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Nuclear retinoid receptors and pregnancy: placental transfer, functions, and pharmacological aspects

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Abstract

Animal models of vitamin A (retinol) deficiency have highlighted its crucial role in reproduction and placentation, whereas an excess of retinoids (structurally or functionally related entities) can cause toxic and teratogenic effects in the embryo and foetus, especially in the first trimester of human pregnancy. Knock-out experimental strategies-targeting retinoid nuclear receptors RARs and RXRs have confirmed that the effects of vitamin A are mediated by retinoic acid (especially all-trans retinoic acid) and that this vitamin is essential for the developmental process. All these data show that the vitamin A pathway and metabolism are as important for the well-being of the foetus, as they are for that of the adult. Accordingly, during this last decade, extensive research on retinoid metabolism has yielded detailed knowledge on all the actors in this pathway, spurring the development of antagonists and agonists for therapeutic and research applications. Natural and synthetic retinoids are currently used in clinical practice, most often on the skin for the treatment of acne, and as anti-oncogenic agents in acute promyelocytic leukaemia. However, because of the toxicity and teratogenicity of retinoids during pregnancy, their pharmacological use needs a sound knowledge of their metabolism, molecular aspects, placental transfer, and action.

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References

  1. Hale F (1933) Pigs born without eyeballs. J Heredity 24:105

    Google Scholar 

  2. Deligdish L (1992) Pathology of the placenta. In: Pasqualini JRT, Scholler R (eds) Hormone and fetal pathophysiology. Marcel Dekker Inc., New York, pp 203–249

    Google Scholar 

  3. Rinkenberger JL, Cross JC, Werb Z (1997) Molecular genetics of implantation in the mouse. Dev Genet 21:6–20

    Article  CAS  PubMed  Google Scholar 

  4. Kaufmann P, Burton G (1994) Anatomy and genesis of the placenta. In: Knobil E, Neill JD (eds) The physiology of reproduction, 2nd edn. Raven Press Ltd, New York, pp 441–484

    Google Scholar 

  5. Enders AC, Blankenship TN (2012) Interstitial trophoblast cells: an enigmatic and variable component of the developing macaque placenta. Placenta 9:672–676

    Article  CAS  Google Scholar 

  6. Enders AC, Carter AM (2012) The evolving placenta: convergent evolution of variations in the endotheliochorial relationship. Placenta 5:319–326

    Article  Google Scholar 

  7. Carter AM, Croy BA, Dantzer V, Enders AC, Hayakawa S, Mess A, Soma H (2007) Comparative aspects of placental evolution: a workshop report. Placenta, pp 129–132

  8. Bauer MK, Harding JE, Bassett NS, Breier BH, Oliver MH, Gallaher BH, Evans PC, Woodall SM, Gluckman PD (1998) Fetal growth and placental function. Mol Cell Endocrinol 140:115–120

    Article  CAS  PubMed  Google Scholar 

  9. Gude NM, Roberts CT, Kalionis B, King RG (2004) Growth and function of the normal human placenta. Thromb Res 114:397–407

    Article  CAS  PubMed  Google Scholar 

  10. Zeldovich VB, Clausen CH, Bradford E, Fletcher DA, Maltepe E, Robbins JR, Bakardjiev AI (2013) Placental syncytium forms a biophysical barrier against pathogen invasion. PLoS Pathog 9:12

    Article  CAS  Google Scholar 

  11. Caserta D, Graziano A, Monte GL, Bordi G, Moscarini M (2013) Heavy metals and placental fetal-maternal barrier: a mini-review on the major concerns. Eur Rev Med Pharmacol Sci 17:2198–2206

    CAS  PubMed  Google Scholar 

  12. Evain-Brion D, Malassine A (2003) Human placenta as an endocrine organ. Growth Horm IGF Res 13:34–37

    Article  CAS  Google Scholar 

  13. Edmonds DK, Lindsay KS, Miller JF, Williamson E, Wood PJ (1982) Early embryonic mortality in women. Fertil Steril 4:447–453

    Article  Google Scholar 

  14. Zinaman MJ, Clegg ED, Brown CC, O’Connor J, Selevan SG (1996) Estimates of human fertility and pregnancy loss. Fertil Steril 3:503–509

    Article  Google Scholar 

  15. Sapin V, Blanchon L, Serre AF, Lémery D, Dastugue B, Ward SW (2001) Use of transgenic mice model for understanding the placentation: towards clinical applications in human obstetrical pathologies? Transgenic Res 10:377–398

    Article  CAS  PubMed  Google Scholar 

  16. Hollenberg SM, Weinberger C, Ong ES, Cerelli G, Oro A, Lebo R, Thompson EB, Rosenfeld MG, Evans RM (1985) Primary structure and expression of a functional human glucocorticoid receptor cDNA. Nature 318:635–641

    Article  CAS  PubMed  Google Scholar 

  17. Green S, Walter P, Kumar V, Krust A, Bornert JM, Argos P, Chambon P (1986) Human oestrogen receptor cDNA: sequence, expression and homology to v-erb-A. Nature 320:134–139

    Article  CAS  PubMed  Google Scholar 

  18. Khan SH, Arnott JA, Kumar R (2011) Naturally occurring osmolyte, trehalose induces functional conformation in an intrinsically disordered activation domain of glucocorticoid receptor. PLoS One 6:e19689

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Bastien J, Rochette-Egly C (2004) Nuclear retinoid receptors and the transcription of retinoid-target genes. Gene 328:1–16

    Article  CAS  PubMed  Google Scholar 

  20. Zechel C, Shen XQ, Chambon P, Gronemeyer H (1994) Dimerization interfaces formed between the DNA binding domains determine the cooperative binding of RXR/RAR and RXR/TR heterodimers to DR5 and DR4 elements. EMBO J 13:1414–1424

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Beato M (1991) Transcriptional control by nuclear receptors. FASEB J 5:2044–2051

