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Thyroxine Exposure Effects on the Cranial Base

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Abstract

Thyroid hormone is important for skull bone growth, which primarily occurs at the cranial sutures and synchondroses. Thyroid hormones regulate metabolism and act in all stages of cartilage and bone development and maintenance by interacting with growth hormone and regulating insulin-like growth factor. Aberrant thyroid hormone levels and exposure during development are exogenous factors that may exacerbate susceptibility to craniofacial abnormalities potentially through changes in growth at the synchondroses of the cranial base. To elucidate the direct effect of in utero therapeutic thyroxine exposure on the synchondroses in developing mice, we provided scaled doses of the thyroid replacement drug, levothyroxine, in drinking water to pregnant C57BL6 wild-type dams. The skulls of resulting pups were subjected to micro-computed tomography analysis revealing less bone volume relative to tissue volume in the synchondroses of mouse pups exposed in utero to levothyroxine. Histological assessment of the cranial base area indicated more active synchondroses as measured by metabolic factors including Igf1. The cranial base of the pups exposed to high levels of levothyroxine also contained more collagen fiber matrix and an increase in markers of bone formation. Such changes due to exposure to exogenous thyroid hormone may drive overall morphological changes. Thus, excess thyroid hormone exposure to the fetus during pregnancy may lead to altered craniofacial growth and increased risk of anomalies in offspring.

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References

  1. Pirinen S (1995) Endocrine regulation of craniofacial growth. Acta Odontol Scand 53:179–185

    Article  CAS  PubMed  Google Scholar 

  2. Akita S, Hirano A, Fujii T (1996) Identification of IGF-I in the calvarial suture of young rats: histochemical analysis of the cranial sagittal sutures in a hyperthyroid rat model. Plast Reconstr Surg 97:1–12

    Article  CAS  PubMed  Google Scholar 

  3. Akita S, Nakamura T, Hirano A, Fujii T, Yamashita S (1994) Thyroid hormone action on rat calvarial sutures. Thyroid 4:99–106

    Article  CAS  PubMed  Google Scholar 

  4. Stevens DA, Harvey CB, Scott AJ, O’Shea PJ, Barnard JC, Williams AJ, Brady G, Samarut J, Chassande O, Williams GR (2003) Thyroid hormone activates fibroblast growth factor receptor-1 in bone. Mol Endocrinol 17:1751–1766

    Article  CAS  PubMed  Google Scholar 

  5. Ortner DJ, Hotz G (2005) Skeletal manifestations of hypothyroidism from Switzerland. Am J Phys Anthropol 127:1–6

    Article  PubMed  Google Scholar 

  6. McNabb FMA (1992) Thyroid hormones. Prentice Hall, Englewood Cliffs

    Google Scholar 

  7. Oppenheimer JH, Samuels HH, Apriletti JW (1983) Molecular basis of thyroid hormone action. Academic Press, New York

    Google Scholar 

  8. Bassett JH, Williams GR (2003) The molecular actions of thyroid hormone in bone. Trends Endocrinol Metab 14:356–364

    Article  CAS  PubMed  Google Scholar 

  9. Harvey CB, O’Shea PJ, Scott AJ, Robson H, Siebler T, Shalet SM, Samarut J, Chassande O, Williams GR (2002) Molecular mechanisms of thyroid hormone effects on bone growth and function. Mol Genet Metab 75:17–30

    Article  CAS  PubMed  Google Scholar 

  10. Mosekilde L, Eriksen EF, Charles P (1990) Effects of thyroid hormones on bone and mineral metabolism. Endocrinol Metab Clin North Am 19:35–63

    CAS  PubMed  Google Scholar 

  11. Robson H, Siebler T, Shalet SM, Williams GR (2002) Interactions between GH, IGF-I, glucocorticoids, and thyroid hormones during skeletal growth. Pediatr Res 52:137–147

    Article  CAS  PubMed  Google Scholar 

  12. Wei X, Hu M, Mishina Y, Liu F (2016) Developmental regulation of the growth plate and cranial synchondrosis. J Dent Res 95(11):1221–1229

