Increased uptake of dietary retinoids at the maternal-fetal barrier in the nitrofen model of congenital diaphragmatic hernia

Published:February 06, 2014DOI:



      The retinol signaling pathway is disrupted in congenital diaphragmatic hernia (CDH). Since there is no fetal retinol synthesis, maternal retinol has to cross the placenta. Nitrofen interferes with the retinol-binding protein (RBP) transfer pathway in CDH. However, in RBP knockout mice, retinol has been shown to be present. In this model, increased uptake of maternal dietary retinyl ester (RE) bounded in low-dense-lipoprotein (LDL) through low-density-lipoprotein-receptor 1 (LRP1) and increased activity of RE hydrolysis by lipoprotein-lipase (LPL) have been found. The aim of this study was to investigate the RE transfer pathway in the nitrofen CDH model.


      Pregnant rats were treated with nitrofen or vehicle on gestational day (D9) and sacrificed on D21. Immunohistochemistry was performed to evaluate LRP1 and LPL protein expression. Serum LDL levels were measured by ELISA. Pulmonary and serum retinoid levels were measured using HPLC.


      Markedly increased trophoblastic and pulmonary LRP1 and LPL immunoreactivity were observed in CDH compared to controls. Significantly increased serum LDL and RE levels were observed in CDH compared to controls.


      The increased uptake of dietary retinoids at the maternal-fetal barrier in the nitrofen CDH model suggests that the RE transfer pathway may be the main source of retinol in this model.

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        • Colvin J.
        • Bower C.
        • Dickinson J.E.
        • et al.
        Outcomes of congenital diaphragmatic hernia: a population-based study in Western Australia.
        Pediatrics. 2005; 116: e356-e363
        • Robinson P.D.
        • Fitzgerald D.A.
        Congenital diaphragmatic hernia.
        Paediatr Respir Rev. 2007; 8: 323-334
        • Montedonico S.
        • Nakazawa N.
        • Puri P.
        Congenital diaphragmatic hernia and retinoids: searching for an etiology.
        Pediatr Surg Int. 2008; 24: 755-761
        • Clagett-Dame M.
        • DeLuca H.F.
        The role of vitamin A in mammalian reproduction and embryonic development.
        Annu Rev Nutr. 2002; 22: 347-381
        • Beurskens L.W.
        • Tibboel D.
        • Lindemans J.
        • et al.
        Retinol status of newborn infants is associated with congenital diaphragmatic hernia.
        Pediatrics. 2010; 126: 712-720
        • Nakazawa N.
        • Montedonico S.
        • Takayasu H.
        • et al.
        Disturbance of retinol transportation causes nitrofen-induced hypoplastic lung.
        J Pediatr Surg. 2007; 42: 345-349
        • Quadro L.
        • Hamberger L.
        • Colantuoni V.
        • et al.
        Understanding the physiological role of retinol-binding protein in vitamin A metabolism using transgenic and knockout mouse models.
        Mol Aspects Med. 2003; 24: 421-430
        • Spiegler E.
        • Kim Y.K.
        • Wassef L.
        • et al.
        Maternal-fetal transfer and metabolism of vitamin A and its precursor beta-carotene in the developing tissues.
        Biochim Biophys Acta. 2012; 1821: 88-98
        • Wassef L.
        • Quadro L.
        Uptake of dietary retinoids at the maternal-fetal barrier: in vivo evidence for the role of lipoprotein lipase and alternative pathways.
        J Biol Chem. 2011; 286: 32198-32207
        • Quadro L.
        • Hamberger L.
        • Gottesman M.E.
        • et al.
        Transplacental delivery of retinoid: the role of retinol-binding protein and lipoprotein retinyl ester.
        Am J Physiol Endocrinol Metab. 2004; 286: E844-E851
        • Sapin V.
        • Ward S.J.
        • Bronner S.
        • et al.
        Differential expression of transcripts encoding retinoid binding proteins and retinoic acid receptors during placentation of the mouse.
        Dev Dyn. 1997; 208: 199-210
        • Kutasy B.
        • Gosemann J.H.
        • Doi T.
        • et al.
        Nitrofen interferes with trophoblastic expression of retinol-binding protein and transthyretin during lung morphogenesis in the nitrofen-induced congenital diaphragmatic hernia model.
        Pediatr Surg Int. 2012; 28: 143-148
        • Roebroek A.J.
        • Reekmans S.
        • Lauwers A.
        • et al.
        Mutant Lrp1 knock-in mice generated by recombinase-mediated cassette exchange reveal differential importance of the NPXY motifs in the intracellular domain of LRP1 for normal fetal development.
        Mol Cell Biol. 2006; 26: 605-616
        • Blaner W.S.
        • Obunike J.C.
        • Kurlandsky S.B.
        • et al.
        Lipoprotein lipase hydrolysis of retinyl ester. Possible implications for retinoid uptake by cells.
        J Biol Chem. 1994; 269: 16559-16565
        • Moulas A.N.Z.I.
        • Taitzoglou I.A.
        • Tsantarliotou M.P.
        • et al.
        Simultaneous determination of retinoic acid, retinol, and retinyl palmitate in ram plasma by liquid chromatography.
        J Liq Chromatogr. 2003; 26: 559-572
        • Quadro L.
        • Hamberger L.
        • Gottesman M.E.
        • et al.
        Pathways of vitamin A delivery to the embryo: insights from a new tunable model of embryonic vitamin A deficiency.
        Endocrinology. 2005; 146: 4479-4490
        • Wendler C.C.
        • Schmoldt A.
        • Flentke G.R.
        • et al.
        Increased fibronectin deposition in embryonic hearts of retinol-binding protein-null mice.
        Circ Res. 2003; 92: 920-928
        • Montedonico S.
        • Nakazawa N.
        • Puri P.
        Retinoic acid rescues lung hypoplasia in nitrofen-induced hypoplastic foetal rat lung explants.
        Pediatr Surg Int. 2006; 22: 2-8
        • Doi T.
        • Hajduk P.
        • Puri P.
        Upregulation of Slit-2 and Slit-3 gene expressions in the nitrofen-induced hypoplastic lung.
        J Pediatr Surg. 2009; 44: 2092-2095
        • Doi T.
        • Puri P.
        Up-regulation of Wnt5a gene expression in the nitrofen-induced hypoplastic lung.
        J Pediatr Surg. 2009; 44: 2302-2306
        • Kling D.E.
        • Cavicchio A.J.
        • Sollinger C.A.
        • et al.
        Nitrofen induces apoptosis independently of retinaldehyde dehydrogenase (RALDH) inhibition.
        Birth Defects Res B Dev Reprod Toxicol. 2010; 89: 223-232
        • Clugston R.D.
        • Zhang W.
        • Greer J.J.
        Early development of the primordial mammalian diaphragm and cellular mechanisms of nitrofen-induced congenital diaphragmatic hernia.
        Birth Defects Res A Clin Mol Teratol. 2010; 88: 15-24
        • Major D.
        • Cadenas M.
        • Fournier L.
        • et al.
        Retinol status of newborn infants with congenital diaphragmatic hernia.
        Pediatr Surg Int. 1998; 13: 547-549