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Pediatric Surgery International

Published in:

01-02-2012 | Original Article

Nitrofen interferes with trophoblastic expression of retinol-binding protein and transthyretin during lung morphogenesis in the nitrofen-induced congenital diaphragmatic hernia model

Authors: Balazs Kutasy, Jan H. Gosemann, Takashi Doi, Naho Fujiwara, Florian Friedmacher, Prem Puri

Published in: Pediatric Surgery International | Issue 2/2012

Abstract

Background

Retinoids play a key role in lung development. Retinoid signaling pathway has been shown to be disrupted in the nitrofen model of congenital diaphragmatic hernia (CDH) but the exact mechanism is not clearly understood. Retinol-binding protein (RBP) and transthyretin (TTR) are transport proteins for delivery of retinol to the tissues via circulation. Previous studies have shown that pulmonary retinol levels are decreased during lung morphogenesis in the nitrofen CDH model. In human newborns with CDH, both retinol and RBP levels are decreased. It has been reported that maternal RBP does not cross the placenta and the fetus produces its own RBP by trophoblast. RBP and TTR synthesized in the fetus are essential for retinol transport to the developing organs including lung morphogenesis. We hypothesized that nitrofen interferes with the trophoblastic expression of RBP and TTR during lung morphogenesis and designed this study to examine the trophoblastic expression of RBP and TTR, and the total level of RBP and TTR in the lung in the nitrofen model of CDH.

Methods

Pregnant rats were exposed to either olive oil or nitrofen on day 9 of gestation (D9). Fetal lungs and placenta harvested on D21 and divided into two groups: control (n = 8) and nitrofen with CDH (n = 8). Total lung RBP and TTR levels using protein extraction were compared with enzyme linked immunoassay (ELISA). Immunohistochemistry was performed to evaluate trophoblastic RBP and TTR expression.

Results

Total protein levels of lung RBP and TTR were significantly lower in CDH (0.26 ± 0.003 and 6.4 ± 0.5 μg/mL) compared with controls (0.4 ± 0.001 and 9.9 ± 1.6 μg/mL, p < 0.05). In the control group, immunohistochemical staining showed strong immunoreactivity of RBP and TTR in the trophoblast compared to CDH group.

Conclusions

Decreased trophoblast expression of retinol transport proteins suggest that nitrofen may interfere with the fetal retinol transport resulting in reduced pulmonary RBP and TTR levels and causing pulmonary hypoplasia in CDH.

Colvin J, Bower C, Dickinson JE et al (2005) Outcomes of congenital diaphragmatic hernia: a population-based study in Western Australia. Pediatrics 116:e356–e363PubMedCrossRef

Stege G, Fenton A, Jaffray B (2003) Nihilism in the 1990 s: the true mortality of congenital diaphragmatic hernia. Pediatrics 112:532–535PubMedCrossRef

Gosche JR, Islam S, Boulanger SC (2005) Congenital diaphragmatic hernia: searching for answers. Am J Surg 190:324–332PubMedCrossRef

Robinson PD, Fitzgerald DA (2007) Congenital diaphragmatic hernia. Paediatr Respir Rev 8:323–334 (quiz 334–325)PubMedCrossRef

Montedonico S, Nakazawa N, Puri P (2008) Congenital diaphragmatic hernia and retinoids: searching for an etiology. Pediatr Surg Int 24:755–761PubMedCrossRef

Noble BR, Babiuk RP, Clugston RD et al (2007) Mechanisms of action of the congenital diaphragmatic hernia-inducing teratogen nitrofen. Am J Physiol Lung Cell Mol Physiol 293:L1079–L1087PubMedCrossRef

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

Beurskens LW, Tibboel D, Lindemans J et al (2010) Retinol status of newborn infants is associated with congenital diaphragmatic hernia. Pediatrics 126:712–720PubMedCrossRef

Gallot D, Marceau G, Coste K et al (2005) Congenital diaphragmatic hernia: a retinoid-signaling pathway disruption during lung development? Birth Defects Res A Clin Mol Teratol 73:523–531PubMedCrossRef

10.

Nakazawa N, Montedonico S, Takayasu H et al (2007) Disturbance of retinol transportation causes nitrofen-induced hypoplastic lung. J Pediatr Surg 42:345–349PubMedCrossRef

11.

Ruttenstock E, Doi T, Dingemann J et al (2011) Prenatal administration of retinoic acid upregulates insulin-like growth factor receptors in the nitrofen-induced hypoplastic lung. Birth Defects Res B Dev Reprod Toxicol 92:148–151PubMedCrossRef

12.

Quadro L, Hamberger L, Gottesman ME et al (2005) Pathways of vitamin A delivery to the embryo: insights from a new tunable model of embryonic vitamin A deficiency. Endocrinology 146:4479–4490PubMedCrossRef

13.

