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Environmental Factors and Axial Skeletal Dysmorphogenesis

  • Peter G. Alexander
  • Ricardo Londono
  • Thomas P. Lozito
  • Rocky S. Tuan
Chapter

Abstract

Clinical data show that the axial skeleton dysmorphogenesis is present in approximately 1 in 1000 live births. Most of these defects have no known etiology, caused by an as-yet uncharacterized interaction of the genome with environmental insults. Humans are exposed to thousands of natural and synthetic compounds that have uncharacterized impacts in human development. Developmentally, these defects have their origin in somitogenesis, the initial manifestation of the vertebral column’s metameric segmentation. Development of the axial skeleton and the surrounding tissues occurs in an interdependent and hierarchical manner over an extended period of time. This may make the axial skeleton disproportionately susceptible to environmental influence. This fact highlights the need for investigating the role of environmental factors, alone or in combination, in the production of this particular class of defects. Such study requires the convergence of at least two broad fields of study: developmental biology, to understand the details of normal development, and teratology, to understand the causes, mechanisms, and manifestation of congenital birth defects. In this review, we focus on environmental factors that cause congenital scoliosis and their potential mechanisms, including maternal conditions and exposures such as hyperthermia, diabetes, valproic and retinoic acid, alcohols, and arsenic to illustrate the many potential pathways environmental factors disrupt to cause congenital scoliosis.

References

  1. 1.
    Abbott BD, Ebron-McCoy M, Andrews JE. Cell death in rat and mouse embryos exposed to methanol in whole embryo culture. Toxicology. 1995;97:159–71.CrossRefPubMedGoogle Scholar
  2. 2.
    Aberg A, Westbom L, Källén B. Congenital malformations among infants whose mothers had gestational diabetes or preexisting diabetes. Early Hum Dev. 2001;61:85–95.CrossRefPubMedGoogle Scholar
  3. 3.
    Ahmad M, Wadaa MA, Farooq M, Daghestani MH, Sami AS. Effectiveness of zinc in modulating perinatal effects of arsenic on the teratological effects in mice offspring. Biol Res. 2013;46:131–8. https://doi.org/10.4067/S0716-97602013000200003.CrossRefPubMedGoogle Scholar
  4. 4.
    Akazawa S. Diabetic embryopathy: studies using a rat embryo culture system and an animal model. Congenit Anom (Kyoto). 2005;45:73–9.CrossRefGoogle Scholar
  5. 5.
    Alexander PG, Boyce AT, Tuan RS. Skeletal development. In: Moody SA, editor. Principles of developmental genetics. New York: Elsevier Academic Press; 2007. p. 866–905.Google Scholar
  6. 6.
    Alexander PG, Chau L, Tuan RS. Role of nitric oxide in chick embryonic organogenesis and dysmorphogenesis. Birth Defects Res A Clin Mol Teratol. 2007;79:581–94. https://doi.org/10.1002/bdra.20386.CrossRefPubMedGoogle Scholar
  7. 7.
    Alexander PG, Tuan RS. Carbon monoxide-induced axial skeletal dysmorphogenesis in the chick embryo. Birth Defects Res A Clin Mol Teratol. 2003;67:219–30. https://doi.org/10.1002/bdra.10041.CrossRefPubMedGoogle Scholar
  8. 8.
    Alsdorf R, Wyszynski DF. Teratogenicity of sodium valproate. Expert Opin Drug Saf. 2005;4:345–53.CrossRefPubMedGoogle Scholar
  9. 9.
    Arsic D, Qi BQ, Beasley SW. Hedgehog in the human: a possible explanation for the VATER association. J Paediatr Child Health. 2002;38:117–21.CrossRefPubMedGoogle Scholar
  10. 10.
    Assadi FK, Zajac CS. Ultrastructural changes in the rat kidney following fetal exposure to ethanol. Alcohol. 1992;9:509–12.CrossRefPubMedGoogle Scholar
  11. 11.
    Astrup P, Trolle D, Olsen HM, Kjeldsen K. Moderate hypoxia exposure and fetal development. Arch Environ Health. 1975;30:15–6.CrossRefPubMedGoogle Scholar
  12. 12.
    Aung KH, Tsukahara S, Maekawa F, Nohara K, Nakamura K, Tanoue A. Role of environmental chemical insult in neuronal cell death and cytoskeleton damage. Biol Pharm Bull. 2015;38(8):1109–12. https://doi.org/10.1248/bpb.b14-00890.CrossRefPubMedGoogle Scholar
  13. 13.
    Bailey LJ, Johnston MC, Billet J. Effects of carbon monoxide and hypoxia on cleft lip in A/J mice. Cleft Palate Craniofac J. 1995;32:14–9. https://doi.org/10.1597/1545-1569(1995)032<0014:EOCMAH>2.3.CO;2.CrossRefPubMedGoogle Scholar
  14. 14.
    Baker FD, Tumasonis CF. Carbon monoxide and avian embryogenesis. Arch Environ Health. 1972;24:53–61.CrossRefPubMedGoogle Scholar
  15. 15.
    Barnes GL, Alexander PG, Hsu CW, Mariani BD, Tuan RS. Cloning and characterization of chicken Paraxis: a regulator of paraxial mesoderm development and somite formation. Dev Biol. 1997;189:95–111. https://doi.org/10.1006/dbio.1997.8663.CrossRefPubMedGoogle Scholar
  16. 16.
    Barnes GL, Hsu CW, Mariani BD, Tuan RS. Chicken Pax-1 gene: structure and expression during embryonic somite development. Differentiation. 1996;61:13–23. https://doi.org/10.1046/j.1432-0436.1996.6110013.x.CrossRefPubMedGoogle Scholar
  17. 17.
    Barnes GL Jr, Mariani BD, Tuan RS. Valproic acid-induced somite teratogenesis in the chick embryo: relationship with Pax-1 gene expression. Teratology. 1996;54:93–102. https://doi.org/10.1002/(SICI)1096-9926(199606)54:2<93::AID-TERA5>3.0.CO;2-5.CrossRefPubMedGoogle Scholar
  18. 18.
    Basu A, Wezeman FH. Developmental toxicity of valproic acid during embryonic chick vertebral chondrogenesis. Spine (Phila Pa 1976). 2000;25:2158–64.CrossRefGoogle Scholar
  19. 19.
    Beaudoin AR. Teratogenicity of sodium arsenate in rats. Teratology. 1974;10:153–7.CrossRefPubMedGoogle Scholar
  20. 20.
    Becker HC, Diaz-Granados JL, Randall CL. Teratogenic actions of ethanol in the mouse: a minireview. Pharmacol Biochem Behav. 1996;55:501–13.CrossRefPubMedGoogle Scholar
  21. 21.
    Bernstam L, Nriagu J. Molecular aspects of arsenic stress. J Toxicol Environ Health B Crit Rev. 2000;3:293–322.CrossRefPubMedGoogle Scholar
  22. 22.
    Bnait KS, Seller MJ. Ultrastructural changes in 9-day old mouse embryos following maternal tobacco smoke inhalation. Exp Toxicol Pathol. 1995;47:453–61. https://doi.org/10.1016/S0940-2993(11)80327-1.CrossRefPubMedGoogle Scholar
  23. 23.
    Boer LL, Morava E, Klein WM, Schepens-Franke AN, Oostra RJ. Sirenomelia: a multi-systemic polytopic field defect with ongoing controversies. Birth Defects Res. 2017;109:791–804. https://doi.org/10.1002/bdr2.1049.CrossRefPubMedGoogle Scholar
  24. 24.
    Bohring A, Lewin SO, Reynolds JF, Voigtländer T, Rittinger O, Carey JC, et al. Polytopic anomalies with agenesis of the lower vertebral column. Am J Med Genet. 1999;87:99–114.CrossRefPubMedGoogle Scholar
  25. 25.
    Botto LD, Khoury MJ, Mastroiacovo P, Castilla EE, Moore CA, Skjaerven R, et al. The spectrum of congenital anomalies of the VATER association: an international study. Am J Med Genet. 1997;71:8–15.CrossRefPubMedGoogle Scholar
  26. 26.
