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As infertile gametes are used in human ICSI procedures, it has remained unclear whether the procedure per se influences fertility of the resulting offspring. Here, we report on increased abortion rates and the induction of immunotolerance breakdown in mice following ICSI. Although sperm concentration was normal, sperm from ICSI-derived males showed higher curvilinear velocity and greater amplitude of lateral head displacement, suggesting a potentially increased fertilization capacity. However, when ICSI-produced males were naturally mated with wild-type females, 27.1% of the fetuses were aborted, compared to a loss of 7.5% of fetuses in control pregnancies, despite identical H2 haplotypes. Analysis of the placenta revealed infiltrating macrophages and granulocytes, as well as increased levels of 8-oxoguanine. This was accompanied by activation of innate immunity and significant downregulation of microRNAs located in the Dlk1-Dio3 microRNA cluster. Several organs of the grand-offspring exhibited inflammation. Therefore, ICSI procedure using wild-type gametes impairs the fertility of ICSI-derived male offspring by activating innate immunity during pregnancy.<\/jats:p>","DOI":"10.1242\/dev.205500","type":"journal-article","created":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T14:43:16Z","timestamp":1778164996000},"source":"Crossref","is-referenced-by-count":1,"title":["Mouse ICSI impairs fertility of male offspring by disruption of fetomaternal tolerance"],"prefix":"10.1242","volume":"153","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0093-7501","authenticated-orcid":false,"given":"Mito","family":"Kanatsu-Shinohara","sequence":"first","affiliation":[{"name":"Graduate School of Medicine and Faculty of Medicine, Kyoto University 1 Department of Molecular Genetics , , Kyoto 606-8501 ,","place":["Japan"]},{"name":"AMED 2 , 1-7-1 Otemachi, Chiyodaku, Tokyo 100-0004 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yusuke","family":"Shiromoto","sequence":"additional","affiliation":[{"name":"Graduate School of Medicine and Faculty of Medicine, Kyoto University 1 Department of Molecular Genetics , , Kyoto 606-8501 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Narumi","family":"Ogonuki","sequence":"additional","affiliation":[{"name":"RIKEN BioResource Research Center 3 Bioresource Engineering Division , , Ibaraki , 305-0074","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kimiko","family":"Inoue","sequence":"additional","affiliation":[{"name":"RIKEN BioResource Research Center 3 Bioresource Engineering Division , , Ibaraki , 305-0074","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keiji","family":"Mochida","sequence":"additional","affiliation":[{"name":"RIKEN BioResource Research Center 3 Bioresource Engineering Division , , Ibaraki , 305-0074","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenji","family":"Kabashima","sequence":"additional","affiliation":[{"name":"Graduate School of Medicine, Kyoto University 4 Department of Dermatology , , Kyoto 606-8507 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yingyi","family":"Kong","sequence":"additional","affiliation":[{"name":"Nagoya University Graduate School of Medicine 5 Department of Pathology and Biological Responses , , 65 Tsurumai-Cho, Showa-ku, Nagoya 466-8550 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shinya","family":"Toyokuni","sequence":"additional","affiliation":[{"name":"Nagoya University Graduate School of Medicine 5 Department of Pathology and Biological Responses , , 65 Tsurumai-Cho, Showa-ku, Nagoya 466-8550 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takuya","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Center for iPS Cell Research and Application, Kyoto University 6 Department of Life Science Frontiers , , Kyoto 606-8507 ,","place":["Japan"]},{"name":"Institute for the Advanced Study of Human Biology (WPI-ASHIBi), Kyoto University 7 , Yoshida-Konoe, Sakyo, Kyoto 606-8501 ,","place":["Japan"]},{"name":"RIKEN Center for Advanced Intelligence Project (AIP) 8 Medical-risk Avoidance based on iPS Cells Team , , Kyoto, 606-8507 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Atsuo","family":"Ogura","sequence":"additional","affiliation":[{"name":"RIKEN BioResource Research Center 3 Bioresource Engineering Division , , Ibaraki , 305-0074","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takashi","family":"Shinohara","sequence":"additional","affiliation":[{"name":"Graduate School of Medicine and Faculty of Medicine, Kyoto University 1 Department of Molecular Genetics , , Kyoto 606-8501 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"237","published-online":{"date-parts":[[2026,5,7]]},"reference":[{"key":"2026050710430795900_DEV205500C1","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1113\/expphysiol.2005.031765","article-title":"Molecular physiology of SLC4 anion exchangers","volume":"91","author":"Alper","year":"2006","journal-title":"Exp. 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