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Compromised oocyte quality and assisted reproduction contribute to sex-specific effects on offspring outcomes and epigenetic patterning
Clinical studies have revealed an increased incidence of growth and genomic imprinting disorders in children conceived using assisted reproductive technologies (ARTs), and aberrant DNA methylation has been implicated. We propose that compromised oocyte quality associated with female infertility may...
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Published in: | Human molecular genetics 2016-11, Vol.25 (21), p.4649-4660 |
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creator | Whidden, Laura Martel, Josée Rahimi, Sophia Chaillet, J Richard Chan, Donovan Trasler, Jacquetta M |
description | Clinical studies have revealed an increased incidence of growth and genomic imprinting disorders in children conceived using assisted reproductive technologies (ARTs), and aberrant DNA methylation has been implicated. We propose that compromised oocyte quality associated with female infertility may make embryos more susceptible to the induction of epigenetic defects by ART. DNA methylation patterns in the preimplantation embryo are dependent on the oocyte-specific DNA methyltransferase 1o (DNMT1o), levels of which are decreased in mature oocytes of aging females. Here, we assessed the effects of maternal deficiency in DNMT1o (Dnmt1Δ1o/+) in combination with superovulation and embryo transfer on offspring DNA methylation and development. We demonstrated a significant increase in the rates of morphological abnormalities in offspring collected from Dnmt1Δ1o/+ females only when combined with ART. Together, maternal oocyte DNMT1o deficiency and ART resulted in an accentuation of placental imprinting defects and the induction of genome-wide DNA methylation alterations, which were exacerbated in the placenta compared to the embryo. Significant sex-specific trends were also apparent, with a preponderance of DNA hypomethylation in females. Among genic regions affected, a significant enrichment for neurodevelopmental pathways was observed. Taken together, our results demonstrate that oocyte DNMT1o-deficiency exacerbates genome-wide DNA methylation abnormalities induced by ART in a sex-specific manner and plays a role in mediating poor embryonic outcome. |
doi_str_mv | 10.1093/hmg/ddw293 |
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We propose that compromised oocyte quality associated with female infertility may make embryos more susceptible to the induction of epigenetic defects by ART. DNA methylation patterns in the preimplantation embryo are dependent on the oocyte-specific DNA methyltransferase 1o (DNMT1o), levels of which are decreased in mature oocytes of aging females. Here, we assessed the effects of maternal deficiency in DNMT1o (Dnmt1Δ1o/+) in combination with superovulation and embryo transfer on offspring DNA methylation and development. We demonstrated a significant increase in the rates of morphological abnormalities in offspring collected from Dnmt1Δ1o/+ females only when combined with ART. Together, maternal oocyte DNMT1o deficiency and ART resulted in an accentuation of placental imprinting defects and the induction of genome-wide DNA methylation alterations, which were exacerbated in the placenta compared to the embryo. Significant sex-specific trends were also apparent, with a preponderance of DNA hypomethylation in females. Among genic regions affected, a significant enrichment for neurodevelopmental pathways was observed. Taken together, our results demonstrate that oocyte DNMT1o-deficiency exacerbates genome-wide DNA methylation abnormalities induced by ART in a sex-specific manner and plays a role in mediating poor embryonic outcome.</description><identifier>ISSN: 0964-6906</identifier><identifier>EISSN: 1460-2083</identifier><identifier>DOI: 10.1093/hmg/ddw293</identifier><identifier>PMID: 28173052</identifier><language>eng</language><publisher>England</publisher><subject>Age Factors ; Animals ; DNA (Cytosine-5-)-Methyltransferase 1 - metabolism ; DNA Methylation ; Epigenesis, Genetic ; Female ; Infertility, Female - physiopathology ; Mice ; Models, Animal ; Oocytes - pathology ; Oocytes - physiology ; Placenta - metabolism ; Pregnancy ; Reproductive Techniques - adverse effects ; Superovulation - genetics ; Superovulation - physiology</subject><ispartof>Human molecular genetics, 2016-11, Vol.25 (21), p.4649-4660</ispartof><rights>The Author 2016. Published by Oxford University Press. All rights reserved. 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We propose that compromised oocyte quality associated with female infertility may make embryos more susceptible to the induction of epigenetic defects by ART. DNA methylation patterns in the preimplantation embryo are dependent on the oocyte-specific DNA methyltransferase 1o (DNMT1o), levels of which are decreased in mature oocytes of aging females. Here, we assessed the effects of maternal deficiency in DNMT1o (Dnmt1Δ1o/+) in combination with superovulation and embryo transfer on offspring DNA methylation and development. We demonstrated a significant increase in the rates of morphological abnormalities in offspring collected from Dnmt1Δ1o/+ females only when combined with ART. Together, maternal oocyte DNMT1o deficiency and ART resulted in an accentuation of placental imprinting defects and the induction of genome-wide DNA methylation alterations, which were exacerbated in the placenta compared to the embryo. Significant sex-specific trends were also apparent, with a preponderance of DNA hypomethylation in females. Among genic regions affected, a significant enrichment for neurodevelopmental pathways was observed. Taken together, our results demonstrate that oocyte DNMT1o-deficiency exacerbates genome-wide DNA methylation abnormalities induced by ART in a sex-specific manner and plays a role in mediating poor embryonic outcome.