Hostname: page-component-78c5997874-lj6df Total loading time: 0 Render date: 2024-11-10T12:10:20.113Z Has data issue: false hasContentIssue false

Reduced apoptosis in term placentas from gestational diabetic pregnancies

Published online by Cambridge University Press:  27 March 2013

L. Belkacemi*
Affiliation:
Department of Obstetrics and Gynecology, Perinatal Research Laboratories, David Geffen School of Medicine, University of California, Los Angeles, California, USA Los Angeles Biomedical Research Institute, Harbor-UCLA, Torrance, California, USA
S. Kjos
Affiliation:
Department of Obstetrics and Gynecology, Perinatal Research Laboratories, David Geffen School of Medicine, University of California, Los Angeles, California, USA
D. M. Nelson
Affiliation:
Department of Obstetrics and Gynecology, Washington University, School of Medicine, St. Louis, Missouri, USA
M. Desai
Affiliation:
Department of Obstetrics and Gynecology, Perinatal Research Laboratories, David Geffen School of Medicine, University of California, Los Angeles, California, USA Los Angeles Biomedical Research Institute, Harbor-UCLA, Torrance, California, USA
M. G. Ross
Affiliation:
Department of Obstetrics and Gynecology, Perinatal Research Laboratories, David Geffen School of Medicine, University of California, Los Angeles, California, USA Los Angeles Biomedical Research Institute, Harbor-UCLA, Torrance, California, USA
*
*Address for correspondence: Dr Louiza Belkacemi, London Health Sciences Center, 339 Windermere Road, London, Ontario, Canada N6A 5A5. (Email lbelkace@uwo.ca)

Abstract

Gestational diabetic mellitus (GDM) pregnancies have an increased risk of macrosomic infants and large placental mass, though the mechanisms explaining each of these is uncertain. We sought to evaluate the contribution of apoptosis to placental size and the expression of glucose transporters (SLC2A) in GDM pregnancies. Maternal age and pre-pregnancy body weight were documented. Newborn weights were recorded after delivery. Placentas 37–40-week gestation from control patients (no pregnancy complication) (n = 5), or with GDM (n = 5) were weighed immediately after delivery. Villous samples (4 mm diameter) were collected and divided into specimens; one was fixed in 4% paraformaldehyde for immunostaining using terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling (TUNEL) and activated caspase-3. The other specimen was snap frozen in liquid nitrogen and stored at −80°C for active caspase-3, poly(ADP-ribose) polymerase (PARP), SLC2A1 and SLC2A3 gene expression analysis. Our results showed that maternal age and pre-pregnancy body weight were significantly higher in the GDM group when compared with those from the controls (P < 0.05). The mean neonatal birth weight and placenta weight were significantly higher in the GDM group compared with that from the controls (P < 0.05). The apoptotic index of placentas (0.05 ± 0.01 v. 0.17 ± 0.04, P < 0.04), active caspase-3 polypeptide fragments and PARP protein were significantly decreased in GDM placentas as compared with controls. Further, the level of placental SLC2A1 protein expression was ∼3-fold higher in GDM placentas. Our results suggest that reduced apoptosis in GDM placentas may contribute to increased placental tissue, which together with enhanced SLC2A1 expression, could play a role in fetal macrosomia.

Type
Original Article
Copyright
Copyright © Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2013 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

