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Here, we used transcriptomic analysis in an established zebrafish model of embryonic alcohol exposure (EAE) to identify the ubiquitin-proteasome system (UPS) as a critical target of EtOH during development. Surprisingly, EAE alters 20S, 19S, and 11S proteasome gene expression and increases ubiquitylated protein load. EtOH and its metabolite acetaldehyde decrease proteasomal peptidase activity in a cell type\u2013specific manner. Proteasome 20S subunit \u03b2 1 (\n                    <jats:italic>\n                      psmb1\n                      <jats:sup>hi2939Tg<\/jats:sup>\n                    <\/jats:italic>\n                    ) and proteasome 26S subunit, ATPase 6 (\n                    <jats:italic>\n                      psmc6\n                      <jats:sup>hi3593Tg<\/jats:sup>\n                    <\/jats:italic>\n                    ), genetic KOs define the developmental impact of decreased proteasome function. Importantly, loss of\n                    <jats:italic>psmb1<\/jats:italic>\n                    or\n                    <jats:italic>psmc6<\/jats:italic>\n                    results in widespread developmental abnormalities resembling EAE phenotypes, including growth restriction, abnormal craniofacial structure, neurodevelopmental defects, and failed hepatopancreas maturation. Furthermore, pharmacologic inhibition of chymotrypsin-like proteasome activity potentiates the teratogenic effects of EAE on craniofacial structure, the nervous system, and the endoderm. Our studies identify the proteasome as a target of EtOH exposure and signify that UPS disruptions contribute to craniofacial, neurological, and endodermal phenotypes in FASDs.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.156914","type":"journal-article","created":{"date-parts":[[2022,12,7]],"date-time":"2022-12-07T14:01:03Z","timestamp":1670421663000},"source":"Crossref","is-referenced-by-count":15,"title":["Embryonic alcohol exposure disrupts the ubiquitin-proteasome system"],"prefix":"10.1172","volume":"7","author":[{"given":"Olivia","family":"Weeks","sequence":"first","affiliation":[{"name":"Division of Genetics, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9868-5436","authenticated-orcid":true,"given":"Bess M.","family":"Miller","sequence":"additional","affiliation":[{"name":"Division of Genetics, Brigham and Women\u2019s Hospital, 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