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Clomifene and Assisted Reproductive Technology in Humans Are Associated with Sex-Specific Offspring Epigenetic Alterations in Imprinted Control Regions.

Publication ,  Journal Article
Lloyd, DT; Skinner, HG; Maguire, R; Murphy, SK; Motsinger-Reif, AA; Hoyo, C; House, JS
Published in: Int J Mol Sci
September 9, 2022

Children conceived with assisted reproductive technology (ART) have an increased risk of adverse outcomes, including congenital malformations and imprinted gene disorders. In a retrospective North Carolina-based-birth-cohort, we examined the effect of ovulation drugs and ART on CpG methylation in differentially methylated CpGs in known imprint control regions (ICRs). Nine ICRs containing 48 CpGs were assessed for methylation status by pyrosequencing in mixed leukocytes from cord blood. After restricting to non-smoking, college-educated participants who agreed to follow-up, ART-exposed (n = 27), clomifene-only-exposed (n = 22), and non-exposed (n = 516) groups were defined. Associations of clomifene and ART with ICR CpG methylation were assessed with linear regression and stratifying by offspring sex. In males, ART was associated with hypomethylation of the PEG3 ICR [β(95% CI) = -1.46 (-2.81, -0.12)] and hypermethylation of the MEG3 ICR [3.71 (0.01, 7.40)]; clomifene-only was associated with hypomethylation of the NNAT ICR [-5.25 (-10.12, -0.38)]. In female offspring, ART was associated with hypomethylation of the IGF2 ICR [-3.67 (-6.79, -0.55)]. Aberrant methylation of these ICRs has been associated with cardiovascular disease and metabolic and behavioral outcomes in children. The results suggest that the increased risk of adverse outcomes in offspring conceived through ART may be due in part to altered methylation of ICRs. Larger studies utilizing epigenome-wide interrogation are warranted.

Duke Scholars

Published In

Int J Mol Sci

DOI

EISSN

1422-0067

Publication Date

September 9, 2022

Volume

23

Issue

18

Location

Switzerland

Related Subject Headings

  • Retrospective Studies
  • Reproductive Techniques, Assisted
  • Male
  • Humans
  • Genomic Imprinting
  • Female
  • DNA Methylation
  • Clomiphene
  • Child
  • Chemical Physics
 

Citation

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Lloyd, D. T., Skinner, H. G., Maguire, R., Murphy, S. K., Motsinger-Reif, A. A., Hoyo, C., & House, J. S. (2022). Clomifene and Assisted Reproductive Technology in Humans Are Associated with Sex-Specific Offspring Epigenetic Alterations in Imprinted Control Regions. Int J Mol Sci, 23(18). https://doi.org/10.3390/ijms231810450
Lloyd, Dillon T., Harlyn G. Skinner, Rachel Maguire, Susan K. Murphy, Alison A. Motsinger-Reif, Cathrine Hoyo, and John S. House. “Clomifene and Assisted Reproductive Technology in Humans Are Associated with Sex-Specific Offspring Epigenetic Alterations in Imprinted Control Regions.Int J Mol Sci 23, no. 18 (September 9, 2022). https://doi.org/10.3390/ijms231810450.
Lloyd DT, Skinner HG, Maguire R, Murphy SK, Motsinger-Reif AA, Hoyo C, et al. Clomifene and Assisted Reproductive Technology in Humans Are Associated with Sex-Specific Offspring Epigenetic Alterations in Imprinted Control Regions. Int J Mol Sci. 2022 Sep 9;23(18).
Lloyd, Dillon T., et al. “Clomifene and Assisted Reproductive Technology in Humans Are Associated with Sex-Specific Offspring Epigenetic Alterations in Imprinted Control Regions.Int J Mol Sci, vol. 23, no. 18, Sept. 2022. Pubmed, doi:10.3390/ijms231810450.
Lloyd DT, Skinner HG, Maguire R, Murphy SK, Motsinger-Reif AA, Hoyo C, House JS. Clomifene and Assisted Reproductive Technology in Humans Are Associated with Sex-Specific Offspring Epigenetic Alterations in Imprinted Control Regions. Int J Mol Sci. 2022 Sep 9;23(18).

Published In

Int J Mol Sci

DOI

EISSN

1422-0067

Publication Date

September 9, 2022

Volume

23

Issue

18

Location

Switzerland

Related Subject Headings

  • Retrospective Studies
  • Reproductive Techniques, Assisted
  • Male
  • Humans
  • Genomic Imprinting
  • Female
  • DNA Methylation
  • Clomiphene
  • Child
  • Chemical Physics