title: Effects of thyroxine exposure on the Twist 1 +/- phenotype: A test of gene-environment interaction modeling for craniosynostosis.
abstract: BACKGROUND
  Craniosynostosis, the premature fusion of one or more of the cranial sutures, is estimated to occur in 1:1800 to 2500 births. Genetic murine models of craniosynostosis exist, but often imperfectly model human patients. Case, cohort, and surveillance studies have identified excess thyroid hormone as an agent that can either cause or exacerbate human cases of craniosynostosis.
  
  
  METHODS
  Here we investigate the influence of in utero and in vitro exogenous thyroid hormone exposure on a murine model of craniosynostosis, Twist 1 +/-.
  
  
  RESULTS
  By 15 days post-natal, there was evidence of coronal suture fusion in the Twist 1 +/- model, regardless of exposure. With the exception of craniofacial width, there were no significant effects of exposure; however, the Twist 1 +/- phenotype was significantly different from the wild-type control. Twist 1 +/- cranial suture cells did not respond to thyroxine treatment as measured by proliferation, osteogenic differentiation, and gene expression of osteogenic markers. However, treatment of these cells did result in modulation of thyroid associated gene expression.
  
  
  CONCLUSIONS
  Our findings suggest the phenotypic effects of the genetic mutation largely outweighed the effects of thyroxine exposure in the Twist 1 +/- model. These results highlight difficultly in experimentally modeling gene-environment interactions for craniosynostotic phenotypes. Birth Defects Research (Part A) 106:803-813, 2016. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Oral Health Sciences, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Emily L
authors.initials: EL
authors.lastname: Durham
authors.affiliation: Department of Oral Health Sciences, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: R Nicole
authors.initials: RN
authors.lastname: Howie
authors.affiliation: Department of Oral Health Sciences, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Laurel
authors.initials: L
authors.lastname: Black
authors.affiliation: Department of Oral Health Sciences, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Grace
authors.initials: G
authors.lastname: Bennfors
authors.affiliation: Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Trish E
authors.initials: TE
authors.lastname: Parsons
authors.affiliation: Departments of Oral Biology, Cellular Biology and Anatomy, Orthopaedic Surgery and Oral and Maxillofacial Surgery, Augusta University, Augusta, Georgia.|Institute for Regenerative and Reparative Medicine, Augusta University, Augusta, Georgia.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Elsalanty
authors.affiliation: Institute for Regenerative and Reparative Medicine, Augusta University, Augusta, Georgia.|Department of Surgery, Division of Plastic Surgery, Augusta University, Augusta, Georgia.
authors.forename: Jack C
authors.initials: JC
authors.lastname: Yu
authors.affiliation: Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Seth M
authors.initials: SM
authors.lastname: Weinberg
authors.affiliation: Department of Oral Health Sciences, Medical University of South Carolina, Charleston, South Carolina. crayj@musc.edu.
authors.forename: James J
authors.initials: JJ
authors.lastname: Cray
mesh_terms: D000014:Abnormalities, Drug-Induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D003398:Craniosynostoses / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D059647:Gene-Environment Interaction; D051379:Mice; D008817:Mice, Mutant Strains; D009687:Nuclear Proteins / Q000235:genetics*; D010012:Osteogenesis / Q000187:drug effects / Q000235:genetics; D010641:Phenotype; D013974:Thyroxine / Q000009:adverse effects* / Q000494:pharmacology; D051879:Twist-Related Protein 1 / Q000235:genetics*
chemical_list: D009687:Nuclear Proteins; D051879:Twist-Related Protein 1; C067250:Twist1 protein, mouse; D013974:Thyroxine
keywords: cephalometrics; cranial suture; craniosynostosis; gene expression; thyroid hormone