    CAS  PubMed  Google Scholar 

  22. Rastinejad F, Perlmann T, Evans RM, Sigler PB (1995) Structural determinants of nuclear receptor assembly on DNA direct repeats. Nature 375:203–211

    Article  CAS  PubMed  Google Scholar 

  23. Koenig RJ, Brent GA, Warne RL, Larsen PR, Moore DD (1987) Thyroid hormone receptor binds to a site in the rat growth hormone promoter required for induction by thyroid hormone. Proc Natl Acad Sci 84:5670–5674

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Umesono K, Murakami KK, Thompson CC, Evans RM (1991) Direct repeats as selective response elements for the thyroid hormone, retinoic acid, and vitamin D3 receptors. Cell 65:1255–1266

    Article  CAS  PubMed  Google Scholar 

  25. Sladek R, Bader JA, Giguère V (1997) The orphan nuclear receptor estrogen-related receptor alpha is a transcriptional regulator of the human medium-chain acyl coenzyme A dehydrogenase gene. Mol Cell Biol 17:5400–5409

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Klaholz BP, Renaud JP, Mitschler A, Zusi C, Chambon P, Gronemeyer H, Moras D (1998) Conformational adaptation of agonists to the human nuclear receptor RAR gamma. Nat Struct Biol 5:199–202

    Article  CAS  PubMed  Google Scholar 

  27. Lavery DN, McEwan IJ (2005) Structure and function of steroid receptor AF1 transactivation domains: induction of active conformations. Biochem J 391:449–464

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Verhoeven G, Willems A, Denolet E, Swinnen JV, DeGendt K (2010) Androgens and spermatogenesis: lessons from transgenic mouse models. Philos Trans R Soc Lond B Biol Sci 365:1537–1556

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Borel V, Gallot D, Marceau G, Sapin V, Blanchon L (2008) Placental implications of peroxisome proliferator-activated receptors in gestation and parturition. PPAR Res 2008:758562

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Serpente P, Tümpel S, Ghyselinck NB, Niederreither K, Wiedemann LM, Dollé P, Chambon P, Krumlauf R, Gould AP (2005) Direct crossregulation between retinoic acid receptor beta and Hox genes during hindbrain segmentation. Development 132:503–513

    Article  CAS  PubMed  Google Scholar 

  31. Luo J, Sladek R, Bader JA, Matthyssen A, Rossant J, Giguère V (1997) Placental abnormalities in mouse embryos lacking the orphan nuclear receptor ERR-beta. Nature 388:778–782

    Article  CAS  PubMed  Google Scholar 

  32. Schaiff WT, Barak Y, Sadovsky Y (2006) The pleiotropic function of PPAR gamma in the placenta. Mol Cell Endocrinol 249(1–2):10–15

    Article  CAS  PubMed  Google Scholar 

  33. Barak Y, Sadovsky Y, Shalom-Barak T (2008) PPAR signaling in placental development and function. PPAR Res 2008:142082

    Article  PubMed  CAS  Google Scholar 

  34. Murthi P, Kalionis B, Cocquebert M, Rajaraman G, Chui A, Keogh RJ, Evain-Brion D, Fournier T (2013) Homeobox genes and down-stream transcription factor PPARγ in normal and pathological human placental development. Placenta 34(4):299–309

    Article  CAS  PubMed  Google Scholar 

  35. Ding NZ, Teng CB, Ma H, Ni H, Ma XH, Xu LB, Yang ZM (2003) Peroxisome proliferator-activated receptor delta expression and regulation in mouse uterus during embryo implantation and decidualization. Mol Reprod Dev 66:218–224

    Article  CAS  PubMed  Google Scholar 

  36. Tarrade A, Schoonjans K, Pavan L, Auwerx J, Rochette-Egly C, Evain-Brion D, Fournier T (2001) PPARgamma/RXRalpha heterodimers control human trophoblast invasion. J Clin Endocrinol Metab 86:5017–5024

    CAS  PubMed  Google Scholar 

  37. Fournier T, Handschuh K, Tsatsaris V, Evain-Brion D (2007) Involvement of PPARgamma in human trophoblast invasion. Placenta 28 Suppl A:S76–S81

    Article  CAS  PubMed  Google Scholar 

  38. Barak Y, Nelson MC, Ong ES, Jones YZ, Ruiz-Lozano P, Chien KR, Koder A, Evans RM (1999) PPAR gamma is required for placental, cardiac, and adipose tissue development. Mol Cell 4:585–595

    Article  CAS  PubMed  Google Scholar 

  39. Kubota N, Terauchi Y, Miki H, Tamemoto H, Yamauchi T, Komeda K, Satoh S, Nakano R, Ishii C, Sugiyama T, Eto K, Tsubamoto Y, Okuno A, Murakami K, Sekihara H, Hasegawa G, Naito M, Toyoshima Y, Tanaka S, Shiota K, Kitamura T, Fujita T, Ezaki O, Aizawa S, Kadowaki T et al (1999) PPAR gamma mediates high-fat diet-induced adipocyte hypertrophy and insulin resistance. Mol Cell 4(4):597–609

    Article  CAS  PubMed  Google Scholar 

  40. Nadra K, Quignodon L, Sardella C, Joye E, Mucciolo A, Chrast R, Desvergne B (2010) PPARgamma in placental angiogenesis. Endocrinology 151(10):4969–4981

    Article  CAS  PubMed  Google Scholar 

  41. Holdsworth-Carson SJ, Lim R, Mitton A, Whitehead C, Rice GE, Permezel M, Lappas M (2010) Peroxisome proliferator-activated receptors are altered in pathologies of the human placenta: gestational diabetes mellitus, intrauterine growth restriction and preeclampsia. Placenta 31:222–229

    Article  CAS  PubMed  Google Scholar 

  42. Waite LL, Louie RE, Taylor RN (2005) Circulating activators of peroxisome proliferator-activated receptors are reduced in preeclamptic pregnancy. J Clin Endocrinol Metab 90(2):620–626