    Breen JG, Claggett TW, Kimmel GL, Kimmel CA. Heat shock during rat embryo development in vitro results in decreased mitosis and abundant cell death. Reprod Toxicol. 1999;13:31–9.CrossRefPubMedGoogle Scholar
  27. 27.
    Brent RL, Fawcett LB. Developmental toxicology, drugs, and fetal teratogenesis. In: Reece EA, Hobbins JC, editors. Clinical obstetrics: the fetus and mother. 3rd ed. Malden: Blackwell; 2007. p. 217–35.Google Scholar
  28. 28.
    Buckiová D, Kubínová L, Soukup A, Jelínek R, Brown NA. Hyperthermia in the chick embryo: HSP and possible mechanisms of developmental defects. Int J Dev Biol. 1998;42:737–40.PubMedGoogle Scholar
  29. 29.
    Burton GJ, Hempstock J, Jauniaux E. Oxygen, early embryonic metabolism and free radical-mediated embryopathies. Reprod Biomed Online. 2003;6:84–96.CrossRefPubMedGoogle Scholar
  30. 30.
    Cammas L, Romand R, Fraulob V, Mura C, Dollé P. Expression of the murine retinol dehydrogenase 10 (Rdh10) gene correlates with many sites of retinoid signalling during embryogenesis and organ differentiation. Dev Dyn. 2007;236:2899–908. https://doi.org/10.1002/dvdy.21312.CrossRefPubMedGoogle Scholar
  31. 31.
    Carvan MJ 3rd, Loucks E, Weber DN, Williams FE. Ethanol effects on the developing zebrafish: neurobehavior and skeletal morphogenesis. Neurotoxicol Teratol. 2004;26:757–68. https://doi.org/10.1016/j.ntt.2004.06.016.CrossRefPubMedGoogle Scholar
  32. 32.
    Castori M, Silvestri E, Cappellacci S, Binni F, Sforzolini GS, Grammatico P. Sirenome lia and VACTERL association in the offspring of a woman with diabetes. Am J Med Genet A. 2010;152A(7):1803–7. https://doi.org/10.1002/ajmg.a.33460.CrossRefPubMedGoogle Scholar
  33. 33.
    Chaineau E, Binet S, Pol D, Chatellier G, Meininger V. Embryotoxic effects of sodium arsenite and sodium arsenate on mouse embryos in culture. Teratology. 1990;41(1):105–12. https://doi.org/10.1002/tera.1420410111.CrossRefPubMedGoogle Scholar
  34. 34.
    Chaudhuri JD. Alcohol and the developing fetus--a review. Med Sci Monit. 2000;6:1031–41.PubMedGoogle Scholar
  35. 35.
    Chen EY, Fujinaga M, Giaccia AJ. Hypoxic microenvironment within an embryo induces apoptosis and is essential for proper morphological development. Teratology. 1999;60:215–25. https://doi.org/10.1002/(SICI)1096-9926(199910)60:4<215::AID-TERA6>3.0.CO;2-2.CrossRefPubMedGoogle Scholar
  36. 36.
    Child DF, Hudson PR, Hunter-Lavin C, Mukhergee S, China S, Williams CP, Williams JH. Birth defects and anti-heat shock protein 70 antibodies in early pregnancy. Cell Stress Chaperones. 2006;11:101–5.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Christ B, Huang R, Scaal M. Formation and differentiation of the avian sclerotome. Anat Embryol (Berl). 2004;208:333–50. https://doi.org/10.1007/s00429-004-0408-z.CrossRefGoogle Scholar
  38. 38.
    Christ B, Huang R, Wilting J. The development of the avian vertebral column. Anat Embryol (Berl). 2000;202(3):179–94.CrossRefGoogle Scholar
  39. 39.
    Cohen MM. The child with multiple birth defects. New York: Oxford University Press; 1997.Google Scholar
  40. 40.
    Coll TA, Tito LP, Sobarzo CM, Cebral E. Embryo developmental disruption during organogenesis produced by CF-1 murine periconceptional alcohol consumption. Birth Defects Res B Dev Reprod Toxicol. 2011;92:560–74. https://doi.org/10.1002/bdrb.20329.CrossRefPubMedGoogle Scholar
  41. 41.
    Connelly LE, Rogers JM. Methanol causes posteriorization of cervical vertebrae in mice. Teratology. 1997;55:138–44. https://doi.org/10.1002/(SICI)1096-9926(199702)55:2<138::AID-TERA4>3.0.CO;2-#.CrossRefPubMedGoogle Scholar
  42. 42.
    Copp AJ, Greene ND. Genetics and development of neural tube defects. J Pathol. 2010;220:217–30. https://doi.org/10.1002/path.2643.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Cui J, Michaille JJ, Jiang W, Zile MH. Retinoid receptors and vitamin A deficiency: differential patterns of transcription during early avian development and the rapid induction of RARs by retinoic acid. Dev Biol. 2003;260:496–511.CrossRefPubMedGoogle Scholar
  44. 44.
    Cui Y, Han Z, Hu Y, Song G, Hao C, Xia H, Ma X. MicroRNA-181b and microRNA-9 mediate arsenic-induced angiogenesis via NRP1. J Cell Physiol. 2012;227:772–83. https://doi.org/10.1002/jcp.22789.CrossRefPubMedGoogle Scholar
  45. 45.
    Danielson MK, Danielsson BR, Marchner H, Lundin M, Rundqvist E, Reiland S. Histopathological and hemodynamic studies supporting hypoxia and vascular disruption as explanation to phenytoin teratogenicity. Teratology. 1992;46(5):485–97. https://doi.org/10.1002/tera.1420460513.CrossRefPubMedGoogle Scholar
  46. 46.
    Daughtrey WC, Newby-Schmidt MB, Norton S. Forebrain damage in chick embryos exposed to carbon monoxide. Teratology. 1983;28(1):83–9. https://doi.org/10.1002/tera.1420280111.CrossRefPubMedGoogle Scholar
  47. 47.
    Dennery PA. Effects of oxidative stress on embryonic development. Birth Defects Res C Embryo Today. 2007;81:155–62. https://doi.org/10.1002/bdrc.20098.CrossRefPubMedGoogle Scholar
  48. 48.
    DeSesso JM, Jacobson CF, Scialli AR, Farr CH, Holson JF. An assessment of the developmental toxicity of inorganic arsenic. Prod Toxicol. 1998;12:385–433.Google Scholar
  49. 49.
    Duester G. Retinoic acid regulation of the somitogenesis clock. Birth Defects Res C Embryo Today. 2007;81:84–92. https://doi.org/10.1002/bdrc.20092.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Dias MS. Normal and abnormal development of the spine. Neurosurg Clin N Am. 2007;18(3):415–29. https://doi.org/10.1016/j.nec.2007.05.003.CrossRefPubMedGoogle Scholar
  51. 51.
    Dumollard R, Duchen M, Carroll J. The role of mitochondrial function in the oocyte and embryo. Curr Top Dev Biol. 2007;77:21–49. https://doi.org/10.1016/S0070-2153(06)77002-8.CrossRefPubMedGoogle Scholar
  52. 52.
    Dunty WC Jr, Chen SY, Zucker RM, Dehart DB, Sulik KK. Selective vulnerability of embryonic cell populations to ethanol-induced apoptosis: implications for alcohol-related birth defects and neurodevelopmental disorder. Alcohol Clin Exp Res. 2001;25:1523–35.CrossRefPubMedGoogle Scholar
  53. 53.
    Eckalbar WL, Fisher RE, Rawls A, Kusumi K. Scoliosis and segmentation defects of the vertebrae. Wiley Interdiscip Rev Dev Biol. 2012;1:401–23. https://doi.org/10.1002/wdev.34.CrossRefPubMedGoogle Scholar
  54. 54.
    Edwards MJ, Walsh DA, Li Z. Hyperthermia, teratogenesis and the heat shock response in mammalian embryos in culture. Int J Dev Biol. 1997;41:345–58.Google Scholar
  55. 55.
    Ehlers K, Stürje H, Merker HJ, Nau H. Valproic acid-induced spina bifida: a mouse model. Teratology. 1992;45:145–54. https://doi.org/10.1002/tera.1420450208.CrossRefPubMedGoogle Scholar
  56. 56.
