Skip to main content
Log in

Heat shock protein production and immunity and altered fetal development in diabetic pregnant rats

  • Original Paper
  • Published:
Cell Stress and Chaperones Aims and scope

Abstract

We evaluated associations between the concentrations of heat shock proteins (hsp60 and hsp70) and their respective antibodies, alterations in maternal reproductive performance, and fetal malformations in pregnant rats with hyperglycemia. Mild diabetes (MD) or severe diabetes (SD) was induced in Sprague-Dawley rats prior to mating; non-treated non-diabetic rats (ND) served as controls. On day 21 of pregnancy, maternal blood was analyzed for hsp60 and hsp70 and their antibodies; and fetuses were weighed and analyzed for congenital malformations. Hsp and anti-hsp levels were correlated with blood glucose levels during gestation. There was a positive correlation between hsp60 and hsp70 levels and the total number of malformations (R = 0.5908, P = 0.0024; R = 0.4877, P = 0.0134, respectively) and the number of malformations per fetus (R = 0.6103, P = 0.0015; R = 0.4875, P = 0.0134, respectively). The anti-hsp60 IgG concentration was correlated with the number of malformations per fetus (R = 0.3887, P = 0.0451) and the anti-hsp70 IgG level correlated with the total number of malformations (R = 0.3999, P = 0.0387). Moreover, both hsp and anti-hsp antibodies showed negative correlations with fetal weight. The results suggest that there is a relationship between hsp60 and hsp70 levels and their respective antibodies and alterations in maternal reproductive performance and impaired fetal development and growth in pregnancies associated with diabetes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Akerfelt M, Trouillet D, Mezger V, Sistonen L (2007) Heat shock factors at a crossroad between stress and development. Ann N Y Acad Sci 1113:15–27

    Article  PubMed  CAS  Google Scholar 

  • Aliverti V, Bonanomi L, Giavini E (1979) The extent of fetal ossification as an index of delayed development in teratogenic studies on the rat. Teratology 20:237–242

    Article  PubMed  CAS  Google Scholar 

  • Alsat E, Marcotty C, Gabriel R, Igout A, Frankenne F, Hennen G, Evain-Brion D (1995) Molecular approach to intrauterine growth retardation: an overview of recent data. Reprod Fertil Dev 7:1457–1464

    Article  PubMed  CAS  Google Scholar 

  • American Diabetes Association (2011) Diagnosis and classification of diabetes mellitus. Diabetes Care 34:S62–S69

    Article  Google Scholar 

  • Anderson RL (1998) Stress proteins and apoptosis in prenatal development, cancer and medicine. Cell Stress Chaperones 3:209–212

    Article  PubMed  CAS  Google Scholar 

  • Belhia F, Gremlich S, Muller-Brochut AC, Damnon F, Hohlfeld P, Witkin SS, Gerber S (2010) Anti-60-kDa heat shock protein antibodies in fetal serum: a biomarker for unexplained small for gestational age fetuses. Gynecol Obstet Investig 70:299–305

    Article  CAS  Google Scholar 

  • Bruce CR, Carey AL, Hawley JA, Febbraio MA (2003) Intramuscular heat shock protein 72 and heme oxygenase-1 mRNA are reduced in patients with type 2 diabetes: evidence that insulin resistance is associated with a disturbed antioxidant defense mechanism. Diabetes 52:2338–2345

    Article  PubMed  CAS  Google Scholar 

  • Calabrese V, Mancuso C, Sapienza M, Puleo E, Calafato S, Cornelius C, Finocchiaro M, Mangiameli A, Di Mauro M, Stella AM, Castellino P (2007) Oxidative stress and cellular stress response in diabetic nephropathy. Cell Stress Chaperones 12:299–306

    Article  PubMed  CAS  Google Scholar 

  • Calderon IMP, Rudge MVC, Brasil MAM, Henry MACA (1992) Diabete e gravidez experimental em ratas I. Indução do diabete, obtenção e evolução da prenhez. Acta Cirúrgica Brasileira 7:142–146