    Article  CAS  PubMed  Google Scholar 

  43. Rodie VA, Young A, Jordan F, Sattar N, Greer IA, Freeman DJ (2005) Human placental peroxisome proliferator-activated receptor delta and gamma expression in healthy pregnancy and in preeclampsia and intrauterine growth restriction. J Soc Gynecol Investig 12(5):320–329

    Article  CAS  PubMed  Google Scholar 

  44. Weedon-Fekjær MS, Johnsen GM, Anthonisen EH, Sugulle M, Nebb HI, Duttaroy AK, Staff AC (2010) Expression of liver X receptors in pregnancies complicated by preeclampsia. Placenta 31:818–824

    Article  PubMed  CAS  Google Scholar 

  45. Pavan L, Hermouet A, Tsatsaris V, Thérond P, Sawamura T, Evain-Brion D, Fournier T (2004) Lipids from oxidized low-density lipoprotein modulate human trophoblast invasion: involvement of nuclear liver X receptors. Endocrinology 145(10):4583–4591

    Article  CAS  PubMed  Google Scholar 

  46. Petkovich M, Brand NJ, Krust A, Chambon P (1987) Human retinoic acid receptor which belongs to the family of nuclear receptors. Nature 330(6147):444–450

    Article  CAS  PubMed  Google Scholar 

  47. Giguere V, Ong ES, Segui P, Evans RM (1987) Identification of a receptor for the morphogen retinoic acid. Nature 330(6149):624–629

    Article  CAS  PubMed  Google Scholar 

  48. Brand N, Petkovich M, Krust A, Chambon P, de Thé H, Marchio A, Tiollais P, Dejean A (1988) Identification of a second human retinoic acid receptor. Nature 332(6167):850–853

    Article  CAS  PubMed  Google Scholar 

  49. Benbrook D, Lernhardt E, Pfahl M (1988) A new retinoic acid receptor identified from a hepatocellular carcinoma. Nature 333(6174):669–672

    Article  CAS  PubMed  Google Scholar 

  50. Zelent A, Krust A, Petkovich M, Kastner P, Chambon P (1989) Cloning of murine alpha and beta retinoic acid receptors and a novel receptor gamma predominantly expressed in skin. Nature 339(6227):714–717

    Article  CAS  PubMed  Google Scholar 

  51. Krust A, Kastner P, Petkovich M, Zelent A, Chambon P (1989) A third human retinoic acid receptor, hRAR-gamma. Proc Natl Acad Sci 86(14):5310–5314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Mangelsdorf DJ, Ong ES, Dyck JA, Evans RM (1990) Nuclear receptor that identifies a novel retinoic acid response pathway. Nature 345(6272):224–229

    Article  CAS  PubMed  Google Scholar 

  53. Chambon P (1996) A decade of molecular biology of retinoic acid receptors. FASEB J 10(9):940–954

    CAS  PubMed  Google Scholar 

  54. Lufkin T, Lohnes D, Mark M, Dierich A, Gorry P, Gaub M-P, LeMeur M, Chambon P (1993) High postnatal lethality and testis degeneration in retinoic acid receptor alpha mutant mice. Proc Natl Acad Sci 90:7225–7229

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Dollé P (2009) Developmental expression of retinoic acid receptors (RARs). Nucl Recept Signal 7:e006

    PubMed  PubMed Central  Google Scholar 

  56. Berry DC, Noy N (2009) All-trans-retinoic acid represses obesity and insulin resistance by activating both peroxisome proliferation-activated receptor/and retinoic acid receptor. Mol Cell Biol 29:3286–3296

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Mangelsdorf DJ, Evans RM (1995) The RXR heterodimers and orphan receptors. Cell 83(6):841–850

    Article  CAS  PubMed  Google Scholar 

  58. Leid M, Kastner P, Chambon P (1992) Multiplicity generates diversity in the retinoic acid signalling pathways. Trends Biochem Sci 17(10):427–433

    Article  CAS  PubMed  Google Scholar 

  59. Lalevee S, Anno YN, Chatagnon A, Samarut E, Poch O, Laudet V, Benoit G, Lecompte O, Rochette-Egly C (2011) Genome-wide in silico identification of new conserved and functional retinoic acid receptor response elements (direct repeats separated by 5 bp). J Biol Chem 286:33322–33334

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Clagett-Dame M, DeLuca HF (2002) The role of vitamin A in mammalian reproduction and embryonic development. Annu Rev Nutr 22:347–381

    Article  CAS  PubMed  Google Scholar 

  61. McCollum EV, Davis M (1913) The necessity of certain lipids in the diet during growth. J Biol Chem 15:167–175

    CAS  Google Scholar 

  62. Blomhoff R, Blomhoff HK (2006) Overview of retinoid metabolism and function. J Neurobiol 66:606–630

    Article  CAS  PubMed  Google Scholar 

  63. Venkatachalam PS, Belavady B, Gopalan C (1962) Studies on vitamin A nutritional status of mothers and infants in poor communities of India. J Pediatr 61:262–268

    Article  CAS  PubMed  Google Scholar 

  64. Wilson JG, Roth CB, Warkany J (1953) An analysis of the syndrome of malformations induced by maternal vitamin A deficiency. Effects of restoration of vitamin A at various times during gestation. Am J Anat 92:189–217

    Article  CAS  PubMed  Google Scholar 

  65. Mason KE (1935) Fetal death, prolonged gestation, and difficult parturition in the rat as a result of vitamin A-deficiency. Am J Anat 57:303–349

    Article  CAS  Google Scholar 

  66. Sommer A, Tarwotjo I, Djunaedi E, West KP Jr, Loeden AA, Tilden R, Mele L (1986) Impact of vitamin A supplementation on childhood mortality. A randomised controlled community trial. Lancet 1:1169–1173