    Article  CAS  PubMed  Google Scholar 

  13. Robson H, Siebler T, Stevens DA, Shalet SM, Williams GR (2000) Thyroid hormone acts directly on growth plate chondrocytes to promote hypertrophic differentiation and inhibit clonal expansion and cell proliferation. Endocrinology 141:3887–3897

    Article  CAS  PubMed  Google Scholar 

  14. Rasmussen SA, Yazdy MM, Carmichael SL, Jamieson DJ, Canfield MA, Honein MA (2007) Maternal thyroid disease as a risk factor for craniosynostosis. Obstet Gynecol 110:369–377

    Article  PubMed  Google Scholar 

  15. Radetti G, Zavallone A, Gentili L, Beck-Peccoz P, Bona G (2002) Foetal and neonatal thyroid disorders. Minerva Pediatr 54:383–400

    CAS  PubMed  Google Scholar 

  16. Mauceri L, Ruggieri M, Pavone V, Rizzo R, Sorge G (1997) Craniofacial anomalies, severe cerebellar hypoplasia, psychomotor and growth delay in a child with congenital hypothyroidism. Clin Dysmorphol 6:375–378

    Article  CAS  PubMed  Google Scholar 

  17. Rogers GF, Mulliken JB (2005) Involvement of the basilar coronal ring in unilateral coronal synostosis. Plast Reconstr Surg 115:1887–1893

    Article  CAS  PubMed  Google Scholar 

  18. Burdi AR, Kusnetz AB, Venes JL, Gebarski SS (1986) The natural history and pathogenesis of the cranial coronal ring articulations: implications in understanding the pathogenesis of the Crouzon craniostenotic defects. Cleft Palate J 23:28–39

    CAS  PubMed  Google Scholar 

  19. Sperber GH, Sperber SM, Guttmann GD, Sperber GH (2010) Craniofacial embryogenetics and development. People’s Medical Pub. House USA, Shelton

    Google Scholar 

  20. Bosma JF (1976) Symposium on Development of the Basicranium. U.S. Dept. of Health, Education, and Welfare, Public Health Service for sale by the Supt. of Docs., U.S. Govt. Print. Off., Bethesda, Md. Washington

  21. McGrath J, Gerety PA, Derderian CA, Steinbacher DM, Vossough A, Bartlett SP, Nah HD, Taylor JA (2012) Differential closure of the spheno-occipital synchondrosis in syndromic craniosynostosis. Plast Reconstr Surg 130:681e–689e

    Article  CAS  PubMed  Google Scholar 

  22. Nagata M, Nuckolls GH, Wang X, Shum L, Seki Y, Kawase T, Takahashi K, Nonaka K, Takahashi I, Noman AA, Suzuki K, Slavkin HC (2011) The primary site of the acrocephalic feature in Apert Syndrome is a dwarf cranial base with accelerated chondrocytic differentiation due to aberrant activation of the FGFR2 signaling. Bone 48:847–856

    Article  CAS  PubMed  Google Scholar 

  23. Tahiri Y, Paliga JT, Vossough A, Bartlett SP, Taylor JA (2014) The spheno-occipital synchondrosis fuses prematurely in patients with Crouzon syndrome and midface hypoplasia compared with age- and gender-matched controls. J Oral Maxillofac Surg 72:1173–1179

    Article  PubMed  Google Scholar 

  24. Richardson S, Browne ML, Rasmussen SA, Druschel CM, Sun L, Jabs EW, Romitti PA, National Birth Defects Prevention S (2011) Associations between periconceptional alcohol consumption and craniosynostosis, omphalocele, and gastroschisis. Birth Defects Res Part A 91:623–630

    Article  CAS  Google Scholar 

  25. Browne ML, Hoyt AT, Feldkamp ML, Rasmussen SA, Marshall EG, Druschel CM, Romitti PA (2011) Maternal caffeine intake and risk of selected birth defects in the National Birth Defects Prevention Study. Birth Defects Res Part A 91:93–101