    Erol B, Tracy MR, Dormans JP, Zackai EH, Maisenbacher MK, O’Brien ML, Turnpenny PD, Kusumi K. Congenital scoliosis and vertebral malformations: characterization of segmental defects for genetic analysis. J Pediatr Orthop. 2004; 24:674–82.CrossRefPubMedGoogle Scholar
  57. 57.
    Fantel AG. Reactive oxygen species in developmental toxicity: review and hypothesis. Teratology. 1996;53:196–217. https://doi.org/10.1002/(SICI)1096-9926(199603)53:3<196::AID-TERA7>3.0.CO;2-2.CrossRefPubMedGoogle Scholar
  58. 58.
    Farley FA, Hall J, Goldstein SA. Characteristics of congenital scoliosis in a mouse model. J Pediatr Orthop. 2006;26:341–6. https://doi.org/10.1097/01.bpo.0000203011.58529.d8.CrossRefPubMedGoogle Scholar
  59. 59.
    Fathe K, Palacios A, Finnell RH. Brief report novel mechanism for valproate-induced teratogenicity. Birth Defects Res A Clin Mol Teratol. 2014;100:592–7. https://doi.org/10.1002/bdra.23277.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Fernandez K, Caul WF, Boyd JE, Henderson GI, Michaelis RC. Malformations and growth of rat fetuses exposed to brief periods of alcohol in utero. Teratog Carcinog Mutagen. 1983;3:457–60.CrossRefPubMedGoogle Scholar
  61. 61.
    Ferrer-Vaquer A, Hadjantonakis AK. Birth defects associated with perturbations in preimplantation, gastrulation, and axis extension: from conjoined twinning to caudal dysgenesis. Wiley Interdiscip Rev Dev Biol. 2013;2(4):427–42. https://doi.org/10.1002/wdev.97.CrossRefPubMedGoogle Scholar
  62. 62.
    Fichtner RR, Sullivan KM, Zyrkowski CL, Trowbridge FL. Racial/ethnic differences in smoking, other risk factors, and low birth weight among low-income pregnant women, 1978-1988. MMWR CDC Surveill Summ. 1990;39:13–21.PubMedGoogle Scholar
  63. 63.
    Fine EL, Horal M, Chang TI, Fortin G, Loeken MR. Evidence that elevated glucose causes altered gene expression, apoptosis, and neural tube defects in a mouse model of diabetic pregnancy. Diabetes. 1999;48:2454–62.CrossRefPubMedGoogle Scholar
  64. 64.
    Finnell RH, Dansky LV. Parental epilepsy, anticonvulsant drugs, and reproductive outcome: epidemiologic and experimental findings spanning three decades; 1: animal studies. Reprod Toxicol. 1991;5(4):281–99.CrossRefPubMedGoogle Scholar
  65. 65.
    Forsberg H, Borg LA, Cagliero E, Eriksson UJ. Altered levels of scavenging enzymes in embryos subjected to a diabetic environment. Free Radic Res. 1996;24:451–9.CrossRefPubMedGoogle Scholar
  66. 66.
    Francesca LC, Claudia R, Molinario C, Annamaria M, Chiara F, Natalia C, et al. Variants in TNIP1, a regulator of the NF-kB pathway, found in two patients with neural tube defects. Childs Nerv Syst. 2016;32:1061–7. https://doi.org/10.1007/s00381-016-3087-1.CrossRefPubMedGoogle Scholar
  67. 67.
    Galloway CA, Yoon Y. Mitochondrial dynamics in diabetic cardiomyopathy. Antioxid Redox Signal. 2015;22:1545–62. https://doi.org/10.1089/ars.2015.6293.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Geneviève D, de Pontual L, Amiel J, Sarnacki S, Lyonnet S. An overview of isolated and syndromic oesophageal atresia. Clin Genet. 2007;71:392–9. https://doi.org/10.1111/j.1399-0004.2007.00798.x.CrossRefPubMedGoogle Scholar
  69. 69.
    German J, Louie E, Banerjee D. The heat-shock response in vivo: experimental induction during mammalian organogenesis. Teratog Carcinog Mutagen. 1986;6:555–62.CrossRefPubMedGoogle Scholar
  70. 70.
    Giampietro PF, Dunwoodie SL, Kusumi K, Pourquié O, Tassy O, Offiah AC, et al. Progress in the understanding of the genetic etiology of vertebral segmentation disorders in humans. Ann N Y Acad Sci. 2009;1151:38–67. https://doi.org/10.1111/j.1749-6632.2008.03452.x.CrossRefPubMedGoogle Scholar
  71. 71.
    Gilbert-Barness E, Debich-Spicer D, Cohen MM Jr, Opitz JM. Evidence for the “midline” hypothesis in associated defects of laterality formation and multiple midline anomalies. Am J Med Genet. 2001;101:382–7.CrossRefPubMedGoogle Scholar
  72. 72.
    Grabowski CT. A quantitative study of the lethal and teratogenic effects of hypoxia on the three-day chick embryo. Am J Anat. 1961;109:25–35. https://doi.org/10.1002/aja.1001090104.CrossRefPubMedGoogle Scholar
  73. 73.
    Grabowski CT, Paar JA. The teratogenic effects of graded doses of hypoxia on the chick embryo. Am J Anat. 1958;103(3):313–47. https://doi.org/10.1002/aja.1001030302.CrossRefPubMedGoogle Scholar
  74. 74.
    Graham JM Jr, Edwards MJ, Edwards MJ. Teratogen update: gestational effects of maternal hyperthermia due to febrile illnesses and resultant patterns of defects in humans. Teratology. 1998;58:209–21. https://doi.org/10.1002/(SICI)1096-9926(199811)58:5<209::AID-TERA8>3.0.CO;2-Q.CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Greene ND, Copp AJ. Mouse models of neural tube defects: investigating preventive mechanisms. Am J Med Genet C Semin Med Genet. 2005;135C:31–41. https://doi.org/10.1002/ajmg.c.30051.CrossRefPubMedGoogle Scholar
  76. 76.
    Gridley T. The long and short of it: somite formation in mice. Dev Dyn. 2006;235:2330–6. https://doi.org/10.1002/dvdy.20850.CrossRefPubMedGoogle Scholar
  77. 77.
    Gudas LJ. Retinoids and vertebrate development. J Biol Chem. 1994;269:15399–402.PubMedGoogle Scholar
  78. 78.
    Hamburger V, Hamilton HL. A series of normal stages in the development of the chick embryo. 1951. Dev Dyn. 1992;195:231–72. https://doi.org/10.1002/aja.1001950404.CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Hansen JM, Harris C. Redox control of teratogenesis. Reprod Toxicol. 2013;35:165–79. https://doi.org/10.1016/j.reprotox.2012.09.004.CrossRefPubMedGoogle Scholar
  80. 80.
    Harrouk WA, Wheeler KE, Kimmel GL, Hogan KA, Kimmel CA. Effects of hyperthermia and boric acid on skeletal development in rat embryos. Birth Defects Res B Dev Reprod Toxicol. 2005;74:268–76. https://doi.org/10.1002/bdrb.20047.CrossRefPubMedGoogle Scholar
  81. 81.
    Healy C, Uwanogho D, Sharpe PT. Regulation and role of Sox9 in cartilage formation. Dev Dyn. 1999;215(1):69–78. https://doi.org/10.1002/(SICI)1097-0177(199905)215:1<69::AID-DVDY8>3.0.CO;2-N.CrossRefPubMedGoogle Scholar
  82. 82.
    Hendrickx AG, Nau H, Binkerd P, Rowland JM, Rowland JR, Cukierski MJ, Cukierski MA. Valproic acid developmental toxicity and pharmacokinetics in the rhesus monkey: an interspecies comparison. Teratology. 1988;38:329–45. https://doi.org/10.1002/tera.1420380405.CrossRefPubMedGoogle Scholar
  83. 83.
    Herion NJ, Salbaum JM, Kappen C. Traffic jam in the primitive streak: the role of defective mesoderm migration in birth defects. Birth Defects Res A Clin Mol Teratol. 2014;100:608–22. https://doi.org/10.1002/bdra.23283.CrossRefPubMedGoogle Scholar
  84. 84.