    Article  CAS  PubMed  Google Scholar 

  67. Ross SA, McCaffery PJ, Drager UC, De Luca LM (2000) Retinoids in embryonal development. Physiol Rev 80:1021–1054

    CAS  PubMed  Google Scholar 

  68. Cohlan SQ (1953) Excessive intake of vitamin A as a cause of congenital anomalies in the rat. Science 117:535–536

    Article  CAS  PubMed  Google Scholar 

  69. Durston AJ, Timmermans JP, Hage WJ, Hendriks HF, de Vries NJ, Heideveld M, Nieuwkoop PD (1989) Retinoic acid causes an anteroposterior transformation in the developing central nervous system. Nature 340(6229):140–144

    Article  CAS  PubMed  Google Scholar 

  70. Avantaggiato V, Acampora D, Tuorto F, Simeone A (1996) Retinoic acid induces stage-specific repatterning of the rostral central nervous system. Dev Biol 175(2):347–357

    Article  CAS  PubMed  Google Scholar 

  71. D’Ambrosio DN, Clugston RD, Blaner WS (2011) Vitamin A metabolism: an update. Nutrients 3:63–103

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Kawaguchi R, Yu J, Honda J, Hu J, Whitelegge J, Ping P, Wiita P, Bok D, Sun H (2007) A membrane receptor for retinol binding protein mediates cellular uptake of vitamin A. Science 315:820–825

    Article  CAS  PubMed  Google Scholar 

  73. Parés X, Farrés J, Kedishvili N, Duester G (2008) Medium- and short-chain dehydrogenase/reductase gene and protein families: medium-chain and short-chain dehydrogenases/reductases in retinoid metabolism. Cell Mol Life Sci 65:3936–3949

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Niederreither K, Subbarayan V, Dollé P, Chambon P (1999) Embryonic retinoic acid synthesis is essential for early mouse post-implantation development. Nat Genet 21:444–448

    Article  CAS  PubMed  Google Scholar 

  75. Chithalen JV, Luu L, Petkovich M, Jones G (2002) HPLC-MS/MS analysis of the products generated from all-trans-retinoic acid using recombinant human CYP26A. J Lipid Res 43:1133–1142

    Article  CAS  PubMed  Google Scholar 

  76. Reijntjes S, Blentic A, Gale E, Maden M (2005) The control of morphogen signalling: regulation of the synthesis and catabolism of retinoic acid in the developing embryo. Dev Biol 285:224–237

    Article  CAS  PubMed  Google Scholar 

  77. Wu L, Ross AC (2010) Acidic retinoids synergize with vitamin A to enhance retinol uptake and STRA6, LRAT, and CYP26B1 expression in neonatal lung. J Lipid Res 51:378–387

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Bouillet P, Sapin V, Chazaud C, Messaddeq N, Décimo D, Dollé P, Chambon P (1997) Developmental expression pattern of Stra6, a retinoic acid-responsive gene encoding a new type of membrane protein. Mech Dev 63:173–186

    Article  CAS  PubMed  Google Scholar 

  79. Kastner P, Mark M, Chambon P (1995) Nonsteroid nuclear receptors: what are genetic studies telling us about their role in real life? Cell 83:859–869

    Article  CAS  PubMed  Google Scholar 

  80. Mark M, Chambon P (2003) Functions of RARs and RXRs in vivo: genetic dissection of the retinoid signaling pathway. Pure Appl Chem 75:1709–1732

    Article  CAS  Google Scholar 

  81. Mark M, Ghyselinck N, Chambon P (2009) Function of retinoic acid receptors during embryonic development. J Nucl Recept Signal Atlas 7:e002. doi:10.1621/nrs.07002

    Google Scholar 

  82. Germain P, Chambon P, Eichele G, Evans RM, Lazar MA, Leid M, De Lera AR, Lotan R, Mangelsdorf DJ, Gronemeyer H (2006) International Union of Pharmacology. LX. Retinoic acid receptors. Pharmacol Rev 58:712–725

    Article  CAS  PubMed  Google Scholar 

  83. Lohnes D, Mark M, Mendelsohn C, Dolle P, Dierich A, Gorry P, Gansmuller A, Chambon P (1994) Function of the retinoic acid receptors (RARs) during development (I). Craniofacial and skeletal abnormalities in RAR double mutants. Development 120:2723–2748

    CAS  PubMed  Google Scholar 

  84. Luo J, Sucov HM, Bader JA, Evans RM, Giguère V (1996) Compound mutants for retinoic acid receptor (RAR) beta and RAR alpha 1 reveal developmental functions for multiple RAR beta isoforms. Mech Dev 55:33–44

    Article  CAS  PubMed  Google Scholar 

  85. Kastner P, Grondona JM, Mark M, Gansmuller A, LeMeur M, Decimo D, Vonesch JL, Dolle P, Chambon P (1994) Genetic analysis of RXR α developmental function: convergence of RXR and RAR signaling pathways in heart and eye morphogenesis. Cell 78:987–1003

    Article  CAS  PubMed  Google Scholar 

  86. Conlon RA (1995) Retinoic acid and pattern formation in vertebrates. Trends Genet 11:314–319

    Article  CAS  PubMed  Google Scholar 

  87. Sapin V, Ward SJ, Bronner S, Chambon P, Dollé P (1997) Differential expression of transcripts encoding retinoid binding proteins and retinoic acid receptors during placentation of the mouse. Dev Dyn 208:199–210

    Article  CAS  PubMed  Google Scholar 

  88. Sapin V, Bouillet P, Oulad-Abdelghani M, Dastugue B, Chambon P, Dollé P (2000) Differential expression of retinoic acid-inducible (Stra) genes during mouse placentation. Mech Dev 92:295–299

    Article  CAS  PubMed  Google Scholar 

  89. McC Howell, Thompson N, Pitt G (1964) Histology of the lesions produced in the reproductive tract of animals fed a diet deficient in vitamin A alcohol but containing vitamin A acid. J Reprod Fertil 7:251–258

