Abstract
Diabetes is known to be associated with delayed lung development in humans and in experimental animals. This includes delayed expression of surfactant apoproteins. An important component of the metabolic abnormalities in diabetes is elevated levels of analogs of butyric acid, and the effects of diabetes on surfactant apoproteins can be reproduced by exposure of fetal rat lung explants to butyrate. Dexamethasone has the opposite effects on lung development. In humans, antenatal exposure to dexamethasone results in a lower incidence of RDS, whereas in experimental animals, dexamethasone increases the expression of surfactant apoproteins. A subset of Hox genes are expressed in developing lung, and their level of expression decreases with advancing gestation. We hypothesized that:1) lungs of fetuses of rats with streptozotocin-induced diabetes would have altered levels of expression of Hox genes,2) the effect would be mediated in part through elevated levels of butyrate, and 3) dexamethasone would reverse the effect. We tested our hypotheses in vivo using fetuses from streptozotocin-treated rats and in vitro by treating lung explants from normal rats with sodium butyrate. Streptozotocin treatment increased expression of Hoxb-5 at 18 d of gestation, but did not affect Hoxa-5 expression. This was associated with a 20-fold increase inĪ±-aminobutyrate levels. Dexamethasone tended to reverse this effect. In contrast, butyrate treatment of explants decreased the expression of Hoxa-5 and Hoxb-5. We conclude that diabetes alters expression of Hox genes, but that the effect of butyrate on lung development, and in particular on surfactant apoprotein expression, in independent of its effects on Hox genes.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Abbreviations
- STZ :
-
streptozotocin
- SP :
-
surfactant protein
References
Cardoso W 1995 Transcription factors and pattern formation in the developing lung. Am J Physiol 269: L429āL442.
Chisaka O, Capecchi MR 1991 Regionally restricted developmental defects resulting from targeted disruption of the mouse homeobox gene Hox-1.5. Nature 350: 473ā479.
Bogue CW, Gross I, Vasavada H, Dynia DW, Wilson CM, Jacobs HC 1994 Identification of Hox genes in newborn lung and the effects of gestational age and retinoic acid on their expression. Am J Physiol 266: L448āL454.
Bogue CW, Lou LL, Vasavada H, Wilson CM, Jacobs HC 1996 Expression of Hoxb genes in the developing mouse foregut and lung. Am J Respir Cell Mol Biol 15: 163ā171.
Gaunt SJ, Krumlauf R, Duboule D 1989 Mouse homeo-genes within a subfamily, Hox-1.4, -2.6 and -5.1, display similar anteroposterior domains of expression in the embryo, but show stage- and tissue-dependent differences in their regulation. Development 107: 131ā141.
Holland PWH, Hogan B, LM 1988 Spatially restricted patterns of expression of the homeobox-containing gene Hox 2.1 during mouse embryogenesis. Development 102: 159ā174.
Krumlauf R, Holland PWH, McVey JH, Hogan BLM 1987 Developmental and spatial patterns of expression of the mouse homeobox gene,Hox 2.1. Development 99: 603ā617.
McGinnis W, Krumlauf R 1992 Homeobox genes and axial patterning. Cell 68: 283ā302.
McGinnis W, Garber RL, Wirz J, Kuroiwa A, Gehring WJ 1984 A homologous protein-coding sequence in Drosophila homeotic genes and its conservation in other metazoans. Cell 37: 403ā408.
Krumlauf R 1994 Hox genes in vertebrate development. Cell 78: 191ā201.
Mortlock DP, Innis JW 1997 Mutation ofHOXA13 in hand-foot-genital syndrome. Nat Genet 15: 179ā180.
Morgan BA, Izpisua-Belmonte J-C, Duboule D, Tabin C 1992 Targeted misexpression of Hox-4.6 in the avian limb bud causes apparent homeotic transformations. Nature 358: 236ā239.
Kondo T, Dolle P, Zakany J, Duboule D 1996 Function of posterior HoxD genes in the morphogenesis of the anal sphincter. Development 122: 2651ā2659.