</description><subject>Age Factors</subject><subject>Animals</subject><subject>DNA (Cytosine-5-)-Methyltransferase 1 - metabolism</subject><subject>DNA Methylation</subject><subject>Epigenesis, Genetic</subject><subject>Female</subject><subject>Infertility, Female - physiopathology</subject><subject>Mice</subject><subject>Models, Animal</subject><subject>Oocytes - pathology</subject><subject>Oocytes - physiology</subject><subject>Placenta - metabolism</subject><subject>Pregnancy</subject><subject>Reproductive Techniques - adverse effects</subject><subject>Superovulation - genetics</subject><subject>Superovulation - physiology</subject><issn>0964-6906</issn><issn>1460-2083</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><recordid>eNo9kM1KxDAUhYMozji68QEkSxHqpEmbpEsZ_IMBN7ouaXI7RtqmJik6T-BrG53R1V3c7xw4H0LnObnOScWWr_1macwHrdgBmucFJxklkh2iOal4kfGK8Bk6CeGNkJwXTByjGZW5YKSkc_S1cv3oXW8DGOyc3kbA75PqbNxiNRisQrAhpp-HhJlJR-sGrN0QvW2mBEeHA3xmYQRtW6sxtC3oGHCiXNuG0dthg90Utesh_FbCaDcwQEzwqGIEPyTkFB21qgtwtr8L9HJ3-7x6yNZP94-rm3WmGWUx41oKAUWhZCOFoUSUlJea6oqBYsCKUmqqOKcqh9IYwwgRDdFlskQLLrlgC3S5601r3icIsU7TNXSdGsBNoc5lSlcyuUno1Q7V3oXgoa3TmF75bZ2T-kd8ncTXO_EJvtj3Tk0P5h_9M82-ARTKgo4</recordid><startdate>20161101</startdate><enddate>20161101</enddate><creator>Whidden, Laura</creator><creator>Martel, Josée</creator><creator>Rahimi, Sophia</creator><creator>Chaillet, J Richard</creator><creator>Chan, Donovan</creator><creator>Trasler, Jacquetta M</creator><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>7X8</scope></search><sort><creationdate>20161101</creationdate><title>Compromised oocyte quality and assisted reproduction contribute to sex-specific effects on offspring outcomes and epigenetic patterning</title><author>Whidden, Laura ; Martel, Josée ; Rahimi, Sophia ; Chaillet, J Richard ; Chan, Donovan ; Trasler, Jacquetta M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c323t-6c877e44a8b87d2075265c2c93ea3e3458c2a662a1e5ddd3007b0c50932468673</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Age Factors</topic><topic>Animals</topic><topic>DNA (Cytosine-5-)-Methyltransferase 1 - metabolism</topic><topic>DNA Methylation</topic><topic>Epigenesis, Genetic</topic><topic>Female</topic><topic>Infertility, Female - physiopathology</topic><topic>Mice</topic><topic>Models, Animal</topic><topic>Oocytes - pathology</topic><topic>Oocytes - physiology</topic><topic>Placenta - metabolism</topic><topic>Pregnancy</topic><topic>Reproductive Techniques - adverse effects</topic><topic>Superovulation - genetics</topic><topic>Superovulation - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Whidden, Laura</creatorcontrib><creatorcontrib>Martel, Josée</creatorcontrib><creatorcontrib>Rahimi, Sophia</creatorcontrib><creatorcontrib>Chaillet, J Richard</creatorcontrib><creatorcontrib>Chan, Donovan</creatorcontrib><creatorcontrib>Trasler, Jacquetta M</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Human molecular genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Whidden, Laura</au><au>Martel, Josée</au><au>Rahimi, Sophia</au><au>Chaillet, J Richard</au><au>Chan, Donovan</au><au>Trasler, Jacquetta M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Compromised oocyte quality and assisted reproduction contribute to sex-specific effects on offspring outcomes and epigenetic patterning</atitle><jtitle>Human molecular genetics</jtitle><addtitle>Hum Mol Genet</addtitle><date>2016-11-01</date><risdate>2016</risdate><volume>25</volume><issue>21</issue><spage>4649</spage><epage>4660</epage><pages>4649-4660</pages><issn>0964-6906</issn><eissn>1460-2083</eissn><abstract>Clinical studies have revealed an increased incidence of growth and genomic imprinting disorders in children conceived using assisted reproductive technologies (ARTs), and aberrant DNA methylation has been implicated. We propose that compromised oocyte quality associated with female infertility may make embryos more susceptible to the induction of epigenetic defects by ART. DNA methylation patterns in the preimplantation embryo are dependent on the oocyte-specific DNA methyltransferase 1o (DNMT1o), levels of which are decreased in mature oocytes of aging females. Here, we assessed the effects of maternal deficiency in DNMT1o (Dnmt1Δ1o/+) in combination with superovulation and embryo transfer on offspring DNA methylation and development. We demonstrated a significant increase in the rates of morphological abnormalities in offspring collected from Dnmt1Δ1o/+ females only when combined with ART. Together, maternal oocyte DNMT1o deficiency and ART resulted in an accentuation of placental imprinting defects and the induction of genome-wide DNA methylation alterations, which were exacerbated in the placenta compared to the embryo. Significant sex-specific trends were also apparent, with a preponderance of DNA hypomethylation in females. Among genic regions affected, a significant enrichment for neurodevelopmental pathways was observed. Taken together, our results demonstrate that oocyte DNMT1o-deficiency exacerbates genome-wide DNA methylation abnormalities induced by ART in a sex-specific manner and plays a role in mediating poor embryonic outcome.</abstract><cop>England</cop><pmid>28173052</pmid><doi>10.1093/hmg/ddw293</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Age Factors Animals DNA (Cytosine-5-)-Methyltransferase 1 - metabolism DNA Methylation Epigenesis, Genetic Female Infertility, Female - physiopathology Mice Models, Animal Oocytes - pathology Oocytes - physiology Placenta - metabolism Pregnancy Reproductive Techniques - adverse effects Superovulation - genetics Superovulation - physiology |
title | Compromised oocyte quality and assisted reproduction contribute to sex-specific effects on offspring outcomes and epigenetic patterning |
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