1.Catalano, PM, Huston, L, Amini, SB, Kalhan, SC. Longitudinal changes in glucose metabolism during pregnancy in obese women with normal glucose tolerance and gestational diabetes mellitus. Am J Obstet Gynecol. 1999; 180, 903916.Google Scholar
2.Crowther, CA, Hiller, JE, Moss, JR, McPhee, AJ, Jeffries, WS, Robinson, JS. Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. N Engl J Med. 2005; 352, 24772486.CrossRefGoogle ScholarPubMed
3.Kjos, SL, Buchanan, TA. Gestational diabetes mellitus. N Engl J Med. 1999; 341, 17491756.Google Scholar
4.Reece, EA, Leguizamon, G, Wiznitzer, A. Gestational diabetes: the need for a common ground. Lancet. 2009; 373, 17891797.Google Scholar
5.Barker, DJ. Adult consequences of fetal growth restriction. Clin Obstet Gynecol. 2006; 49, 270283.Google Scholar
6.Higgins, M, Mc Auliffe, F. A review of maternal and fetal growth factors in diabetic pregnancy. Curr Diabetes Rev. 2010; 6, 116125.Google Scholar
7.Ashfaq, M, Janjua, MZ, Channa, MA. Effect of gestational diabetes and maternal hypertension on gross morphology of placenta. J Ayub Med Coll Abbottabad. 2005; 17, 4447.Google Scholar
8.Schafer-Graf, UM, Dupak, J, Vogel, M, et al. Hyperinsulinism, neonatal obesity and placental immaturity in infants born to women with one abnormal glucose tolerance test value. J Perinat Med. 1998; 26, 2736.Google Scholar
9.Freinkel, N. Banting Lecture 1980. Of pregnancy and progeny. Diabetes. 1980; 29, 10231035.Google Scholar
10.American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. Suppl 1, S67S74.Google Scholar
11.Belkacemi, L, Chen, CH, Ross, MG, Desai, M. Increased placental apoptosis in maternal food restricted gestations: role of the Fas pathway. Placenta. 2009; 30, 739751.CrossRefGoogle ScholarPubMed
12.Konstantinidou, A, Patsouris, E, Kavantzas, N, Pavlopoulos, PM, Bouropoulou, V, Davaris, P. Computerized determination of proliferating cell nuclear antigen expression in meningiomas. A comparison with non-automated method. Gen Diagn Pathol. 1997; 142, 311316.Google Scholar
13.Longtine, MS, Chen, B, Odibo, AO, Zhong, Y, Nelson, DM. Caspase-mediated apoptosis of trophoblasts in term human placental villi is restricted to cytotrophoblasts and absent from the multinucleated syncytiotrophoblast. Reproduction. 2012; 143, 107121.Google Scholar
14.Longtine, MS, Chen, B, Odibo, AO, Zhong, Y, Nelson, DM. Villous trophoblast apoptosis is elevated and restricted to cytotrophoblasts in pregnancies complicated by preeclampsia, IUGR, or preeclampsia with IUGR. Placenta. 2012; 33, 352359.Google Scholar
15.Ivarsson, K, Myllymaki, L, Jansner, K, Bruun, A, Stenram, U, Tranberg, KG. Heat shock protein 70 (HSP70) after laser thermotherapy of an adenocarcinoma transplanted into rat liver. Anticancer Res. 2003; 23, 37033712.Google Scholar
16.Belkacemi, L, Jelks, A, Chen, CH, Ross, MG, Desai, M. Altered placental development in undernourished rats: role of maternal glucocorticoids. Reprod Biol Endocrinol. 2011; 9, 105.Google Scholar
17.Liang, M, Ekblad, E, Gustafsson, JA, Nilsson, BO. Stimulation of vascular protein synthesis by activation of oestrogen receptor beta. J Endocrinol. 2001; 171, 417423.Google Scholar
18.Taricco, E, Radaelli, T, Rossi, G, et al. Effects of gestational diabetes on fetal oxygen and glucose levels in vivo. Bjog. 2009; 116, 17291735.Google Scholar
19.Smith, SC, Baker, PN, Symonds, EM. Increased placental apoptosis in intrauterine growth restriction. Am J Obstet Gynecol. 1997; 177, 13951401.Google Scholar