Hsieh-Li HM, Witte DP, Weinstein M, Branford W, Li H, Small K, Potter SS 1995 Hoxa 11 structure, extensive antisense transcription, and function in male and female fertility. Development 121: 1373ā1385.
Benson GV, Lim H, Paria BC, Satokata I, Dey SK, Maas RL 1996 Mechanisms of reduced fertility in Hoxa-10 mutant mice: uterine homeosis and loss of maternal Hoxa-10 expression. Development 122: 2687ā2696.
Robert MF, Neff RK, Hubbell JP, Taeusch HW, Avery ME 1976 Association between maternal diabetes and the respiratory-distress syndrome in the newborn. N Engl J Med 294: 357ā360.
James DK, Chiswick ML, Harkes A, Williams M, Tindall VR 1984 Maternal diabetes and neonatal respiratory distress. I. Maturation of fetal surfactant. Br J Obstet Gynaecol 91: 316ā324.
Bourbon JR, Farrell PM 1985 Fetal lung development in the diabetic pregnancy. Pediatr Res 19: 253ā267.
Bourbon JR, Pignol B, Marin L, Rieutort M, Tordet C 1985 Maturation of fetal rat lung in diabetic pregnancies of graduated severity. Diabetes 34: 734ā743.
Gewolb IH, Rooney SA, Barrett C, Ingleson LD, Light D, Wilson CM, Walker Smith GJ, Gross I, Warshaw JB 1985 Delayed pulmonary maturation in the fetus of the streptozotocin-diabetic rat. Exp Lung Res 8: 141ā151.
Boehme DS, Roberts CM, Bessman SP 1990 High-performance liquid chromatographic analysis of lung phospholipids and their precursors in the offspring of diabetic rats. Biochem Med Metab Biol 44: 29ā36.
Perrine SP, Miller BA, Greene MF, Cohen RA, Cook N, Shackleton C, Faller DV 1987 Butryic acid analogues augment -globin gene expression in neonatal erythroid progenitors. Biochem Biophys Res Commun 148: 694ā700.
Glauber JG, Wandersee NJ, Little JA, Ginder GD 1991 5-Flanking sequences mediate butyrate stimulation of embryonic globin gene expression in adult erythroid cells. Mol Cell Biol 11: 4690ā4697.
Pace BS, Li Q, Samatoyannopoulos G 1996 In vivo search for butyrate responsive sequences using transgenic mice carrying A gene promoter mutants. Blood 88: 1079ā1083.
Nakano K, Mizuno T, Sowa Y, Orita T, Yoshino T, Okuyama Y, Fujita T, Ohtani-Fujita N, Matsukawa Y, Tokino T, Yamagishi H, Oka T, Nomura H, Sakai T 1997 Butyrate activates the WAF-1/Cip1 gene promoter through Sp1 sites in a p53-negative human colon cancer cell line. J Biol Chem 272: 22199ā22206.
Peterec SM, Nichols KV, Dynia DW, Wilson CM, Gross I 1994 Butyrate modulates surfactant protein mRNA in fetal rat lung by altering mRNA transcription and stability. Am J Physiol 267: L9āL15.
Phelps DS, Giannopoulos G 1984 Effect of dexamethasone on the synthesis of specific proteins in fetal rabbit lung in vivo and in organ culture. Exp Lung Res 7: 195ā210.
Nichols KV, Floros J, Dynia DW, Veletza SV, Wilson CM, Gross I 1990 Regulation of surfactant protein A mRNA by hormones and butyrate in cultured fetal rat lung. Am J Physiol 259: L488ā495.
Floros J, Phelps DS, Harding HP, Church S, Ware J 1989 Postnatal stimulation of rat surfactant protein A synthesis by dexamethasone. Am J Physiol 257: L137āL143.
Phelps DS, Floros J 1991 Dexamethasone in vivo raises surfactant protein B mRNA in alveolar and bronchiolar epithelium. Am J Physiol 260: L146āL152.
Schellhase DE, Shannon JM 1991 Effects of maternal dexamethasone on expression of SP-A, SP-B, and SP-C in the fetal rat lung. Am J Respir Cell Mol Biol 4: 304ā312.