    Hood RD, Bishop SL. Teratogenic effects of sodium arsenate in mice. Arch Environ Health. 1972;24:62–5.CrossRefPubMedGoogle Scholar
  85. 85.
    Horton WE Jr, Sadler TW. Effects of maternal diabetes on early embryogenesis. Alterations in morphogenesis produced by the ketone body, B-hydroxybutyrate. Diabetes. 1983;32:610–6.CrossRefPubMedGoogle Scholar
  86. 86.
    Hunter ES 3rd. Role of oxidative damage in arsenic-induced teratogenesis. Teratology. 2000;62:240. https://doi.org/10.1002/1096-9926(200010)62:4<240::AID-TERA14>3.0.CO;2-8.CrossRefPubMedGoogle Scholar
  87. 87.
    Hunter ES 3rd, Sadler TW. Fuel-mediated teratogenesis: biochemical effects of hypoglycemia during neurulation in mouse embryos in vitro. Am J Phys. 1989;257:E269–76. https://doi.org/10.1152/ajpendo.1989.257.2.E269.CrossRefGoogle Scholar
  88. 88.
    Hunter ES 3rd, Tugman JA. Inhibitors of glycolytic metabolism affect neurulation-staged mouse conceptuses in vitro. Teratology. 1995;52:317–23. https://doi.org/10.1002/tera.1420520602.CrossRefPubMedGoogle Scholar
  89. 89.
    Ingalls TH, Philbrook FR. Monstrosities induced by hypoxia. N Engl J Med. 1958;259:558–64. https://doi.org/10.1056/NEJM195809182591202.CrossRefPubMedGoogle Scholar
  90. 90.
    Iulianella A, Beckett B, Petkovich M, Lohnes D. A molecular basis for retinoic acid-induced axial truncation. Dev Biol. 1999;205:33–48. https://doi.org/10.1006/dbio.1998.9110.CrossRefPubMedGoogle Scholar
  91. 91.
    Iyer NV, Kotch LE, Agani F, Leung SW, Laughner E, Wenger RH, et al. Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha. Genes Dev. 1998;12:149–62.CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    Jain S, Maltepe E, Lu MM, Simon C, Bradfield CA. Expression of ARNT, ARNT2, HIF1 alpha, HIF2 alpha and Ah receptor mRNAs in the developing mouse. Mech Dev. 1998;73:117–23.CrossRefPubMedGoogle Scholar
  93. 93.
    Jaskwhich D, Ali RM, Patel TC, Green DW. Congenital scoliosis. Curr Opin Pediatr. 2000;12:61–6.CrossRefPubMedGoogle Scholar
  94. 94.
    Jentink J, Loane MA, Dolk H, Barisic I, Garne E, Morris JK, et al. Valproic acid monotherapy in pregnancy and major congenital malformations. N Engl J Med. 2010;362:2185–93. https://doi.org/10.1056/NEJMoa0907328.CrossRefPubMedGoogle Scholar
  95. 95.
    Kaushal A, Zhang H, Karmaus WJJ, Everson TM, Marsit CJ, Karagas MR, et al. Genome-wide DNA methylation at birth in relation to in utero arsenic exposure and the associated health in later life. Environ Health. 2017;16:50. https://doi.org/10.1186/s12940-017-0262-0.CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    Kawanishi CY, Hartig P, Bobseine KL, Schmid J, Cardon M, Massenburg G, Chernoff N. Axial skeletal and Hox expression domain alterations induced by retinoic acid, valproic acid, and bromoxynil during murine development. J Biochem Mol Toxicol. 2003;17:346–56. https://doi.org/10.1002/jbt.10098.CrossRefPubMedGoogle Scholar
  97. 97.
    Kennedy LA, Elliott MJ. Ocular changes in the mouse embryo following acute maternal ethanol intoxication. Int J Dev Neurosci. 1986;4:311–7.CrossRefPubMedGoogle Scholar
  98. 98.
    Kessel M, Gruss P. Homeotic transformations of murine vertebrae and concomitant alteration of Hox codes induced by retinoic acid. Cell. 1991;67:89–104.CrossRefGoogle Scholar
  99. 99.
    Kim PC, Mo R, Hui CC. Murine models of VACTERL syndrome: role of sonic hedgehog signaling pathway. J Pediatr Surg. 2001;36:381–4.CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Kimura M, Ichimura S, Sasaki K, Masuya H, Suzuki T, Wakana S, et al. Endoplasmic reticulum stress-mediated apoptosis contributes to a skeletal dysplasia resembling platyspondylic lethal skeletal dysplasia, Torrance type, in a novel Col2a1 mutant mouse line. Biochem Biophys Res Commun. 2015;468:86–91. https://doi.org/10.1016/j.bbrc.2015.10.160.CrossRefPubMedGoogle Scholar
  101. 101.
    Kitchin KT, Ahmad S. Oxidative stress as a possible mode of action for arsenic carcinogenesis. Toxicol Lett. 2003;137(1–2):3–13.CrossRefPubMedGoogle Scholar
  102. 102.
    Kotch LE, Chen SY, Sulik KK. Ethanol-induced teratogenesis: free radical damage as a possible mechanism. Teratology. 1995;52:128–36. https://doi.org/10.1002/tera.1420520304.CrossRefPubMedGoogle Scholar
  103. 103.
    Lammer EJ, Sever LE, Oakley GP Jr. Teratogen update: valproic acid. Teratology. 1987;35:465–73. https://doi.org/10.1002/tera.1420350319.CrossRefPubMedGoogle Scholar
  104. 104.
    Lee QP, Juchau MR. Dysmorphogenic effects of nitric oxide (NO) and NO-synthase inhibition: studies with intra-amniotic injections of sodium nitroprusside and NG-monomethyl-L-arginine. Teratology. 1994;49:452–64. https://doi.org/10.1002/tera.1420490605.CrossRefPubMedGoogle Scholar
  105. 105.
    Lencinas A, Broka DM, Konieczka JH, Klewer SE, Antin PB, Camenisch TD, Runyan RB. Arsenic exposure perturbs epithelial-mesenchymal cell transition and gene expression in a collagen gel assay. Toxicol Sci. 2010;116:273–85. https://doi.org/10.1093/toxsci/kfq086.CrossRefPubMedPubMedCentralGoogle Scholar
  106. 106.
    Leung MCK, Procter AC, Goldstone JV, Foox J, DeSalle R, Mattingly CJ, et al. Applying evolutionary genetics to developmental toxicology and risk assessment. Reprod Toxicol. 2017;69:174–86. https://doi.org/10.1016/j.reprotox.2017.03.003.CrossRefPubMedPubMedCentralGoogle Scholar
  107. 107.
    Levinson W, Oppermann H, Jackson J. Transition series metals and sulfhydryl reagents induce the synthesis of four proteins in eukaryotic cells. Biochim Biophys Acta. 1980;606:170–80.CrossRefPubMedGoogle Scholar
  108. 108.
    Li R, Chase M, Jung SK, Smith PJ, Loeken MR. Hypoxic stress in diabetic pregnancy contributes to impaired embryo gene expression and defective development by inducing oxidative stress. Am J Physiol Endocrinol Metab. 2005;289:E591–9. https://doi.org/10.1152/ajpendo.00441.2004.CrossRefPubMedGoogle Scholar
  109. 109.
    Li X, Ma Y, Li D, Gao X, Li P, Bai N, et al. Arsenic impairs embryo development via down-regulating Dvr1 expression in zebrafish. Toxicol Lett. 2012;212:161–8. https://doi.org/10.1016/j.toxlet.2012.05.011.CrossRefPubMedGoogle Scholar
  110. 110.
    Li ZL, Shiota K. Stage-specific homeotic vertebral transformations in mouse fetuses induced by maternal hyperthermia during somitogenesis. Dev Dyn. 1999;216:336–48. https://doi.org/10.1002/(SICI)1097-0177(199912)216:4/5<336::AID-DVDY3>3.0.CO;2-5.CrossRefPubMedGoogle Scholar
  111. 111.
    Li Z, Shen J, Wu WK, Wang X, Liang J, Qiu G, Liu J. Vitamin A deficiency induces congenital spinal deformities in rats. PLoS One. 2012;7:e46565. https://doi.org/10.1371/journal.pone.0046565.CrossRefPubMedPubMedCentralGoogle Scholar
  112. 112.