    Article  Google Scholar 

  90. Wendling O, Chambon P, Mark M (1999) RXRs are essential for early mouse development and placentogenesis. Proc Natl Acad Sci 96:547–551

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Sapin V, Dollé P, Hindelang C, Kastner P, Chambon P (1997) Defects of the chorioallantoic placenta in mouse RXRalpha null fetuses. Dev Biol 191:29–41

    Article  CAS  PubMed  Google Scholar 

  92. Datta K, Kulkarni AP (1996) Co-oxidation of all-trans retinol acetate by human term placental lipoxygenase and soybean lipoxygenase. Reprod Toxicol 10:105–112

    Article  CAS  PubMed  Google Scholar 

  93. Sapin V, Chaïb S, Blanchon L, Alexandre-Gouabau MC, Lémery D, Charbonne F, Gallot D, Jacquetin B, Dastugue B, Azais-Braesco V (2000) Esterification of vitamin A by the human placenta involves villous mesenchymal fibroblasts. Pediatr Res 48(4):565–572

    Article  CAS  PubMed  Google Scholar 

  94. Stephanou A, Handwerger S (1995) Retinoic acid and thyroid hormone regulate placental lactogen expression in human trophoblast cells. Endocrinology 136(3):933–938

    CAS  PubMed  Google Scholar 

  95. Stephanou A, Handwerger S (1995) Identification of a composite steroid hormone response element on the human placental lactogen promoter. Mol Cell Endocrinol 112(1):123–129

    Article  CAS  PubMed  Google Scholar 

  96. Guibourdenche J, Alsat E, Soncin F, Rochette-Egly C, Evain-Brion D (1998) Retinoid receptors expression in human term placenta: involvement of RXR alpha in retinoid induced-hCG secretion. J Clin Endocrinol Metab 4:1384–1387

    Google Scholar 

  97. Roulier S, Rochette-Egly C, Rebut-Bonneton C, Porquet D, Evain-Brion D (1994) Nuclear retinoic acid receptor characterization in cultured human trophoblast cells: effect of retinoic acid on epidermal growth factor receptor expression. Mol Cell Endocrinol 2:165–173

    Article  Google Scholar 

  98. Vu-Dac N, Schoonjans K, Kosykh V, Dallongeville J, Heyman RA, Staels B, Auwerx J (1996) Retinoids increase human apolipoprotein A-11 expression through activation of the retinoid X receptor but not the retinoic acid receptor. Mol Cell Biol 7:3350–3360

    Article  Google Scholar 

  99. Kogai T, Liu YY, Richter LL, Mody K, Kagechika H, Brent GA (2010) Retinoic acid induces expression of the thyroid hormone transporter, monocarboxylate transporter 8 (Mct8). J Biol Chem 35:27279–27288

    Article  CAS  Google Scholar 

  100. Hollung K, Rise CP, Drevon CA, Reseland JE (2004) Tissue-specific regulation of leptin expression and secretion by all-trans retinoic acid. J Cell Biochem 92(2):307–315

    Article  CAS  PubMed  Google Scholar 

  101. Holdsworth-Carson SJ, Permezel M, Riley C, Rice GE, Lappas M (2009) Peroxisome proliferator-activated receptors and retinoid X receptor-alpha in term human gestational tissues: tissue specific and labour-associated changes. Placenta 30(2):176–186

    Article  CAS  PubMed  Google Scholar 

  102. Wang Y, Lin Q, Wang X, Lu P, Sheng Z, Ding C, Hong Y, Li W (2002) Expression of lethal gene mRNA on placenta villi in patients with spontaneous abortion. Zhonghua Fu Chan Ke Za Zhi 37(9):542–545

    PubMed  Google Scholar 

  103. Holdsworth-Carson SJ, Permezel M, Rice GE, Lappas M (2009) Preterm and infection-driven preterm labor: the role of peroxisome proliferator-activated receptors and retinoid X receptor. Reproduction 137(6):1007–1015

    Article  CAS  PubMed  Google Scholar 

  104. Nakanishi T, Nishikawa J, Hiromori Y, Yokoyama H, Koyanagi M, Takasuga S, Ishizaki J, Watanabe M, Isa S, Utoguchi N, Itoh N, Kohno Y, Nishihara T, Tanaka K (2005) Trialkyltin compounds bind retinoid X receptor to alter human placental endocrine functions. Mol Endocrinol 19(10):2502–2516

    Article  CAS  PubMed  Google Scholar 

  105. Marceau G, Gallot D, Borel V, Lémery D, Dastugue B, Dechelotte P, Sapin V (2006) Molecular and metabolic retinoid pathways in human amniotic membranes. Biochem Biophys Res Commun. 346(4):1207–1216

    Article  CAS  PubMed  Google Scholar 

  106. Borel V, Marceau G, Gallot D, Blanchon L, Sapin V (2010) Retinoids regulate human amniotic tissue-type plasminogen activator gene by a two-step mechanism. J Cell Mol Med 6B:1793–1805

    Google Scholar 

  107. Chen Y, Reese D (2013) A screen for disruptors of the retinol (vitamin A) signaling pathway. Birth Defects Res B 98:276–282

    Article  CAS  Google Scholar 

  108. Dawson MI, Xia Z (2012) The retinoid X receptors and their ligands. Biochim Biophys Acta (BBA) Mol Cell Biol Lipids 1821:21–56

    Article  CAS  Google Scholar 

  109. Thacher SM, Vasudevan J, Chandraratna RA (2000) Therapeutic applications for ligands of retinoid receptors. Curr Pharm Des 6(1):25–58

    Article  CAS  PubMed  Google Scholar 

  110. Germain P, Kammerer S, Pérez E, Peluso-Iltis C, Tortolani D, Zusi FC, Starrett J, Lapointe P, Daris JP, Marinier A (2004) Rational design of RAR-selective ligands revealed by RARβ crystal stucture. EMBO Rep 5:877–882