20.Axt, R, Meyberg, R, Mink, D, Wasemann, C, Reitnauer, K, Schmidt, W. Immunohistochemical detection of apoptosis in the human term and post-term placenta. Clin Exp Obstet Gynecol. 1999; 26, 5659.Google Scholar
21.Baker, AJ, Mooney, A, Hughes, J, Lombardi, D, Johnson, RJ, Savill, J. Mesangial cell apoptosis: the major mechanism for resolution of glomerular hypercellularity in experimental mesangial proliferative nephritis. J Clin Invest. 1994; 94, 21052116.CrossRefGoogle ScholarPubMed
22.Jansson, T, Cowley, EA, Illsley, NP. Cellular localization of glucose transporter messenger RNA in human placenta. Reprod Fertil Dev. 1995; 7, 14251430.CrossRefGoogle ScholarPubMed
23.Ericsson, A, Hamark, B, Powell, TL, Jansson, T. Glucose transporter isoform 4 is expressed in the syncytiotrophoblast of first trimester human placenta. Hum Reprod. 2005; 20, 521530.Google Scholar
24.Taricco, E, Radaelli, T, Nobile de Santis, MS, Cetin, I. Foetal and placental weights in relation to maternal characteristics in gestational diabetes. Placenta. 2003; 24, 343347.Google Scholar
25.Kucuk, M, Doymaz, F. Placental weight and placental weight-to-birth weight ratio are increased in diet- and exercise-treated gestational diabetes mellitus subjects but not in subjects with one abnormal value on 100-g oral glucose tolerance test. J Diabetes Complications. 2009; 23, 2531.Google Scholar
26.Mayhew, TM, Sorensen, FB, Klebe, JG, Jackson, MR. The effects of mode of delivery and sex of newborn on placental morphology in control and diabetic pregnancies. J Anat. 1993; 183, 545552.Google Scholar
27.Ericsson, A, Saljo, K, Sjostrand, E, et al. Brief hyperglycaemia in the early pregnant rat increases fetal weight at term by stimulating placental growth and affecting placental nutrient transport. J Physiol. 2007; 581, 13231332.CrossRefGoogle ScholarPubMed
28.Mayhew, TM, Sorensen, FB, Klebe, JG, Jackson, MR. Growth and maturation of villi in placentae from well-controlled diabetic women. Placenta. 1994; 15, 5765.Google Scholar
29.Grasl-Kraupp, B, Ruttkay-Nedecky, B, Koudelka, H, Bukowska, K, Bursch, W, Schulte-Hermann, R. In situ detection of fragmented DNA (TUNEL assay) fails to discriminate among apoptosis, necrosis, and autolytic cell death: a cautionary note. Hepatology. 1995; 21, 14651468.Google Scholar
30.Mundle, SD, Raza, A. The two in situ techniques do not differentiate between apoptosis and necrosis but rather reveal distinct patterns of DNA fragmentation in apoptosis. Lab Invest. 1995; 72, 611613.Google Scholar
31.Cervos-Navarro, J, Schubert, TE. Pitfalls in the evaluation of apoptosis using TUNEL. Brain Pathol. 1996; 6, 347348.Google Scholar
32.Elmore, S. Apoptosis: a review of programmed cell death. Toxicol Pathol. 2007; 35, 495516.Google Scholar
33.de Boer, RA, van Veldhuisen, DJ, van der Wijk, J, et al. Additional use of immunostaining for active caspase 3 and cleaved actin and PARP fragments to detect apoptosis in patients with chronic heart failure. J Card Fail. 2000; 6, 330337.Google Scholar
34.Sgarbosa, F, Barbisan, LF, Brasil, MA, et al. Changes in apoptosis and Bcl-2 expression in human hyperglycemic, term placental trophoblast. Diabetes Res Clin Pract. 2006; 73, 143149.Google Scholar
35.Nicholson, DW, Ali, A, Thornberry, NA, et al. Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis. Nature. 1995; 376, 3743.Google Scholar
36.Stennicke, HR, Salvesen, GS. Properties of the caspases. Biochim Biophys Acta. 1998; 1387, 1731.Google Scholar