Monaco HL, Rizzi M, Coda A (1995) Structure of a complex of two plasma proteins: transthyretin and retinol-binding protein. Science 268:1039–1041PubMedCrossRef

14.

Quadro L, Hamberger L, Colantuoni V et al (2003) Understanding the physiological role of retinol-binding protein in vitamin A metabolism using transgenic and knockout mouse models. Mol Aspects Med 24:421–430PubMedCrossRef

15.

Quadro L, Hamberger L, Gottesman ME et al (2004) Transplacental delivery of retinoid: the role of retinol-binding protein and lipoprotein retinyl ester. Am J Physiol Endocrinol Metab 286:E844–E851PubMedCrossRef

16.

Morriss-Kay GM, Ward SJ (1999) Retinoids and mammalian development. Int Rev Cytol 188:73–131PubMedCrossRef

17.

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

18.

Sapin V, Chaib S, Blanchon L et al (2000) Esterification of vitamin A by the human placenta involves villous mesenchymal fibroblasts. Pediatr Res 48:565–572PubMedCrossRef

19.

Quadro L, Blaner WS, Salchow DJ et al (1999) Impaired retinal function and vitamin A availability in mice lacking retinol-binding protein. EMBO J 18:4633–4644PubMedCrossRef

20.

Episkopou V, Maeda S, Nishiguchi S et al (1993) Disruption of the transthyretin gene results in mice with depressed levels of plasma retinol and thyroid hormone. Proc Natl Acad Sci USA 90:2375–2379PubMedCrossRef

21.

Wei S, Episkopou V, Piantedosi R et al (1995) Studies on the metabolism of retinol and retinol-binding protein in transthyretin-deficient mice produced by homologous recombination. J Biol Chem 270:866–870PubMedCrossRef

22.

Kling DE, Cavicchio AJ, Sollinger CA et al (2010) Nitrofen induces apoptosis independently of retinaldehyde dehydrogenase (RALDH) inhibition. Birth Defects Res B Dev Reprod Toxicol 89:223–232PubMed

23.

Quadro L, Blaner WS, Hamberger L et al (2004) The role of extrahepatic retinol binding protein in the mobilization of retinoid stores. J Lipid Res 45:1975–1982PubMedCrossRef

24.

van Bennekum AM, Wei S, Gamble MV et al (2001) Biochemical basis for depressed serum retinol levels in transthyretin-deficient mice. J Biol Chem 276:1107–1113PubMedCrossRef

25.

Montedonico S, Nakazawa N, Puri P (2006) Retinoic acid rescues lung hypoplasia in nitrofen-induced hypoplastic foetal rat lung explants. Pediatr Surg Int 22:2–8PubMedCrossRef

26.

Guilbert TW, Gebb SA, Shannon JM (2000) Lung hypoplasia in the nitrofen model of congenital diaphragmatic hernia occurs early in development. Am J Physiol Lung Cell Mol Physiol 279:L1159–L1171PubMed

27.

Jay PY, Bielinska M, Erlich JM et al (2007) Impaired mesenchymal cell function in Gata4 mutant mice leads to diaphragmatic hernias and primary lung defects. Dev Biol 301:602–614PubMedCrossRef

28.

Doi T, Hajduk P, Puri P (2009) Upregulation of Slit-2 and Slit-3 gene expressions in the nitrofen-induced hypoplastic lung. J Pediatr Surg 44:2092–2095PubMedCrossRef

29.

Doi T, Puri P (2009) Up-regulation of Wnt5a gene expression in the nitrofen-induced hypoplastic lung. J Pediatr Surg 44:2302–2306PubMedCrossRef

30.

Tong QS, Zheng LD, Tang ST et al (2007) Nitrofen suppresses cell proliferation and promotes mitochondria-mediated apoptosis in type II pneumocytes. Acta Pharmacol Sin 28:672–684PubMedCrossRef

31.

Clugston RD, Zhang W, Greer JJ (2010) Early development of the primordial mammalian diaphragm and cellular mechanisms of nitrofen-induced congenital diaphragmatic hernia. Birth Defects Res A Clin Mol Teratol 88:15–24PubMed

Title: Nitrofen interferes with trophoblastic expression of retinol-binding protein and transthyretin during lung morphogenesis in the nitrofen-induced congenital diaphragmatic hernia model
Authors: Balazs Kutasy
Jan H. Gosemann
Takashi Doi
Naho Fujiwara
Florian Friedmacher
Prem Puri
Publication date: 01-02-2012
Publisher: Springer-Verlag
Published in: Pediatric Surgery International / Issue 2/2012
Print ISSN: 0179-0358
Electronic ISSN: 1437-9813
DOI: https://doi.org/10.1007/s00383-011-2995-0

At a glance: The STEP trials

Springer Medicine

Nitrofen interferes with trophoblastic expression of retinol-binding protein and transthyretin during lung morphogenesis in the nitrofen-induced congenital diaphragmatic hernia model

Abstract

Background

Methods

Results

Conclusions

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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