    Article  CAS  Google Scholar 

  26. Reefhuis J, Honein MA, Schieve LA, Rasmussen SA, National Birth Defects Prevention S (2011) Use of clomiphene citrate and birth defects, National Birth Defects Prevention Study, 1997–2005. Hum Reprod 26:451–457

    Article  CAS  PubMed  Google Scholar 

  27. Carmichael SL, Rasmussen SA, Lammer EJ, Ma C, Shaw GM, National Birth Defects Prevention S (2010) Craniosynostosis and nutrient intake during pregnancy. Birth Defects Res Part A 88:1032–1039

    Article  CAS  Google Scholar 

  28. Alwan S, Reefhuis J, Rasmussen SA, Olney RS, Friedman JM, National Birth Defects Prevention S (2007) Use of selective serotonin-reuptake inhibitors in pregnancy and the risk of birth defects. N Engl J Med 356:2684–2692

    Article  CAS  PubMed  Google Scholar 

  29. Rasmussen SA, Yazdy MM, Frias JL, Honein MA (2008) Priorities for public health research on craniosynostosis: summary and recommendations from a centers for disease control and prevention-sponsored meeting. Am J Med Genet Part A 146A:149–158

    Article  PubMed  Google Scholar 

  30. Krause K, Weiner J, Hones S, Kloting N, Rijntjes E, Heiker JT, Gebhardt C, Kohrle J, Fuhrer D, Steinhoff K, Hesse S, Moeller LC, Tonjes A (2015) The effects of thyroid hormones on gene expression of acyl-coenzyme a thioesterases in adipose tissue and liver of mice. Eur Thyroid J 4:59–66

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Capuco AV, Kahl S, Jack LJ, Bishop JO, Wallace H (1999) Prolactin and growth hormone stimulation of lactation in mice requires thyroid hormones. Proc Soc Exp Biol Med 221:345–351

    Article  CAS  PubMed  Google Scholar 

  32. Thordarson G, Fielder P, Lee C, Hom YK, Robleto D, Ogren L, Talamantes F (1992) Mammary gland differentiation in hypophysectomized, pregnant mice treated with corticosterone and thyroxine. Biol Reprod 47:676–682

    Article  CAS  PubMed  Google Scholar 

  33. Capelo LP, Beber EH, Huang SA, Zorn TM, Bianco AC, Gouveia CH (2008) Deiodinase-mediated thyroid hormone inactivation minimizes thyroid hormone signaling in the early development of fetal skeleton. Bone 43:921–930

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Darnerud PO, Morse D, Klasson-Wehler E, Brouwer A (1996) Binding of a 3,3′, 4,4′-tetrachlorobiphenyl (CB-77) metabolite to fetal transthyretin and effects on fetal thyroid hormone levels in mice. Toxicology 106:105–114

    Article  CAS  PubMed  Google Scholar 

  35. Lamb JCt, Harris MW, McKinney JD, Birnbaum LS (1986) Effects of thyroid hormones on the induction of cleft palate by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in C57BL/6 N mice. Toxicol Appl Pharmacol 84:115–124

    Article  CAS  PubMed  Google Scholar 

  36. Lamberg BA, Helenius T, Liewendahl K (1986) Assessment of thyroxine suppression in thyroid carcinoma patients with a sensitive immunoradiometric TSH assay. Clin Endocrinol 25:259–263

    Article  CAS  Google Scholar 

  37. Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG (2010) Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biol 8:e1000412

    Article  PubMed  PubMed Central  Google Scholar 

  38. Parsons TE, Weinberg SM, Khaksarfard K, Howie RN, Elsalanty M, Yu JC, Cray JJ Jr (2014) Craniofacial shape variation in Twist1 ± mutant mice. Anat Rec 297:826–833

    Article  Google Scholar 

  39. Varghese F, Bukhari AB, Malhotra R, De A (2014) IHC Profiler: an open source plugin for the quantitative evaluation and automated scoring of immunohistochemistry images of human tissue samples. PLoS ONE 9:e96801