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Bourguet W, Germain P, Gronemeyer H (2000) Nuclear receptor ligand-binding domains: three-dimensional structures, molecular interactions and pharmacological implications. Trends Pharmacol Sci 21:381–388

    Article  CAS  PubMed  Google Scholar 

  112. Dilworth FJ, Chambon P (2001) Nuclear receptors coordinate the activities of chromatin remodeling complexes and coactivators to facilitate initiation of transcription. Oncogene 20:3047–3054

    Article  CAS  PubMed  Google Scholar 

  113. Renaud JP, Rochel N, Ruff M, Vivat V, Chambon P, Gronemeyer H, Moras D (1995) Crystal structure of RAR-gamma ligand-binding domain bound to all-trans retinoic acid. Nature 378(6558):681–689

    Article  CAS  PubMed  Google Scholar 

  114. de Lera AR, Bourguet W, Altucci L, Gronemeyer H (2007) Design of selective nuclear receptor modulators: RAR and RXR as a case study. Nat Rev Drug Discov 6(10):811–820

    Article  PubMed  CAS  Google Scholar 

  115. Maire A, Alvarez S, Shankaranarayanan P, Lera AR, Bourguet W, Gronemeyer H (2012) Retinoid receptors and therapeutic applications of RAR/RXR modulators. Curr Top Med Chem 12(6):505–527

    Article  PubMed  Google Scholar 

  116. Germain P, Gaudon C, Pogenberg V, Sanglier S, Van Dorsselaer A, Royer CA, Lazar MA, Bourguet W, Gronemeyer H (2009) Differential action on coregulator interaction defines inverse retinoid agonists and neutral antagonists. Chem Biol 16(5):479–489

    Article  CAS  PubMed  Google Scholar 

  117. Elias PM (1987) Retinoid effects on the epidermis. Dermatologica 1:28–36

    Article  Google Scholar 

  118. Gottlieb S, Hayes E, Gilleaudeau P, Cardinale I, Gottlieb AB, Krueger JG (1996) Cellular actions of etretinate in psoriasis enhanced epidermal differentiation and reduced cell -mediated inflammation are unexpected outcomes. J Cutan Pathol 23(5):404–418

    Article  CAS  PubMed  Google Scholar 

  119. Gisondi P, Del Giglio M, Cotena C, Girolomoni G (2008) Combining etanercept and acitretin in the therapy of chronic plaque psoriasis: a 24-week, randomized, controlled, investigator-blinded pilot trial. Br J Dermatol 158(6):1345–1349

    Article  CAS  PubMed  Google Scholar 

  120. Lee CS, Li K (2009) A review of acitretin for the treatment of psoriasis. Expert Opin Drug Saf 8(6):769–779

    Article  CAS  PubMed  Google Scholar 

  121. Mérot Y, Camenzind M, Geiger JM, Saurat JH (1987) Arotinoid ethyl ester (Ro 13-6298): a long term pilot study in various dermatoses. Acta Derm Venereol 67(3):237–242

    PubMed  Google Scholar 

  122. Altucci L, Gronemeyer H (2001) The promise of retinoids to fight against cancer. Nat Rev Cancer 1(3):181–193

    Article  CAS  PubMed  Google Scholar 

  123. Widschwendter M, Berger J, Müller HM, Zeimet AG, Marth C (2001) Epigenetic downregulation of the retinoic acid receptor-beta2 gene in breast cancer. J Mammary Gland Biol Neoplasia 6(2):193–201

    Article  CAS  PubMed  Google Scholar 

  124. Xu XC, Ro JY, Lee JS, Shin DM, Hong WK, Lotan R (1994) Differential expression of nuclear retinoid receptors in normal, premalignant, and malignant head and neck tissues. Cancer Res 54(13):3580–3587

    CAS  PubMed  Google Scholar 

  125. Lotan R, Xu XC, Lippman SM, Ro JY, Lee JS, Lee JJ, Hong WK (1995) Suppression of retinoic acid receptor-beta in premalignant oral lesions and its up-regulation by isotretinoin. N Engl J Med 332(21):1405–1410

    Article  CAS  PubMed  Google Scholar 

  126. Ablain J, de Thé H (2014) Retinoic acid signaling in cancer: the parable of acute promyelocytic leukemia. Int J Cancer 135(10):2262–2272

    Article  CAS  PubMed  Google Scholar 

  127. Shalita AR, Armstrong RB, Leyden JJ, Pochi PE, Strauss JS (1988) Isotretinoin revisited. Cutis 42(6A):1–19

    CAS  PubMed  Google Scholar 

  128. Perry MD, McEvoy GK (1983) Isotretinoin: new therapy for severe acne. Clin Pharmacol 2(1):12–19

    CAS  Google Scholar 

  129. Brogden RN, Goa KE (1997) Adapalene: a review of its pharmacological properties and clinical potential in the management of mild to moderate acne. Drugs 53(3):511–519

    Article  CAS  PubMed  Google Scholar 

  130. Ismadi SD, Olson JA (1982) Dynamics of the fetal distribution and transfer of vitamin A between rat fetuses and their mother. Int J Vitam Nutr Res 52(2):112–119

    CAS  PubMed  Google Scholar 

  131. Donoghue S, Richardson DW, Sklan D, Kronfeld DS (1982) Placental transport of retinol in sheep. J Nutr 112(11):2197–2203

    CAS  PubMed  Google Scholar 

  132. Shukla RR, Kumar V, Banerjee R, Misra UK (1986) Placental transfer and fetal distribution of 3H-retinoic acid in rats. Int J Vitam Nutr Res 56(1):29–33

    CAS  PubMed  Google Scholar 

  133. Wassef L, Quadro L (2011) Uptake of dietary retinoids at the maternal–fetal barrier: in vivo evidence for the role of lipoprotein lipase and alternative pathways. J Biol Chem 286(37):32198–32207