    Lindgren A, Danielsson BR, Dencker L, Vahter M. Embryotoxicity of arsenite and arsenate: distribution in pregnant mice and monkeys and effects on embryonic cells in vitro. Acta Pharmacol Toxicol (Copenh). 1984;54:311–20.CrossRefGoogle Scholar
  113. 113.
    Ling M, Li Y, Xu Y, Pang Y, Shen L, Jiang R, et al. Regulation of miRNA-21 by reactive oxygen species-activated ERK/NF-κB in arsenite-induced cell transformation. Free Radic Biol Med. 2012;52:1508–18. https://doi.org/10.1016/j.freeradbiomed.2012.02.020.CrossRefPubMedGoogle Scholar
  114. 114.
    Loder RT, Hernandez MJ, Lerner AL, Winebrener DJ, Goldstein SA, Hensinger RN, et al. The induction of congenital spinal deformities in mice by maternal carbon monoxide exposure. J Pediatr Orthop. 2000;20:662–6.CrossRefPubMedGoogle Scholar
  115. 115.
    Loeken MR. Current perspectives on the causes of neural tube defects resulting from diabetic pregnancy. Am J Med Genet C Semin Med Genet. 2005;135C:77–87. https://doi.org/10.1002/ajmg.c.30056.CrossRefPubMedGoogle Scholar
  116. 116.
    Longo LD. The biological effects of carbon monoxide on the pregnant woman, fetus, and newborn infant. Am J Obstet Gynecol. 1977;129:69–103.CrossRefPubMedGoogle Scholar
  117. 117.
    Ma Y, Zhang C, Gao XB, Luo HY, Chen Y, Li HH, et al. Folic acid protects against arsenic-mediated embryo toxicity by up-regulating the expression of Dvr1. Sci Rep. 2015;5:16093. https://doi.org/10.1038/srep16093.CrossRefPubMedPubMedCentralGoogle Scholar
  118. 118.
    Mackler B, Grace R, Duncan HM. Studies of mitochondrial development during embryogenesis in the rat. Arch Biochem Biophys. 1971;144:603–10.CrossRefPubMedGoogle Scholar
  119. 119.
    Mackler B, Grace R, Tippit DF, Lemire RJ, Shepard TH, Kelley VC. Studies of the development of congenital anomalies in rats. III. Effects of inhibition of mitochondrial energy systems on embryonic development. Teratology. 1975;12:291–6. https://doi.org/10.1002/tera.1420120311.CrossRefPubMedGoogle Scholar
  120. 120.
    Maden M. Distribution of cellular retinoic acid-binding proteins I and II in the chick embryo and their relationship to teratogenesis. Teratology. 1994;50:294–301. https://doi.org/10.1002/tera.1420500404.CrossRefPubMedGoogle Scholar
  121. 121.
    Maines MD. The heme oxygenase system: a regulator of second messenger gases. Annu Rev Pharmacol Toxicol. 1997;37:517–54. https://doi.org/10.1146/annurev.pharmtox.37.1.517.CrossRefPubMedGoogle Scholar
  122. 122.
    Maltepe E, Schmidt JV, Baunoch D, Bradfield CA, Simon MC. Abnormal angiogenesis and responses to glucose and oxygen deprivation in mice lacking the protein ARNT. Nature. 1997;386:403–7. https://doi.org/10.1038/386403a0.CrossRefPubMedGoogle Scholar
  123. 123.
    Martínez-Frías ML, Bermejo E, Rodríguez-Pinilla E, Prieto L, Frías JL. Epidemiological analysis of outcomes of pregnancy in gestational diabetic mothers. Am J Med Genet. 1998;78:140–5.CrossRefPubMedGoogle Scholar
  124. 124.
    Martínez-Frías ML, Frías JL. Primary developmental field. III: clinical and epidemiological study of blastogenetic anomalies and their relationship to different MCA patterns. Am J Med Genet. 1997;70:11–5.CrossRefPubMedGoogle Scholar
  125. 125.
    Martinez-Frias ML, Frias JL. VACTERL as primary, polytopic, developmental field defects. Am J Med Genet. 1999;83:13–6.CrossRefPubMedGoogle Scholar
  126. 126.
    Martinez-Frias ML, Frias JL, Opitz JM. Errors of morphogenesis and developmental field theory. Am J Med Genet. 1998;76:291–6.CrossRefPubMedGoogle Scholar
  127. 127.
    McCollum CW, Hans C, Shah S, Merchant FA, Gustafsson JÅ, Bondesson M. Embryonic exposure to sodium arsenite perturbs vascular development in zebrafish. Aquat Toxicol. 2014;152:152–63. https://doi.org/10.1016/j.aquatox.2014.04.006.CrossRefPubMedGoogle Scholar
  128. 128.
    McCoy CR, Stadelman BS, Brumaghim JL, Liu JT, Bain LJ. Arsenic and its methylated metabolites inhibit the differentiation of neural plate border specifier cells. Chem Res Toxicol. 2015;28:1409–21. https://doi.org/10.1021/acs.chemrestox.5b00036.CrossRefPubMedGoogle Scholar
  129. 129.
    Menegola E, Broccia ML, Nau H, Prati M, Ricolfi R, Giavini E. Teratogenic effects of sodium valproate in mice and rats at midgestation and at term. Teratog Carcinog Mutagen. 1996;16:97–108. https://doi.org/10.1002/(SICI)1520-6866(1996)16:2<97::AID-TCM4>3.0.CO;2-A.CrossRefPubMedGoogle Scholar
  130. 130.
    Menegola E, Di Renzo F, Broccia ML, Giavini E. Inhibition of histone deacetylase as a new mechanism of teratogenesis. Birth Defects Res C Embryo Today. 2006;78:345–53. https://doi.org/10.1002/bdrc.20082.CrossRefPubMedGoogle Scholar
  131. 131.
    Miki A, Fujimoto E, Ohsaki T, Mizoguti H. Effects of oxygen concentration on embryonic development in rats: a light and electron microscopic study using whole-embryo culture techniques. Anat Embryol (Berl). 1988;178:337–43.CrossRefGoogle Scholar
  132. 132.
    Miki A, Mizoguchi A, Mizoguti H. Histochemical studies of enzymes of the energy metabolism in postimplantation rat embryos. Histochemistry. 1988;88:489–95.PubMedGoogle Scholar
  133. 133.
    Minet E, Michel G, Remacle J, Michiels C. Role of HIF-1 as a transcription factor involved in embryonic development, cancer progression and apoptosis (review). Int J Mol Med. 2000;5:253–9.PubMedGoogle Scholar
  134. 134.
    Mirkes PE. Molecular/cellular biology of the heat stress response and its role in agent-induced teratogenesis. Mutat Res. 1997;396:163–73.CrossRefPubMedGoogle Scholar
  135. 135.
    Mirkes PE, Cornel L. A comparison of sodium arsenite- and hyperthermia-induced stress responses and abnormal development in cultured postimplantation rat embryos. Teratology. 1992;46(3):251–9. https://doi.org/10.1002/tera.1420460308.CrossRefPubMedGoogle Scholar
  136. 136.
    Mittapalli VR, Huang R, Patel K, Christ B, Scaal M. Arthrotome: a specific joint forming compartment in the avian somite. Dev Dyn. 2005;234:48–53. https://doi.org/10.1002/dvdy.20502.CrossRefPubMedPubMedCentralGoogle Scholar
  137. 137.
    Moazzen H, Lu X, Liu M, Feng Q. Pregestational diabetes induces fetal coronary artery malformation via reactive oxygen species signaling. Diabetes. 2015;64:1431–43. https://doi.org/10.2337/db14-0190.CrossRefPubMedGoogle Scholar
  138. 138.
    Moreira A, Freitas R, Figueira E, Volpi Ghirardini A, Soares AMVM, Radaelli M, et al. Combined effects of arsenic, salinity and temperature on Crassostrea gigas embryotoxicity. Ecotoxicol Environ Saf. 2018;147:251–9. https://doi.org/10.1016/j.ecoenv.2017.08.043.CrossRefPubMedGoogle Scholar
  139. 139.
