten significantly altered sperm miRNAs (P < 0.05), correlated with altered target gene mRNA expression in the blastocysts from the Poor Group (P < 0.05). Taken together, significantly impacted sperm miRNA and target transcript levels in blastocysts from the Poor Group may contribute alongside aberrant sperm DNA methylation to the compromised blastocyst development observed. LIMITATIONS, REASONS FOR CAUTION: Our examination of CpG island regions restricted to retained histones represents only a small part of the sperm epigenome. The results observed are descriptive and further studies are needed to elucidate the functional effects of differential sperm DNA methylation on unexplained male factor infertility and blastocyst development. WIDER IMPLICATIONS OF THE FINDINGS: Slight epigenetic changes in sperm may have a cumulative effect on fertility and embryonic developmental competence. Knowledge of sperm epigenetics and inheritance has important implications for future generations, while providing evidence for potential causes of unexplained male factor infertility. STUDY FUNDING/COMPETING INTEREST(S): No external funding was used for this study. None of the authors have any competing interest. SN - 1460-2350 UR - https://www.unboundmedicine.com/medline/citation/29087470/Alterations_in_the_sperm_histone_retained_epigenome_are_associated_with_unexplained_male_factor_infertility_and_poor_blastocyst_development_in_donor_oocyte_IVF_cycles_ L2 - https://academic.oup.com/humrep/article-lookup/doi/10.1093/humrep/dex317 DB - PRIME DP - Unbound Medicine ER -