    Google Scholar 

  • Caluwaerts S, Holemans K, Van Bree R, Verhaeghe J, Van Assche A (2003) Is low-dose Streptozotocin in rats adequate model for gestational Diabetes mellitus? J Soc Gynecol Investig 10:216–221

    Article  PubMed  CAS  Google Scholar 

  • Chieri RA, Pivetta OH, Folgia VG (1969) Altered ovulation pattern in experimental diabetes. Fertil Steril 20:661–666

    PubMed  CAS  Google Scholar 

  • Child DF, Hudson PR, Hunter-Lavin C, Mukhergee S, China S, Williams CP, Williams JH (2006) Birth defects and anti-heat shock protein 70 antibodies in early pregnancy. Cell Stress Chaperones 11:101–105

    Article  PubMed  CAS  Google Scholar 

  • Chung J, Nguyen AK, Henstridge DC, Holmes AG, Chan MD, Mesa JL, Lancaster GI, Southgate RJ, Bruce CR, Duffy SJ, Horvath I, Mestril R, Watt MJ, Hooper PL, Kingwell BA, Vigh L, Hevener A, Febbraio MA (2008) HSP72 protects against obesity-induced insulin resistance. Proc Natl Acad Sci USA 105:1739–1744

    Article  PubMed  CAS  Google Scholar 

  • Cnattingius S, Bergström R, Lipworth L, Kramer MS (1998) Prepregnancy weight and the risk of adverse pregnancy outcomes. N Engl J Med 338:147–152

    Article  PubMed  CAS  Google Scholar 

  • Damasceno DC, Sinzato YK, Lima PH, de Souza MS, Campos KE, Dallaqua B, Calderon IM, Rudge MV, Volpato GT (2011) Effects of exposure to cigarette smoke prior to pregnancy in diabetic rats. Diabetol Metab Syndr 3:20

    Article  PubMed  CAS  Google Scholar 

  • Daskalakis G, Marinopoulos S, Krielesi V, Papapanagiotou A, Papantoniou N, Mesogitis S, Antsaklis A (2008) Placental pathology in women with gestational diabetes. Acta Obstet Gynecol Scand 87(4):403–407

    Article  PubMed  Google Scholar 

  • de Souza MSS, Lima PHO, Sinzato YK, Rudge MVC, Pereira OCM, Damasceno DC (2009) Effects of cigarette smoke exposure on pregnancy outcome of diabetic rats and on their offspring. Reprod BioMed Online 18:562–567

    Article  Google Scholar 

  • Dienelt A, Zur Nieden NI (2011) Hyperglycemia impairs skeletogenesis from embryonic stem cells by affecting osteoblast and osteoclast differentiation. Stem Cells Dev 20:465–474

    Article  PubMed  CAS  Google Scholar 

  • Dix DJ, Garges JB, Hong RL (1998) Inhibition of HSP70-1 and HSP70-3 expression disrupts preimplantation embryogenesis and heightens embryo sensitivity to arsenic. Mol Reprod Dev 51:373–380

    Article  PubMed  CAS  Google Scholar 

  • Eriksson UJ (2009) Congenital anomalies in diabetic pregnancy. Semin Fetal Neonatal Med 14:85–93

    Article  PubMed  Google Scholar 

  • Eriksson UJ, Borg LA, Cederberg J, Nordstrand H, Simán CM, Wentzel C, Wentzel P (2000) Pathogenesis of diabetes-induced congenital malformations. Ups J Med Sci 105:53–84

    PubMed  CAS  Google Scholar 

  • Eriksson UJ, Cederberg J, Wentzel P (2003) Congenital malformations in offspring of diabetic mothers—animal and human studies. Rev Endocr Metab Disord 4:79–93

    Article  PubMed  CAS  Google Scholar 

  • Febbraio MA, Mesa JL, Chung J, Steensberg A, Keller C, Nielsen HB, Krustrup P, Ott P, Secher NH, Pedersen BK (2004) Glucose ingestion attenuates the exercise induced increase in circulating heat shock protein 72 and heat shock protein 60 in human cells. Cell Stress Chaperones 9:390–396