    Murray FJ, Schwetz BA, Crawford AA, Henck JW, Quast JF, Staples RE. Embryotoxicity of inhaled sulfur dioxide and carbon monoxide in mice and rabbits. J Environ Sci Health C. 1979;13(3):233–50.PubMedGoogle Scholar
  140. 140.
    Nau H. Valproic acid-induced neural tube defects. Ciba Found Symp. 1994;181:144–52.PubMedGoogle Scholar
  141. 141.
    Nau H, Hauck RS, Ehlers K. Valproic acid-induced neural tube defects in mouse and human: aspects of chirality, alternative drug development, pharmacokinetics and possible mechanisms. Pharmacol Toxicol. 1991;69:310–21.CrossRefPubMedGoogle Scholar
  142. 142.
    Nelson BK, Brightwell WS, MacKenzie DR, Khan A, Burg JR, Weigel WW, Goad PT. Teratological assessment of methanol and ethanol at high inhalation levels in rats. Fundam Appl Toxicol. 1985;5:727–36.CrossRefPubMedGoogle Scholar
  143. 143.
    Nikolopoulou E, Galea GL, Rolo A, Greene ND, Copp AJ. Neural tube closure: cellular, molecular and biomechanical mechanisms. Development. 2017;144:552–66. https://doi.org/10.1242/dev.145904.CrossRefPubMedPubMedCentralGoogle Scholar
  144. 144.
    Niederreither K, Fraulob V, Garnier JM, Chambon P, Dollé P. Differential expression of retinoic acid-synthesizing (RALDH) enzymes during fetal development and organ differentiation in the mouse. Mech Dev. 2002;110:165–71.CrossRefPubMedGoogle Scholar
  145. 145.
    Nishimura H, Tanimura T, Semba R, Uwabe C. Normal development of early human embryos: observation of 90 specimens at Carnegie stages 7 to 13. Teratology. 1974;10:1–5. https://doi.org/10.1002/tera.1420100102.CrossRefPubMedGoogle Scholar
  146. 146.
    Opitz JM, Zanni G, Reynolds JF Jr, Gilbert-Barness E. Defects of blastogenesis. Am J Med Genet. 2002;11:269–86.CrossRefGoogle Scholar
  147. 147.
    O’Rahilly RR, Mueller F. Human embryology and teratology. 3rd ed. New York: Wiley-Liss Publishers; 1996.Google Scholar
  148. 148.
    Ornoy A. Embryonic oxidative stress as a mechanism of teratogenesis with special emphasis on diabetic embryopathy. Reprod Toxicol. 2007;24:31–41. https://doi.org/10.1016/j.reprotox.2007.04.004.CrossRefPubMedGoogle Scholar
  149. 149.
    Ornoy A. Valproic acid in pregnancy: how much are we endangering the embryo and fetus? Reprod Toxicol. 2009;28:1–10. https://doi.org/10.1016/j.reprotox.2009.02.014.CrossRefPubMedGoogle Scholar
  150. 150.
    Ornoy A, Rand SB, Bischitz N. Hyperglycemia and hypoxia are interrelated in their teratogenic mechanism: studies on cultured rat embryos. Birth Defects Res B Dev Reprod Toxicol. 2010;89:106–15. https://doi.org/10.1002/bdrb.20230.CrossRefPubMedGoogle Scholar
  151. 151.
    Ornoy A, Reece EA, Pavlinkova G, Kappen C, Miller RK. Effect of maternal diabetes on the embryo, fetus, and children: congenital anomalies, genetic and epigenetic changes and developmental outcomes. Birth Defects Res C Embryo Today. 2015;105:53–72. https://doi.org/10.1002/bdrc.21090.CrossRefPubMedGoogle Scholar
  152. 152.
    Ornoy A, Zaken V, Kohen R. Role of reactive oxygen species (ROS) in the diabetes-induced anomalies in rat embryos in vitro: reduction in antioxidant enzymes and low-molecular-weight antioxidants (LMWA) may be the causative factor for increased anomalies. Teratology. 1999;60:376–86. https://doi.org/10.1002/(SICI)1096-9926(199912)60:6<376::AID-TERA10>3.0.CO;2-Q.CrossRefPubMedGoogle Scholar
  153. 153.
    Ornoy A, Zusman I, Cohen AM, Shafrir E. Effects of sera from Cohen, genetically determined diabetic rats, streptozotocin diabetic rats and sucrose fed rats on in vitro development of early somite rat embryos. Diabetes Res. 1986;3:43–51.PubMedGoogle Scholar
  154. 154.
    Oskouian RJ Jr, Sansur CA, Shaffrey CI. Congenital abnormalities of the thoracic and lumbar spine. Neurosurg Clin N Am. 2007;18:479–98. https://doi.org/10.1016/j.nec.2007.04.004.CrossRefPubMedGoogle Scholar
  155. 155.
    Ozkan H, Cetinkaya M, Köksal N, Yapici S. Severe fetal valproate syndrome: combination of complex cardiac defect, multicystic dysplastic kidney, and trigonocephaly. J Matern Fetal Neonatal Med. 2011;24:521–4. https://doi.org/10.3109/14767058.2010.501120.CrossRefPubMedGoogle Scholar
  156. 156.
    Padmanabhan R. Retinoic acid-induced caudal regression syndrome in the mouse fetus. Reprod Toxicol. 1998;12:139–51.CrossRefPubMedGoogle Scholar
  157. 157.
    Padmanabhan R, Muawad WM. Exencephaly and axial skeletal dysmorphogenesis induced by acute doses of ethanol in mouse fetuses. Drug Alcohol Depend. 1985;16:215–27.CrossRefPubMedGoogle Scholar
  158. 158.
    Parke WW. Development of the spine. In: Herkowitz HN, Garfin SR, Balderston RA, Eismont FJ, Bell GR, Weisel SW, editors. Rothman-Simeone: The Spine. 4th ed. Philadelphia, PA: W. B. Saunders Company; 1999. p. 3–29.Google Scholar
  159. 159.
    Parnell SE, Dehart DB, Wills TA, Chen SY, Hodge CW, Besheer J, et al. Maternal oral intake mouse model for fetal alcohol spectrum disorders: ocular defects as a measure of effect. Alcohol Clin Exp Res. 2006;30:1791–8. https://doi.org/10.1111/j.1530-0277.2006.00212.x.CrossRefPubMedGoogle Scholar
  160. 160.
    Pauli RM. Lower mesodermal defects: a common cause of fetal and early neonatal death. Am J Med Genet. 1994;50:154–72.CrossRefPubMedGoogle Scholar
  161. 161.
    Pavlinkova G, Salbaum JM, Kappen C. Wnt signaling in caudal dysgenesis and diabetic embryopathy. Birth Defects Res A Clin Mol Teratol. 2008;82:710–9. https://doi.org/10.1002/bdra.20495.CrossRefPubMedPubMedCentralGoogle Scholar
  162. 162.
    Pennimpede T, Proske J, König A, Vidigal JA, Morkel M, Bramsen JB, et al. In vivo knockdown of Brachyury results in skeletal defects and urorectal malformations resembling caudal regression syndrome. Dev Biol. 2012;372:55–67. https://doi.org/10.1016/j.ydbio.2012.09.003.CrossRefPubMedGoogle Scholar
  163. 163.
    Peterková R, Puzanová L. Effect of trivalent and pentavalent arsenic on early developmental stages of the chick embryo. Folia Morphol (Praha). 1976;24:5–13.Google Scholar
  164. 164.
    Pourquié O. Vertebrate segmentation: from cyclic gene networks to scoliosis. Cell. 2011;145:650–63.CrossRefPubMedPubMedCentralGoogle Scholar
  165. 165.
    Primmett DR, Norris WE, Carlson GJ, Keynes RJ, Stern CD. Periodic segmental anomalies induced by heat shock in the chick embryo are associated with the cell cycle. Development. 1989;105:119–30.PubMedGoogle Scholar
  166. 166.
    Primmett DR, Stern CD, Keynes RJ. Heat shock causes repeated segmental anomalies in the chick embryo. Development. 1988;104:331–9.PubMedGoogle Scholar
  167. 167.
    Raddatz E, Kucera P. Mapping of the oxygen consumption in the gastrulating chick embryo. Respir Physiol. 1983;51:153–66.CrossRefPubMedGoogle Scholar
  168. 168.
