{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T17:54:27Z","timestamp":1790445267266,"version":"4.1.0"},"reference-count":79,"publisher":"American Society for Clinical Investigation","issue":"23","license":[{"start":{"date-parts":[[2024,12,6]],"date-time":"2024-12-06T00:00:00Z","timestamp":1733443200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health\/  National Heart, Lung, and Blood Institute","award":["R01HL144009"],"award-info":[{"award-number":["R01HL144009"]}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["T32 HL166149"],"award-info":[{"award-number":["T32 HL166149"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,12,6]]},"abstract":"<jats:p>\n                    Congenital heart disease (CHD) affects approximately 1% of live births. Although genetic and environmental etiologic contributors have been identified, the majority of CHD lacks a definitive cause, suggesting the role of gene-environment interactions (GxEs) in disease pathogenesis. Maternal diabetes mellitus (matDM) is among the most prevalent environmental risk factors for CHD. However, there is a substantial knowledge gap in understanding how matDM acts upon susceptible genetic backgrounds to increase disease expressivity. Previously, we reported a GxE between\n                    <jats:italic>Notch1<\/jats:italic>\n                    haploinsufficiency and matDM leading to increased CHD penetrance. Here, we demonstrate a cell lineage\u2013specific effect of\n                    <jats:italic>Notch1<\/jats:italic>\n                    haploinsufficiency in matDM-exposed embryos, implicating endothelial\/endocardial tissues in the developing heart. We report impaired atrioventricular cushion morphogenesis in matDM-exposed\n                    <jats:italic>\n                      Notch1\n                      <jats:sup>+\/\u2013<\/jats:sup>\n                    <\/jats:italic>\n                    animals and show a synergistic effect of\n                    <jats:italic>NOTCH1<\/jats:italic>\n                    haploinsufficiency and oxidative stress in dysregulation of gene regulatory networks critical for endocardial cushion morphogenesis in vitro. Mitigation of matDM-associated oxidative stress via superoxide dismutase 1 overexpression did not rescue CHD in\n                    <jats:italic>Notch1<\/jats:italic>\n                    -haploinsufficient mice compared to wild-type littermates. Our results show the combinatorial interaction of matDM-associated oxidative stress and a genetic predisposition,\n                    <jats:italic>Notch1<\/jats:italic>\n                    haploinsufficiency, on cardiac development, supporting a GxE model for CHD etiology and suggesting that antioxidant strategies alone may be ineffective in genetically susceptible individuals.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.183516","type":"journal-article","created":{"date-parts":[[2024,10,22]],"date-time":"2024-10-22T14:11:46Z","timestamp":1729606306000},"source":"Crossref","is-referenced-by-count":7,"title":["Impact of genetic factors on antioxidant rescue of maternal diabetes\u2013associated congenital heart disease"],"prefix":"10.1172","volume":"9","author":[{"given":"Talita Z.","family":"Choudhury","sequence":"first","affiliation":[{"name":"Center for Cardiovascular Research, Abigail Wexner Research Institute, and The Heart Center, Nationwide Children\u2019s 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