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...
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| Veröffentlicht in: | International journal of molecular sciences 2022-09, Vol.23 (18), p.10450 |
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| creator | Lloyd, Dillon T Skinner, Harlyn G Maguire, Rachel Murphy, Susan K Motsinger-Reif, Alison A Hoyo, Cathrine House, John S |
| 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 (
= 27), clomifene-only-exposed (
= 22), and non-exposed (
= 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
ICR [β(95% CI) = -1.46 (-2.81, -0.12)] and hypermethylation of the
ICR [3.71 (0.01, 7.40)]; clomifene-only was associated with hypomethylation of the
ICR [-5.25 (-10.12, -0.38)]. In female offspring, ART was associated with hypomethylation of the
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. |
| doi_str_mv | 10.3390/ijms231810450 |
| format | Article |
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= 27), clomifene-only-exposed (
= 22), and non-exposed (
= 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
ICR [β(95% CI) = -1.46 (-2.81, -0.12)] and hypermethylation of the
ICR [3.71 (0.01, 7.40)]; clomifene-only was associated with hypomethylation of the
ICR [-5.25 (-10.12, -0.38)]. In female offspring, ART was associated with hypomethylation of the
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.</description><identifier>ISSN: 1422-0067</identifier><identifier>ISSN: 1661-6596</identifier><identifier>EISSN: 1422-0067</identifier><identifier>DOI: 10.3390/ijms231810450</identifier><identifier>PMID: 36142363</identifier><language>eng</language><publisher>Switzerland: MDPI AG</publisher><subject>Births ; Cancer ; Cardiovascular disease ; Cardiovascular diseases ; Child ; Clomiphene ; Congenital defects ; Congenital diseases ; Cord blood ; CpG islands ; Diabetes ; DNA Methylation ; Drugs ; Epigenetics ; Exposure ; Female ; Females ; Gene expression ; Genomes ; Genomic Imprinting ; Gestational age ; Humans ; In vitro fertilization ; Insulin-like growth factor II ; Interrogation ; Leukocytes ; Male ; Males ; Methylation ; Ovulation ; Peg3 protein ; Reproduction ; Reproductive Techniques, Assisted - adverse effects ; Reproductive technologies ; Retrospective Studies ; Sensitivity analysis ; Sperm</subject><ispartof>International journal of molecular sciences, 2022-09, Vol.23 (18), p.10450</ispartof><rights>2022 by the authors. 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/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2022 by the authors. 2022</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c415t-898e9451e7a7f44420d67bbac95b1e18f4794a1e03f0481eae410e009cd6d6d73</citedby><cites>FETCH-LOGICAL-c415t-898e9451e7a7f44420d67bbac95b1e18f4794a1e03f0481eae410e009cd6d6d73</cites><orcidid>0000-0001-8298-7272 ; 0000-0002-8447-7871</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9499479/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9499479/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36142363$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lloyd, Dillon T</creatorcontrib><creatorcontrib>Skinner, Harlyn G</creatorcontrib><creatorcontrib>Maguire, Rachel</creatorcontrib><creatorcontrib>Murphy, Susan K</creatorcontrib><creatorcontrib>Motsinger-Reif, Alison A</creatorcontrib><creatorcontrib>Hoyo, Cathrine</creatorcontrib><creatorcontrib>House, John S</creatorcontrib><title>Clomifene and Assisted Reproductive Technology in Humans Are Associated with Sex-Specific Offspring Epigenetic Alterations in Imprinted Control Regions</title><title>International journal of molecular sciences</title><addtitle>Int J Mol Sci</addtitle><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 (
= 27), clomifene-only-exposed (
= 22), and non-exposed (
= 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
ICR [β(95% CI) = -1.46 (-2.81, -0.12)] and hypermethylation of the
ICR [3.71 (0.01, 7.40)]; clomifene-only was associated with hypomethylation of the
ICR [-5.25 (-10.12, -0.38)]. In female offspring, ART was associated with hypomethylation of the