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Marceau G, Gallot D, Lemery D, Sapin V (2007) Metabolism of retinol during mammalian placental and embryonic development. Vitam Horm 75:97–115

    Article  CAS  PubMed  Google Scholar 

  135. Ortega-Senovilla H, Alvino G, Taricco E, Cetin I, Herrera E (2009) Enhanced circulating retinol and non-esterified fatty acids in pregnancies complicated with intrauterine growth restriction. Clin Sci (Lond) 118(5):351–358

    Article  CAS  Google Scholar 

  136. Kutasy B, Pes L, Friedmacher F, Paradisi F, Puri P (2014) Nitrofen increases total retinol levels in placenta during lung morphogenesis in the nitrofen model of congenital diaphragmatic hernia. Pediatr Surg Int 30(10):1017–1022

    Article  PubMed  Google Scholar 

  137. Sulik KK, Dehart DB, Rogers JM, Chernoff N (1995) Teratogenicity of low doses of all-trans retinoic acid in presomite mouse embryos. Teratology 51(6):398–403

    Article  CAS  PubMed  Google Scholar 

  138. Creech Kraft J, Kochhar DM, Scott WJ Jr, Nau H (1987) Low Teratogenicity of 13-cis-retinoic acid (isotretinoin) in the mouse corresponds to low embryo concentrations during organogenesis: comparison to the all-trans isomer. Toxicol Appl Pharmacol 87:474–482

    Article  Google Scholar 

  139. Nau H (2001) Teratogenicity of isotretinoin revisited: species variation and the role of all-trans-retinoic acid. J Am Acad Dermatol 45(5):S183–S187

    Article  CAS  PubMed  Google Scholar 

  140. Tsukada M, Schröder M, Roos TC, Chandraratna RA, Reichert U, Merk HF, Orfanos CE, Zouboulis CC (2000) 13-cis retinoic acid exerts its specific activity on human sebocytes through selective intracellular isomerization to all-trans retinoic acid and binding to retinoid acid receptors. J Invest Dermatol 115(2):321–327

    Article  CAS  PubMed  Google Scholar 

  141. Blaner WS (2001) Cellular metabolism and actions of 13-cis-retinoic acid. J Am Acad Dermatol 45(5):S129–S135

    Article  CAS  PubMed  Google Scholar 

  142. Kochhar DM, Jiang H, Penner JD, Heyman RA (1995) Placental transfer and developmental effects of 9-cis retinoic acid in mice. Teratology 51(4):257–265

    Article  CAS  PubMed  Google Scholar 

  143. Collins MD, Tzimas G, Bürgin H, Hummler H, Nau H (1995) Single versus multiple dose administration of all-trans-retinoic acid during organogenesis: differential metabolism and transplacental kinetics in rat and rabbit. Toxicol Appl Pharmacol 130(1):9–18

    Article  CAS  PubMed  Google Scholar 

  144. Sass JO, Hartmann J, Chahoud I, Shroot B, Nau H (1995) Transplacental pharmacokinetics of a synthetic retinoid which is not bound by mouse embryonic cellular retinoic acid-binding protein. Toxicol Lett 75(1–3):159–168

    Article  CAS  PubMed  Google Scholar 

  145. Willhite CC, Lovey A, Eckhoff C (2000) Distribution, teratogenicity, and embryonic delivered dose of retinoid Ro 23-9223. Toxicol Appl Pharmacol 164(2):171–175

    Article  CAS  PubMed  Google Scholar 

  146. Crettaz M, Baron A, Siegenthaler G, Hunziker W (1990) Ligand specificities of recombinant retinoic acid receptors RAR alpha and RAR beta. Biochem J 272(2):391–397

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Kochhar DM, Penner JD (1992) Analysis of high dysmorphogenic activity of Ro 13-6307, a tetramethylated tetralin analog of retinoic acid. Teratology 45(6):637–645

    Article  CAS  PubMed  Google Scholar 

  148. Loeliger P, Bollag W, Mayer H (1980) Arotinoids, a new class of highly active retinoids. Eur J Med Chem 15:9–15

    CAS  Google Scholar 

  149. Arafa HM, Elmazar MM, Hamada FM, Reichert U, Shroot B, Nau H (2000) Selective agonists of retinoic acid receptors: comparative toxicokinetics and embryonic exposure. Arch Toxicol 73(10–11):547–556

    Article  CAS  PubMed  Google Scholar 

  150. Brown NA, Fabro S (1983) The value of animal teratogenicity testing for predicting human risk. Clin Obstet Gynecol 26(2):467–477

    Article  CAS  PubMed  Google Scholar 

  151. Schardein JL, Schwetz BA, Kenel MF (1985) Species sensitivities and prediction of teratogenic potential. Environ Health Perspect 61:55–67

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Buresh JJ, Urban TJ (1970) Palatal abnormalities induced by cortisone and corticosterone in the rat. J Acad Gen Dent 18(2):34–37

    CAS  PubMed  Google Scholar 

  153. Buttar HS, Dupuis I, Khera KS (1976) Fetotoxicity of trimethadione and paramethadione in rats. Toxicol Appl Pharmacol 37:126

    Google Scholar 

  154. Schwetz BA, Smith FA, Staples RE (1978) Teratogenic potential of ethanol in mice, rats and rabbits. Teratology 18:385–392

    Article  CAS  PubMed  Google Scholar 

  155. Neubert D, Merker HJ, Nau H and Langman J (1978) Role of pharmacokinetics in prenatal and perinatal toxicology: third symposium on prenatal development, Berlin, pp 499–506

  156. Centers for Disease Control (1984) Isotretinoin—a newly recognized human teratogen. Morb Mortal Wkly Rep 33:171–173

    Google Scholar 

  157. Loureiro KD, Kao KK, Jones KL, Alvarado S, Chavez C, Dick L, Felix R, Johnson D, Chambers CD (2005) Minor malformations characteristic of the retinoic acid embryopathy and other birth outcomes in children of women exposed to topical tretinoin during early pregnancy. Am J Med Genet A 136(2):117–121