37.Tewari, M, Quan, LT, O'Rourke, K, et al. Yama/CPP32 beta, a mammalian homolog of CED-3, is a CrmA-inhibitable protease that cleaves the death substrate poly(ADP-ribose) polymerase. Cell. 1995; 81, 801809.Google Scholar
38.Le Rhun, Y, Kirkland, JB, Shah, GM. Cellular responses to DNA damage in the absence of Poly(ADP-ribose) polymerase. Biochem Biophys Res Commun. 1998; 245, 110.Google Scholar
39.Wheeler, PD, Yudilevich, DL. Effect of insulin, prostaglandin E1 and uptake inhibitors on glucose transport in the perfused guinea-pig placenta. J Dev Physiol. 1989; 11, 159169.Google Scholar
40.Desoye, G, Gauster, M, Wadsack, C. Placental transport in pregnancy pathologies. Am J Clin Nutr. 2011; 94(Suppl 6), 1896S1902S.CrossRefGoogle ScholarPubMed
41.Joost, HG, Thorens, B. The extended GLUT-family of sugar/polyol transport facilitators: nomenclature, sequence characteristics, and potential function of its novel members (review). Mol Membr Biol. 2001; 18, 247256.Google Scholar
42.Korgun, ET, Demir, R, Hammer, A, et al. Glucose transporter expression in rat embryo and uterus during decidualization, implantation, and early postimplantation. Biol Reprod. 2001; 65, 13641370.Google Scholar
43.Gaither, K, Quraishi, AN, Illsley, NP. Diabetes alters the expression and activity of the human placental GLUT1 glucose transporter. J Clin Endocrinol Metab. 1999; 84, 695701.Google Scholar
44.Hauguel-de Mouzon, S, Leturque, A, Alsat, E, Loizeau, M, Evain-Brion, D, Girard, J. Developmental expression of Glut1 glucose transporter and c-fos genes in human placental cells. Placenta. 1994; 15, 3546.CrossRefGoogle ScholarPubMed
45.Grissa, O, Yessoufou, A, Mrisak, I, et al. Growth factor concentrations and their placental mRNA expression are modulated in gestational diabetes mellitus: possible interactions with macrosomia. BMC Pregnancy Childbirth. 2010; 10, 7.Google Scholar
46.Burleigh, DW, Stewart, K, Grindle, KM, Kay, HH, Golos, TG. Influence of maternal diabetes on placental fibroblast growth factor-2 expression, proliferation, and apoptosis. J Soc Gynecol Investig. 2004; 11, 3641.Google Scholar
47.Hill, DJ, Tevaarwerk, GJ, Caddell, C, Arany, E, Kilkenny, D, Gregory, M. Fibroblast growth factor 2 is elevated in term maternal and cord serum and amniotic fluid in pregnancies complicated by diabetes: relationship to fetal and placental size. J Clin Endocrinol Metab. 1995; 80, 26262632.Google Scholar
48.Boileau, P, Mrejen, C, Girard, J, Hauguel-de Mouzon, S. Overexpression of GLUT3 placental glucose transporter in diabetic rats. J Clin Invest. 1995; 96, 309317.Google Scholar
49.Hauguel-de Mouzon, S, Challier, JC, Kacemi, A, Cauzac, M, Malek, A, Girard, J. The GLUT3 glucose transporter isoform is differentially expressed within human placental cell types. J Clin Endocrinol Metab. 1997; 82, 26892694.Google Scholar
50.Thomas, CR, Eriksson, GL, Eriksson, UJ. Effects of maternal diabetes on placental transfer of glucose in rats. Diabetes. 1990; 39, 276282.Google Scholar
51.Baptiste-Roberts, K, Nicholson, WK, Wang, NY, Brancati, FL. Gestational diabetes and subsequent growth patterns of offspring: the National Collaborative Perinatal Project. Matern Child Health J. 2012; 16, 125132.Google Scholar
52.Makhseed, M, Musini, VM, Ahmed, MA, Al-Harmi, J. Placental pathology in relation to the White's classification of diabetes mellitus. Arch Gynecol Obstet. 2002; 266, 136140.Google Scholar
53.Fowden, AL, Forhead, AJ, Coan, PM, Burton, GJ. The placenta and intrauterine programming. J Neuroendocrinol. 2008; 20, 439450.Google Scholar