    Ralston JD, Hampson NB. Incidence of severe unintentional carbon monoxide poisoning differs across racial/ethnic categories. Public Health Rep. 2000;115:46–51.CrossRefPubMedPubMedCentralGoogle Scholar
  169. 169.
    Rashbass P, Wilson V, Rosen B, Beddington RS. Alterations in gene expression during mesoderm formation and axial patterning in Brachyury (T) embryos. Int J Dev Biol. 1994;38:35–44.PubMedGoogle Scholar
  170. 170.
    Reijntjes S, Gale E, Maden M. Generating gradients of retinoic acid in the chick embryo: Cyp26C1 expression and a comparative analysis of the Cyp26 enzymes. Dev Dyn. 2004;230:509–17. https://doi.org/10.1002/dvdy.20025.CrossRefPubMedGoogle Scholar
  171. 171.
    Ritz B, Wilhelm M. Ambient air pollution and adverse birth outcomes: methodologic issues in an emerging field. Basic Clin Pharmacol Toxicol. 2008;102:182–90. https://doi.org/10.1111/j.1742-7843.2007.00161.x.CrossRefPubMedPubMedCentralGoogle Scholar
  172. 172.
    Rivard CH. Effects of hypoxia on the embryogenesis of congenital vertebral malformations in the mouse. Clin Orthop Relat Res. 1986;(208):126–30.Google Scholar
  173. 173.
    Robkin MA. Carbon monoxide and the embryo. Int J Dev Biol. 1997;41:283–9.PubMedGoogle Scholar
  174. 174.
    Rogers JM, Brannen KC, Barbee BD, Zucker RM, Degitz SJ. Methanol exposure during gastrulation causes holoprosencephaly, facial dysgenesis, and cervical vertebral malformations in C57BL/6J mice. Birth Defects Res B Dev Reprod Toxicol. 2004;71:80–8. https://doi.org/10.1002/bdrb.20003.CrossRefPubMedGoogle Scholar
  175. 175.
    Rovasio RA, Battiato NL. Role of early migratory neural crest cells in developmental anomalies induced by ethanol. Int J Dev Biol. 1995;39(2):421–2.PubMedGoogle Scholar
  176. 176.
    Rubin WW, LaMantia AS. Age-dependent retinoic acid regulation of gene expression distinguishes the cervical, thoracic, lumbar, and sacral spinal cord regions during development. Dev Neurosci. 1999;21:113–25. https://doi.org/10.1159/000017373.CrossRefPubMedGoogle Scholar
  177. 177.
    Sadler TW, Horton WE Jr. Effects of maternal diabetes on early embryogenesis. The role of insulin and insulin therapy. Diabetes. 1983;32:1070–4.CrossRefPubMedGoogle Scholar
  178. 178.
    Sadler TW, Hunter ES 3rd, Balkan W, Horton WE Jr. Effects of maternal diabetes on embryogenesis. Am J Perinatol. 1988;5(4):319–26. https://doi.org/10.1055/s-2007-999717.CrossRefPubMedGoogle Scholar
  179. 179.
    Sadler TW, Hunter ES 3rd. Principles of abnormal development. In: Kimmel CA, Buelke-Sam J, editors. Developmental toxicology. 2nd ed. New York: Raven Press; 1994. p. 53–63.Google Scholar
  180. 180.
    Sadler TW, Hunter ES 3rd, Wynn RE, Phillips LS. Evidence for multifactorial origin of diabetes-induced embryopathies. Diabetes. 1989;38:70–4.CrossRefPubMedGoogle Scholar
  181. 181.
    Sanders EJ, Cheung E. Ethanol treatment induces a delayed segmentation anomaly in the chick embryo. Teratology. 1990;41:289–97. https://doi.org/10.1002/tera.1420410306.CrossRefPubMedGoogle Scholar
  182. 182.
    Sannadi S, Kadeyala PK, Gottipolu RR. Reversal effect of monoisoamyl dimercaptosuccinic acid (MiADMSA) for arsenic and lead induced perturbations in apoptosis and antioxidant enzymes in developing rat brain. Int J Dev Neurosci. 2013;31:586–97. https://doi.org/10.1016/j.ijdevneu.2013.07.003.CrossRefPubMedGoogle Scholar
  183. 183.
    Schardein JL. Chemically induced birth defects. 3rd ed. New York: Marcel Dekker; 2000.CrossRefGoogle Scholar
  184. 184.
    Schwartz ES, Rossi A. Congenital spine anomalies: the closed spinal dysraphisms. Pediatr Radiol. 2015;45(Suppl 3):S413–9. https://doi.org/10.1007/s00247-015-3425-6.CrossRefPubMedGoogle Scholar
  185. 185.
    Semenza GL. Perspectives on oxygen sensing. Cell. 1999;98:281–4.CrossRefPubMedGoogle Scholar
  186. 186.
    Senthinathan B, Sousa C, Tannahill D, Keynes R. The generation of vertebral segmental patterning in the chick. J Anat. 2012;220:591–602. https://doi.org/10.1111/j.1469-7580.2012.01497.x.CrossRefPubMedPubMedCentralGoogle Scholar
  187. 187.
    Sewell W, Kusumi K. Genetic analysis of molecular oscillators in mammalian somitogenesis: clues for studies of human vertebral disorders. Birth Defects Res C Embryo Today. 2007;81:111–20. https://doi.org/10.1002/bdrc.20091.CrossRefPubMedGoogle Scholar
  188. 188.
    Shalat SL, Walker DB, Finnell RH. Role of arsenic as a reproductive toxin with particular attention to neural tube defects. J Toxicol Environ Health. 1996;48(3):253–72. https://doi.org/10.1080/009841096161320.CrossRefPubMedGoogle Scholar
  189. 189.
    Shibley IA Jr, McIntyre TA, Pennington SN. Experimental models used to measure direct and indirect ethanol teratogenicity. Alcohol Alcohol. 1999;34(2):125–40.CrossRefPubMedGoogle Scholar
  190. 190.
    Shifley ET, Cole SE. The vertebrate segmentation clock and its role in skeletal birth defects. Birth Defects Res C Embryo Today. 2007;81:121–33. https://doi.org/10.1002/bdrc.20090.CrossRefPubMedGoogle Scholar
  191. 191.
    Singh J. Interaction of maternal protein and carbon monoxide on pup mortality in mice: implications for global infant mortality. Birth Defects Res B Dev Reprod Toxicol. 2006;77(3):216–26. https://doi.org/10.1002/bdrb.20077.CrossRefPubMedGoogle Scholar
  192. 192.
    Singh J, Aggison L Jr, Moore-Cheatum L. Teratogenicity and developmental toxicity of carbon monoxide in protein-deficient mice. Teratology. 1993;48:149–59. https://doi.org/10.1002/tera.1420480209.CrossRefPubMedGoogle Scholar
  193. 193.
    Singh S, Greene RM, Pisano MM. Arsenate-induced apoptosis in murine embryonic maxillary mesenchymal cells via mitochondrial-mediated oxidative injury. Birth Defects Res A Clin Mol Teratol. 2010;88:25–34. https://doi.org/10.1002/bdra.20623.CrossRefPubMedPubMedCentralGoogle Scholar
  194. 194.
    Solomon BD, Bear KA, Kimonis V, de Klein A, Scott DA, Shaw-Smith C, et al. Clinical geneticists’ views of VACTERL/VATER association. Am J Med Genet A. 2012;158A:3087–100. https://doi.org/10.1002/ajmg.a.35638.CrossRefPubMedPubMedCentralGoogle Scholar
  195. 195.
    Song G, Cui Y, Han ZJ, Xia HF, Ma X. Effects of choline on sodium arsenite-induced neural tube defects in chick embryos. Food Chem Toxicol. 2012;50:4364–74. https://doi.org/10.1016/j.fct.2012.08.023.CrossRefPubMedGoogle Scholar
  196. 196.
    Sparrow DB, Chapman G, Smith AJ, Mattar MZ, Major JA, O'Reilly VC, et al. A mechanism for gene-environment interaction in the etiology of congenital scoliosis. Cell. 2012;149:295–306. https://doi.org/10.1016/j.cell.2012.02.054.CrossRefPubMedPubMedCentralGoogle Scholar
  197. 197.
