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We previously developed a <jats:italic>foxe1<\/jats:italic> mutant zebrafish demonstrating mineralization defects in larvae. In the present study, we investigate the thyroid status and skeletal phenotype of adult <jats:italic>foxe1<\/jats:italic> mutants.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Mutant fish have increased expression of <jats:italic>tsh\u03b2<\/jats:italic> in the pituitary, and of hepatic <jats:italic>dio1<\/jats:italic> and <jats:italic>dio2<\/jats:italic>. In plasma, we found higher Mg levels. Together these findings are indicative of hypothyroidism. We further observed mineralization defects in scales due to enhanced osteoclast activity as measured by increased expression levels of <jats:italic>tracp<\/jats:italic>, <jats:italic>ctsk<\/jats:italic>, and <jats:italic>rankl<\/jats:italic>. Gene\u2013environment interactions in the etiology of FOXE1\u2010related craniofacial abnormalities remain elusive, which prompts the need for models to investigate genotype\u2013phenotype associations. We here investigated whether ethanol exposure increases the risk of developing craniofacial malformations in <jats:italic>foxe1<\/jats:italic> mutant larvae that we compared to wild types. We found in ethanol\u2010exposed mutants an increased incidence of developmental malformations and marked changes in gene expression patterns of cartilage markers (<jats:italic>sox9a<\/jats:italic>), apoptotic markers (<jats:italic>casp3b<\/jats:italic>), retinoic acid metabolism (<jats:italic>cyp26c1<\/jats:italic>), and tissue hypoxia markers (<jats:italic>hifaa, hifab<\/jats:italic>).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Taken together, this study shows that the <jats:italic>foxe1<\/jats:italic> mutant zebrafish recapitulates phenotypes associated with FOXE1 mutations in human patients and a clear <jats:italic>foxe1<\/jats:italic>\u2010ethanol interaction.<\/jats:p><\/jats:sec>","DOI":"10.1002\/dvdy.745","type":"journal-article","created":{"date-parts":[[2024,10,3]],"date-time":"2024-10-03T05:15:18Z","timestamp":1727932518000},"page":"240-256","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["<i>foxe1<\/i> mutant zebrafish show indications of a hypothyroid phenotype and increased sensitivity to ethanol for craniofacial malformations"],"prefix":"10.1002","volume":"254","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4067-171X","authenticated-orcid":false,"given":"Sophie T.","family":"Raterman","sequence":"first","affiliation":[{"name":"Department of Dentistry\u2010Orthodontics and Craniofacial Biology, Research Institute for Medical Innovation Radboud University Medical Center  Nijmegen The Netherlands"},{"name":"Department of Plant &amp; Animal Biology, Radboud Institute for Biological and Environmental Sciences (RIBES) Radboud University  Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4837-1559","authenticated-orcid":false,"given":"Frank A. 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