    Article  PubMed  PubMed Central  Google Scholar 

  40. Yuan JS, Reed A, Chen F, Stewart CN Jr (2006) Statistical analysis of real-time PCR data. BMC Bioinf 7:85

    Article  Google Scholar 

  41. Howie RN, Durham EL, Black L, Bennfors G, Parsons TE, Elsalanty ME, Yu JC, Weinberg SM, Cray JJ Jr (2016) Effects of in utero thyroxine exposure on murine cranial suture growth. PLoS ONE 11:e0167805

    Article  PubMed  PubMed Central  Google Scholar 

  42. O’Shea PJ, Harvey CB, Suzuki H, Kaneshige M, Kaneshige K, Cheng SY, Williams GR (2003) A thyrotoxic skeletal phenotype of advanced bone formation in mice with resistance to thyroid hormone. Mol Endocrinol 17:1410–1424

    Article  PubMed  Google Scholar 

  43. Vora SR, Camci ED, Cox TC (2015) Postnatal ontogeny of the cranial base and craniofacial skeleton in male C57BL/6 J mice: a reference standard for quantitative analysis. Front Physiol 6:417

    PubMed  Google Scholar 

  44. Lieberman DE, Hallgrimsson B, Liu W, Parsons TE, Jamniczky HA (2008) Spatial packing, cranial base angulation, and craniofacial shape variation in the mammalian skull: testing a new model using mice. J Anat 212:720–735

    Article  PubMed  PubMed Central  Google Scholar 

  45. Tsuchiya A, Yano M, Tocharus J, Kojima H, Fukumoto M, Kawaichi M, Oka C (2005) Expression of mouse HtrA1 serine protease in normal bone and cartilage and its upregulation in joint cartilage damaged by experimental arthritis. Bone 37:323–336

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors would like to thank the following funding sources: National Institutes of Health, National Institute of Dental and Craniofacial Research (R03DE023350A to JJC), and Cleft Palate Foundation Cleft/Craniofacial Anomalies Grant Award to JJC. Micro-Computed Tomography scans were made possible by the Nation Institute on Aging (NIA) (1P01AG036675 to ME). ELD and RNH were funded through a National Institutes of Health National Institute of Dental and Craniofacial Research training Grant (5T32DE017551). This study utilized the facilities and resources of the Medical University of South Carolina Center for Oral Health Research supported by the NIH/NIGM (P30GM103331).

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Authors and Affiliations

  1. Department of Oral Health Sciences, Medical University of South Carolina, 173 Ashley Avenue, BS 230B, Charleston, SC, 29425, USA

    Emily Durham, R. Nicole Howie, Grace Bennfors, Laurel Black & James J. Cray Jr.

  2. Department of Oral Biology, School of Dental Medicine, Center for Craniofacial and Dental Genetics, University of Pittsburgh, 3501 Terrace Street, Pittsburgh, PA, 15213, USA

    Trish Parsons & Seth M. Weinberg

  3. Departments of Oral Biology, Cellular Biology and Anatomy, Orthopaedic Surgery and Oral and Maxillofacial Surgery, Augusta University, 1120 15th Street, Augusta, GA, 30912, USA

    Mohammed Elsalanty

  4. Institute for Regenerative and Reparative Medicine, Augusta University, 1120 15th Street, Augusta, GA, 30912, USA

    Mohammed Elsalanty & Jack C. Yu

  5. Division of Plastic Surgery, Department of Surgery, Augusta University, 1120 15th Street, Augusta, GA, 30912, USA

    Jack C. Yu

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  1. Emily Durham
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  2. R. Nicole Howie
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  9. James J. Cray Jr.
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Correspondence to James J. Cray Jr..

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Emily Durham, R. Nicole Howie, Trish Parsons, Gracie Bennfors, Laurel Black, Seth M. Weinberg, Mohammed Elsalanty, Jack C Yu, and James J. Cray Jr. declare no competing financial interests.

Human and Animal Rights and Informed Consent

All procedures and the reporting thereof are in compliance with the Animal Research: Reporting in Vivo Experiments (ARRIVE) guidelines.

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Durham, E., Howie, R.N., Parsons, T. et al. Thyroxine Exposure Effects on the Cranial Base. Calcif Tissue Int 101, 300–311 (2017). https://doi.org/10.1007/s00223-017-0278-z

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