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.</description><subject>Births</subject><subject>Cancer</subject><subject>Cardiovascular disease</subject><subject>Cardiovascular diseases</subject><subject>Child</subject><subject>Clomiphene</subject><subject>Congenital defects</subject><subject>Congenital diseases</subject><subject>Cord blood</subject><subject>CpG islands</subject><subject>Diabetes</subject><subject>DNA Methylation</subject><subject>Drugs</subject><subject>Epigenetics</subject><subject>Exposure</subject><subject>Female</subject><subject>Females</subject><subject>Gene expression</subject><subject>Genomes</subject><subject>Genomic Imprinting</subject><subject>Gestational age</subject><subject>Humans</subject><subject>In vitro fertilization</subject><subject>Insulin-like growth factor II</subject><subject>Interrogation</subject><subject>Leukocytes</subject><subject>Male</subject><subject>Males</subject><subject>Methylation</subject><subject>Ovulation</subject><subject>Peg3 protein</subject><subject>Reproduction</subject><subject>Reproductive Techniques, Assisted - adverse effects</subject><subject>Reproductive technologies</subject><subject>Retrospective Studies</subject><subject>Sensitivity analysis</subject><subject>Sperm</subject><issn>1422-0067</issn><issn>1661-6596</issn><issn>1422-0067</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNpdkUFrFTEQgIMotlaPXiXgxctqsslmNxfh8ai2UCjYeg552cm-PHaTNcm29pf4d83SWlrJISHzzTczDELvKfnMmCRf3GFKNaMdJbwhL9Ax5XVdESLal0_eR-hNSgdCalY38jU6YqKEmGDH6M92DJOz4AFr3-NNSi5l6PEPmGPoF5PdDeBrMHsfxjDcYefx2TJpn_AmwooH4_SacOvyHl_B7-pqBuOsM_jS2jRH5wd8OruhVMjlczNmiDq7UAzFdT6txJq_DT7HMJbCwxp8i15ZPSZ493CfoJ_fTq-3Z9XF5ffz7eaiMpw2uepkB5I3FFrdWs55TXrR7nbayGZHgXaWt5JrCoRZwjsKGjglQIg0vSinZSfo6713XnYT9AZKF3pUpatJxzsVtFPPI97t1RBulORSFnkRfHoQxPBrgZTV5JKBcdQewpJU3dJWdKKmXUE__ocewhJ9GW-lRNOIoixUdU-ZGFKKYB-boUStK1fPVl74D08neKT_7Zj9BVp_qts</recordid><startdate>20220909</startdate><enddate>20220909</enddate><creator>Lloyd, Dillon T</creator><creator>Skinner, Harlyn G</creator><creator>Maguire, Rachel</creator><creator>Murphy, Susan K</creator><creator>Motsinger-Reif, Alison A</creator><creator>Hoyo, Cathrine</creator><creator>House, John S</creator><general>MDPI AG</general><general>MDPI</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>MBDVC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-8298-7272</orcidid><orcidid>https://orcid.org/0000-0002-8447-7871</orcidid></search><sort><creationdate>20220909</creationdate><title>Clomifene and Assisted Reproductive Technology in Humans Are Associated with Sex-Specific Offspring Epigenetic Alterations in Imprinted Control Regions</title><author>Lloyd, Dillon T ; 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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 (
= 27), clomifene-only-exposed (
= 22), and non-exposed (
= 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
ICR [β(95% CI) = -1.46 (-2.81, -0.12)] and hypermethylation of the
ICR [3.71 (0.01, 7.40)]; clomifene-only was associated with hypomethylation of the
ICR [-5.25 (-10.12, -0.38)]. In female offspring, ART was associated with hypomethylation of the
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.</abstract><cop>Switzerland</cop><pub>MDPI AG</pub><pmid>36142363</pmid><doi>10.3390/ijms231810450</doi><orcidid>https://orcid.org/0000-0001-8298-7272</orcidid><orcidid>https://orcid.org/0000-0002-8447-7871</orcidid><oa>free_for_read</oa></addata></record> |
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| source | MDPI - Multidisciplinary Digital Publishing Institute; MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | Births Cancer Cardiovascular disease Cardiovascular diseases Child Clomiphene Congenital defects Congenital diseases Cord blood CpG islands Diabetes DNA Methylation Drugs Epigenetics Exposure Female Females Gene expression Genomes Genomic Imprinting Gestational age Humans In vitro fertilization Insulin-like growth factor II Interrogation Leukocytes Male Males Methylation Ovulation Peg3 protein Reproduction Reproductive Techniques, Assisted - adverse effects Reproductive technologies Retrospective Studies Sensitivity analysis Sperm |
| title | Clomifene and Assisted Reproductive Technology in Humans Are Associated with Sex-Specific Offspring Epigenetic Alterations in Imprinted Control Regions |
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