    Stewart FJ, Nevin NC, Brown S. Axial mesodermal dysplasia spectrum. Am J Med Genet. 1993;45:426–9. https://doi.org/10.1002/ajmg.1320450405.CrossRefPubMedGoogle Scholar
  198. 198.
    Stockdale FE, Nikovits W Jr, Christ B. Molecular and cellular biology of avian somite development. Dev Dyn. 2000;219(3):304–21. https://doi.org/10.1002/1097-0177(2000)9999:9999<::AID-DVDY1057>3.0.CO;2-5.CrossRefPubMedGoogle Scholar
  199. 199.
    Sulik KK. Pathogenesis of abnormal development. In: Hood RD, editor. Handbook of developmental toxicology. New York: CRC Press; 1997. p. 43–60.Google Scholar
  200. 200.
    Sulik KK. Genesis of alcohol-induced craniofacial dysmorphism. Exp Biol Med (Maywood). 2005;230:366–75.CrossRefGoogle Scholar
  201. 201.
    Sulik KK, Cook CS, Webster WS. Teratogens and craniofacial malformations: relationships to cell death. Development. 1988;103(Suppl):213–31.PubMedGoogle Scholar
  202. 202.
    Sulik KK, Johnston MC, Webb MA. Fetal alcohol syndrome: embryogenesis in a mouse model. Science. 1981;214:936–8.CrossRefPubMedGoogle Scholar
  203. 203.
    Swindell EC, Thaller C, Sockanathan S, Petkovich M, Jessell TM, Eichele G. Complementary domains of retinoic acid production and degradation in the early chick embryo. Dev Biol. 1999;216:282–96. https://doi.org/10.1006/dbio.1999.9487.CrossRefPubMedGoogle Scholar
  204. 204.
    Tam PP, Trainor PA. Specification and segmentation of the paraxial mesoderm. Anat Embryol (Berl). 1994;189:275–305.CrossRefGoogle Scholar
  205. 205.
    Takeuchi IK. Embryotoxicity of arsenic acid: light and electron microscopy of its effect on neurulation-stage rat embryo. J Toxicol Sci. 1979;4:405–16.CrossRefPubMedGoogle Scholar
  206. 206.
    Thackray H, Tifft C. Fetal alcohol syndrome. Pediatr Rev. 2001;22:47–55.CrossRefPubMedGoogle Scholar
  207. 207.
    Turner S, Sucheston ME, De Philip RM, Paulson RB. Teratogenic effects on the neuroepithelium of the CD-1 mouse embryo exposed in utero to sodium valproate. Teratology. 1990;41(4):421–42. https://doi.org/10.1002/tera.1420410408.CrossRefPubMedGoogle Scholar
  208. 208.
    Ujházy E, Mach M, Navarová J, Brucknerová I, Dubovický M. Teratology - past, present and future. Interdiscip Toxicol. 2012;5:163–8. https://doi.org/10.2478/v10102-012-0027-0.CrossRefPubMedPubMedCentralGoogle Scholar
  209. 209.
    Versiani BR, Gilbert-Barness E, Giuliani LR, Peres LC, Pina-Neto JM. Caudal dysplasia sequence: severe phenotype presenting in offspring of patients with gestational and pregestational diabetes. Clin Dysmorphol. 2004;13:1–5.CrossRefPubMedGoogle Scholar
  210. 210.
    Vorhees CV. Teratogenicity and developmental toxicity of valproic acid in rats. Teratology. 1987;35:195–202. https://doi.org/10.1002/tera.1420350205.CrossRefPubMedGoogle Scholar
  211. 211.
    Wallin J, Wilting J, Koseki H, Fritsch R, Christ B, Balling R. The role of Pax-1 in axial skeleton development. Development. 1994;120(5):1109–21.PubMedPubMedCentralGoogle Scholar
  212. 212.
    Walsh D, Grantham J, Zhu XO, Wei Lin J, van Oosterum M, Taylor R, Edwards M. The role of heat shock proteins in mammalian differentiation and development. Environ Med. 1999;43:79–87.PubMedGoogle Scholar
  213. 213.
    Wang L, Pinkerton KE. Air pollutant effects on fetal and early postnatal development. Birth Defects Res C Embryo Today. 2007;81(3):144–54. https://doi.org/10.1002/bdrc.20097.CrossRefPubMedGoogle Scholar
  214. 214.
    Ward L, Evans SE, Stern CD. A resegmentation-shift model for vertebral patterning. J Anat. 2017;230:290–6. https://doi.org/10.1111/joa.12540.CrossRefPubMedGoogle Scholar
  215. 215.
    Webster WS, Abela D. The effect of hypoxia in development. Birth Defects Res C Embryo Today. 2007;81:215–28. https://doi.org/10.1002/bdrc.20102.CrossRefPubMedGoogle Scholar
  216. 216.
    Wells PG, Winn LM. Biochemical toxicology of chemical teratogenesis. Crit Rev Biochem Mol Biol. 1996;31:1–40. https://doi.org/10.3109/10409239609110574.CrossRefPubMedGoogle Scholar
  217. 217.
    Willhite CC, Ferm VH. Prenatal and developmental toxicology of arsenicals. Adv Exp Med Biol. 1984;177:205–28.CrossRefPubMedGoogle Scholar
  218. 218.
    Wilson JG. Current status of teratology: general principles and mechanisms derived from animal studies. In: Wilson JG, Fraser CF, editors. Handbook of teratology. New York: Plenum Press; 1997. p. 47.Google Scholar
  219. 219.
    Winterbottom EF, Fei DL, Koestler DC, Giambelli C, Wika E, Capobianco AJ, et al. GLI3 links environmental arsenic exposure and human fetal growth. EBioMedicine. 2015;2:536–43. https://doi.org/10.1016/j.ebiom.2015.04.019.CrossRefPubMedPubMedCentralGoogle Scholar
  220. 220.
    Wlodarczyk BJ, Bennett GD, Calvin JA, Finnell RH. Arsenic-induced neural tube defects in mice: alterations in cell cycle gene expression. Reprod Toxicol. 1996;10:447–54.CrossRefPubMedGoogle Scholar
  221. 221.
    Yamaguchi Y, Miyazawa H, Miura M. Neural tube closure and embryonic metabolism. Congenit Anom (Kyoto). 2017;57:134–7. https://doi.org/10.1111/cga.12219.CrossRefGoogle Scholar
  222. 222.
    Yang P, Reece EA, Wang F, Gabbay-Benziv R. Decoding the oxidative stress hypothesis in diabetic embryopathy through proapoptotic kinase signaling. Am J Obstet Gynecol. 2015;212:569–79. https://doi.org/10.1016/j.ajog.2014.11.036.CrossRefPubMedGoogle Scholar
  223. 223.
    Yelin R, Kot H, Yelin D, Fainsod A. Early molecular effects of ethanol during vertebrate embryogenesis. Differentiation. 2007;75:393–403. https://doi.org/10.1111/j.1432-0436.2006.00147.x.CrossRefPubMedGoogle Scholar
  224. 224.
    Yon JM, Baek IJ, Lee SR, Jin Y, Kim MR, Nahm SS, et al. The spatio-temporal expression pattern of cytoplasmic Cu/Zn superoxide dismutase (SOD1) mRNA during mouse embryogenesis. J Mol Histol. 2008;39:95–103. https://doi.org/10.1007/s10735-007-9134-1.CrossRefPubMedGoogle Scholar
  225. 225.
    Zaken V, Kohen R, Ornoy A. The development of antioxidant defense mechanism in young rat embryos in vivo and in vitro. Early Pregnancy. 2000;4:110–23.PubMedGoogle Scholar
  226. 226.
    Zakeri ZF, Ahuja HS. Cell death/apoptosis: normal, chemically induced, and teratogenic effect. Mutat Res. 1997;396:149–61.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Peter G. Alexander
    • 1
  • Ricardo Londono
    • 1
  • Thomas P. Lozito
    • 1
  • Rocky S. Tuan
    • 1
  1. 1.Center for Cellular and Molecular Engineering, Department of Orthopaedic SurgeryUniversity of Pittsburgh School of MedicinePittsburghUSA

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