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Clomifene and Assisted Reproductive Technology in Humans Are Associated with Sex-Specific Offspring Epigenetic Alterations in Imprinted Control Regions
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 di...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9499479/ https://www.ncbi.nlm.nih.gov/pubmed/36142363 http://dx.doi.org/10.3390/ijms231810450 |
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author | Lloyd, Dillon T. Skinner, Harlyn G. Maguire, Rachel Murphy, Susan K. Motsinger-Reif, Alison A. Hoyo, Cathrine House, John S. |
author_facet | Lloyd, Dillon T. Skinner, Harlyn G. Maguire, Rachel Murphy, Susan K. Motsinger-Reif, Alison A. Hoyo, Cathrine House, John S. |
author_sort | Lloyd, Dillon T. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9499479 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-94994792022-09-23 Clomifene and Assisted Reproductive Technology in Humans Are Associated with Sex-Specific Offspring Epigenetic Alterations in Imprinted Control Regions Lloyd, Dillon T. Skinner, Harlyn G. Maguire, Rachel Murphy, Susan K. Motsinger-Reif, Alison A. Hoyo, Cathrine House, John S. Int J Mol Sci Article 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. MDPI 2022-09-09 /pmc/articles/PMC9499479/ /pubmed/36142363 http://dx.doi.org/10.3390/ijms231810450 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Lloyd, Dillon T. Skinner, Harlyn G. Maguire, Rachel Murphy, Susan K. Motsinger-Reif, Alison A. Hoyo, Cathrine House, John S. Clomifene and Assisted Reproductive Technology in Humans Are Associated with Sex-Specific Offspring Epigenetic Alterations in Imprinted Control Regions |
title | Clomifene and Assisted Reproductive Technology in Humans Are Associated with Sex-Specific Offspring Epigenetic Alterations in Imprinted Control Regions |
title_full | Clomifene and Assisted Reproductive Technology in Humans Are Associated with Sex-Specific Offspring Epigenetic Alterations in Imprinted Control Regions |
title_fullStr | Clomifene and Assisted Reproductive Technology in Humans Are Associated with Sex-Specific Offspring Epigenetic Alterations in Imprinted Control Regions |
title_full_unstemmed | Clomifene and Assisted Reproductive Technology in Humans Are Associated with Sex-Specific Offspring Epigenetic Alterations in Imprinted Control Regions |
title_short | Clomifene and Assisted Reproductive Technology in Humans Are Associated with Sex-Specific Offspring Epigenetic Alterations in Imprinted Control Regions |
title_sort | clomifene and assisted reproductive technology in humans are associated with sex-specific offspring epigenetic alterations in imprinted control regions |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9499479/ https://www.ncbi.nlm.nih.gov/pubmed/36142363 http://dx.doi.org/10.3390/ijms231810450 |
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