Phelps DS, S. C, Kourembanas S, Taeusch HW 1987 Increases in the 35 kDa surfactant-associated protein and its mRNA following in vivo dexamethasone treatment of fetal and neonatal rats. Electrophoresis 8: 235ā238.
Rayani HH, Warshaw JB, Floros J 1995 Dexamethasone enhances surfactant protein gene expression in streptozotocin-induced immature rat lungs. Pediatr Res 38: 870ā877.
Beato M, Sanchez-Pacheco A 1996 Interaction of steroid hormone receptors with the transcription initiation complex. Endocr Rev 17: 587ā609.
Slocum RH, Cummings JG 1991 Amino Acid Analysis of Physiologic Samples. In: Hommes FA (eds) Techniques in Diagnostic Human Biochemical GeneticsāA Laboratory Manual. Wiley-Liss, New York, 87ā126.
Gross I, Wilson CM, Floros J, Dynia DW 1989 Initiation of fetal rat lung phospholipid and surfactant-associated protein A mRNA synthesis. Pediatr Res 25: 239ā244.
Gross I, Wilson CM 1983 Fetal rat lung maturation: initiation and modulation. J Appl Physiol 55: 1725ā1732.
Chomczynski P, Sacchi N 1987 Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 162: 156ā159.
Moglia BB, Phelps DS 1996 Changes in surfactant protein A mRNA levels in a rat model of insulin-treated diabetic pregnancy. Pediatr Res 39: 241ā247.
Duboule D, Dolle P 1989 The structural and functional organization of the murine HOX gene family resembles that ofDrosophila homeotic genes. EMBO J 8: 1497ā1505.
Graham A, Papalopulu N, Krumlauf R 1989 The murine and Drosophila homeobox gene complexes have common features of organization and expression. Cell 57: 367ā378.
Roberts DJ, Johnson RL, Burke AC, Nelson CE, Morgan BR, Tabin C 1995 Sonic hedgehog is an endodermal signal inducingBmp-4 and Hox genes during induction and regionalization of the chick hindgut. Development 121: 3163ā3174.
Nelson CE, Morgan BA, Burke AC, Laufer E, DiMambro E, Murtaugh LC, Gonzales E, Tessarollo L, Parada LF, Tabin C 1996 Analysis ofHox gene expression in the chick limb bud. Development 122: 1449ā1466.
Dolle P, Izpisua-Belmonte J-C, Brown JM, Tickle C, Duboule D 1991 Hox-4 genes and the morphogenesis of mammalian genetalia. Genes Dev 5: 1767ā1776.
Perrine SP, Greene MF, Faller DV 1985 Delay in the fetal globin switch in infants of diabetic mothers. N Engl J Med 312: 334ā338.
Perrine SP, Rudolph A, Faller DV, Roman C, Cohen RA, Chen SJ, Kan YW 1988 Butyrate infusions in the ovine fetus delay the biologic clock for globin gene switching. Proc Natl Acad Sci USA 85: 8540ā8542.
Acknowledgements
The authors thank Piero Rinaldo for help with measurements of Ī±-aminobutyrate levels, Joanna Floros for providing Northern blots, and Chris Snow and Hema Vasavada for technical assistance.
Author information
Authors and Affiliations
Additional information
Supported in part by the Charles H. Hood Foundation (C.W.B.), the Parker B. Francis Fellowship Program (C.W.B.), and the National Heart Lung and Blood Institute Specialized Center of Research Grant P50-HL-46488 (H.C.J., J.W.B., I.G.).
Rights and permissions
About this article
Cite this article
Jacobs, H., Bogue, C., Pinter, E. et al. Fetal Lung mRNA Levels of Hox Genes Are Differentially Altered by Maternal Diabetes and Butyrate in Rats. Pediatr Res 44, 99ā104 (1998). https://doi.org/10.1203/00006450-199807000-00016
Received:
Accepted:
Issue date:
DOI: https://doi.org/10.1203/00006450-199807000-00016
This article is cited by
-
Caudal Regression Syndrome in Twin Pregnancy With Type II Diabetes
Journal of Perinatology (2002)
