title: Effects of In Utero Thyroxine Exposure on Murine Cranial Suture Growth.
abstract: Large scale surveillance studies, case studies, as well as cohort studies have identified the influence of thyroid hormones on calvarial growth and development. Surveillance data suggests maternal thyroid disorders (hyperthyroidism, hypothyroidism with pharmacological replacement, and Maternal Graves Disease) are linked to as much as a 2.5 fold increased risk for craniosynostosis. Craniosynostosis is the premature fusion of one or more calvarial growth sites (sutures) prior to the completion of brain expansion. Thyroid hormones maintain proper bone mineral densities by interacting with growth hormone and aiding in the regulation of insulin like growth factors (IGFs). Disruption of this hormonal control of bone physiology may lead to altered bone dynamics thereby increasing the risk for craniosynostosis. In order to elucidate the effect of exogenous thyroxine exposure on cranial suture growth and morphology, wild type C57BL6 mouse litters were exposed to thyroxine in utero (control = no treatment; low ~167 ng per day; high ~667 ng per day). Thyroxine exposed mice demonstrated craniofacial dysmorphology (brachycranic). High dose exposed mice showed diminished area of the coronal and widening of the sagittal sutures indicative of premature fusion and compensatory growth. Presence of thyroid receptors was confirmed for the murine cranial suture and markers of proliferation and osteogenesis were increased in sutures from exposed mice. Increased Htra1 and Igf1 gene expression were found in sutures from high dose exposed individuals. Pathways related to the HTRA1/IGF axis, specifically Akt and Wnt, demonstrated evidence of increased activity. Overall our data suggest that maternal exogenous thyroxine exposure can drive calvarial growth alterations and altered suture morphology.
authors.affiliation: Department of Oral Health Sciences, Medical University of South Carolina, Charleston, South Carolina, United States of America.
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, United States of America.
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, United States of America.
authors.forename: Laurel
authors.initials: L
authors.lastname: Black
authors.affiliation: Department of Oral Health Sciences, Medical University of South Carolina, Charleston, South Carolina, United States of America.
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, United States of America.
authors.forename: Trish E
authors.initials: TE
authors.lastname: Parsons
authors.affiliation: Departments of Oral Biology, Cellular Biology and Anatomy, Orthopedic Surgery and Oral and Maxillofacial Surgery, Augusta University, Augusta, Georgia, United States of America.|Institute for Regenerative and Reparative Medicine, Augusta University, Augusta, Georgia, United States of America.
authors.forename: Mohammed E
authors.initials: ME
authors.lastname: Elsalanty
authors.affiliation: Institute for Regenerative and Reparative Medicine, Augusta University, Augusta, Georgia, United States of America.|Department of Surgery, Division of Plastic Surgery, Augusta University, Augusta, Georgia, United States of America.
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, United States of America.
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, United States of America.
authors.forename: James J
authors.initials: JJ
authors.lastname: Cray
mesh_terms: D000818:Animals; D003393:Cranial Sutures / Q000187:drug effects*; D005260:Female; D000074289:High-Temperature Requirement A Serine Peptidase 1; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism; D013974:Thyroxine / Q000009:adverse effects*; D060449:Wnt Signaling Pathway / Q000235:genetics
chemical_list: D007334:Insulin-Like Growth Factor I; D051057:Proto-Oncogene Proteins c-akt; D000074289:High-Temperature Requirement A Serine Peptidase 1; C492073:HtrA1 protein, mouse; D012697:Serine Endopeptidases; D013974:Thyroxine