    Article  PubMed  Google Scholar 

  158. Pugashetti R, Shinkai K (2013) Treatment of acne vulgaris in pregnant woman. Dermatol Ther 26(4):302–311

    Article  PubMed  Google Scholar 

  159. Nulman I, Berkovitch M, Klein J, Pastuszak A, Lester RS, Shear N, Koren G (1998) Steady-state pharmacokinetics of isotretinoin and its 4-oxo metabolite: implications for fetal safety. J Clin Pharmacol 38(10):926–930

    Article  CAS  PubMed  Google Scholar 

  160. Yang D, Hladnik L (2009) Treatment of acute promyelocytic leukemia during pregnancy. Pharmacotherapy 29(6):709–724

    Article  PubMed  Google Scholar 

  161. Sanz MA, Grimwade D, Tallman MS, Lowenberg B, Fenaux P, Estey EH, Naoe T, Lengfelder E, Büchner T, Döhner H, Burnett AK, Lo-Coco F (2009) Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 113(9):1875–1891

    Article  CAS  PubMed  Google Scholar 

  162. Culligan DJ, Merriman L, Kell J, Parker J, Jovanovic JV, Smith N, Grimwade D (2007) The management of acute promyelocytic leucemia presenting during pregnancy. Clin Leukemia 1:183–191

    Article  CAS  Google Scholar 

  163. Crowe DL, Chandraratna RA (2004) A retinoid X receptor (RXR)-selective retinoid reveals that RXR-alpha is potentially a therapeutic target in breast cancer cell lines, and that it potentiates antiproliferative and apoptotic responses to peroxisome proliferator-activated receptor ligands. Breast Cancer Res 6(5):R546–R555

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Cramer PE, Cirrito JR, Wesson DW, Lee CY, Karlo JC, Zinn AE, Casali BT, Restivo JL, Goebel WD, James MJ, Brunden KR, Wilson DA, Landreth GE (2012) ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models. Science 335(6075):1503–1506

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Shulman AI, Mangelsdorf DJ (2005) Retinoid X receptor heterodimers in the metabolic syndrome. N Engl J Med 353:604–615

    Article  CAS  PubMed  Google Scholar 

  166. Lowe MN, Plosker GL (2000) Bexarotene. Am J Clin Dermatol 1:245–250 (discussion 251–252)

    Article  CAS  PubMed  Google Scholar 

  167. Sherman SI, Gopal J, Haugen BR, Chiu AC, Whaley K, Nowlakha P, Duvic M (1999) Central hypothyroidism associated with retinoid X receptor-selective ligands. N Engl J Med 340(14):1075–1079

    Article  CAS  PubMed  Google Scholar 

  168. Zhang C, Duvic M (2003) Retinoids: therapeutic applications and mechanisms of action in cutaneous T-cell lymphoma. Dermatol Ther 16:322–330

    Article  PubMed  Google Scholar 

  169. Michellys PY, Ardecky RJ, Chen JH, Crombie DL, Etgen GJ, Faul MM, Faulkner AL, Grese TA, Heyman RA, Karanewsky DS, Klausing K, Leibowitz MD, Liu S, Mais DA, Mapes CM, Marschke KB, Reifel-Miller A, Ogilvie KM, Rungta D, Thompson AW, Tyhonas JS, Boehm MF (2003) Novel (2E,4E,6Z)-7-(2-alkoxy-3,5-dialkylbenzene)-3-methylocta-2,4,6-trienoic acid retinoid X receptor modulators are active in models of type 2 diabetes. J Med Chem 46(13):2683–2696

    Article  CAS  PubMed  Google Scholar 

  170. Michellys PY, Ardecky RJ, Chen JH, D’Arrigo J, Grese TA, Karanewsky DS, Leibowitz MD, Liu S, Mais DA, Mapes CM, Montrose-Rafizadeh C, Ogilvie KM, Reifel-Miller A, Rungta D, Thompson AW, Tyhonas JS, Boehm MF (2003) Design, synthesis, and structure-activity relationship studies of novel 6,7-locked-[7-(2-alkoxy-3,5-dialkylbenzene)-3-methylocta]-2,4,6-trienoic acids. J Med Chem 46(19):4087–4103

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

A. C. was supported by a THEA laboratories grant. M. R. was supported by a thesis grant from the French Ministry of Education and Research (MENRT).

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    Authors and Affiliations

    1. EA7281, Retinoids, Reproduction Developmental Diseases, School of Medicine, Clermont Université, Université d’Auvergne, 63000, Clermont-Ferrand, France

      Aurélie Comptour, Marion Rouzaire, Corinne Belville, Damien Bouvier, Denis Gallot, Loïc Blanchon & Vincent Sapin

    2. GReD, Clermont Université, Université d’Auvergne, 63000, Clermont-Ferrand, France

      Corinne Belville

    3. Biochemistry and Molecular Biology Department, CHU Clermont-Ferrand, 63000, Clermont-Ferrand, France

      Damien Bouvier & Vincent Sapin

    4. Obstetrics and Gynecology Department, CHU Clermont-Ferrand, 63000, Clermont-Ferrand, France

      Denis Gallot

    5. Laboratoire de Biochimie Médicale, 4R3, Faculté de Médecine, 28 Place Henri-Dunant, BP38, 63001, Clermont-Ferrand Cedex, France

      Vincent Sapin

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    1. Aurélie Comptour
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    A. Comptour and M. Rouzaire contributed equally to this work.

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    Comptour, A., Rouzaire, M., Belville, C. et al. Nuclear retinoid receptors and pregnancy: placental transfer, functions, and pharmacological aspects. Cell. Mol. Life Sci. 73, 3823–3837 (2016). https://doi.org/10.1007/s00018-016-2332-9

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