    Article  PubMed  CAS  Google Scholar 

  • Garris DR, West RL, Pekala PH (1986) Ultrastructural and metabolic changes associated with reproductive tract atrophy and adiposity in diabetic female mice. Anat Rec 216:359–366

    Article  PubMed  CAS  Google Scholar 

  • Gruden G, Bruno G, Chaturvedi N, Burt D, Pinach S, Schalkwijk C, Stehouwer CD, Witte DR, Fuller JH, Cavallo-Perin P (2009) ANTI-HSP60 and ANTI-HSP70 antibody levels and micro/macrovascular complications in type 1 diabetes: the EURODIAB Study. J Intern Med 266:527–536

    Article  PubMed  CAS  Google Scholar 

  • Henderson B, Pockley AG (2012) Proteotoxic stress and circulating cell stress proteins in the cardiovascular diseases. Cell Stress Chaperones 17:303–311

    Article  PubMed  CAS  Google Scholar 

  • Hunter-Lavin C, Hudson PR, Mukherjee S, Davies GK, Williams CP, Harvey JN, Child DF, Williams JH (2004) Folate supplementation reduces serum HSP70 levels in patients with type 2 diabetes. Cell Stress Chaperones 9:344–349

    Article  PubMed  CAS  Google Scholar 

  • Iessi IL, Bueno A, Sinzato YK, Taylor KN, Rudge MV, Damasceno DC (2010) Evaluation of neonatally-induced mild diabetes in rats: maternal and fetal repercussions. Diabetol Metab Syndr 8:37

    Article  Google Scholar 

  • Jawerbaum A, González E (2006) Diabetic pregnancies: the challenge of developing in a pro-inflammatory environment. Curr Med Chem 13:2127–2138

    Article  PubMed  CAS  Google Scholar 

  • Jawerbaum A, White V (2010) Animal models in diabetes and pregnancy. Endocr Rev 31:680–701

    Article  PubMed  Google Scholar 

  • Kavanagh K, Zhang L, Wagner JD (2009) Tissue-specific regulation and expression of heat shock proteins in type 2 diabetic monkeys. Cell Stress Chaperones 14:291–300

    Article  PubMed  CAS  Google Scholar 

  • Kirchick HJ, Keyes PL, Frye BE (1978) Etiology of anovulation in the immature alloxan-diabetic rat treated with PMSG: absence of the preovulatory luteinizing hormone surge. Endocrinology 109:316–318

    Google Scholar 

  • Luft JC, Dix DJ (1999) HSP70 expression and function during embryogenesis. Cell Stress Chaperones 4:162–170

    Article  PubMed  CAS  Google Scholar 

  • Matwee C, Kamaruddin M, Betts DH, Basrur PK, King WA (2001) The effects of antibodies to heat shock protein 70 in fertilization and embryo development. Mol Hum Reprod 7:829–837

    Article  PubMed  CAS  Google Scholar 

  • Morange M, Diu A, Bensaude O, Babinet C (1984) Altered expression of heat shock proteins in mouse embryonal carcinoma cells and mouse early embryonic cells. Mol Cell Biol 4:730–735

    PubMed  CAS  Google Scholar 

  • Morgan SC, Relaix F, Sandell LL, Loeken MR (2008) Oxidative stress during diabetic pregnancy disrupts cardiac neural crest migration and causes outflow tract defects. Birth Defects Res A Clin Mol Teratol 82:453–463

    Article  PubMed  CAS  Google Scholar 

  • Neuer A, Mele C, Rosenwaks Z, Witkin SS (1998) Monoclonal antibodies to mammalian heat shock proteins impair mouse embryo development in vitro. Hum Reprod 14:987–990

    Article  Google Scholar 

  • Neuer A, Spandorfer SD, Giraldo P, Dieterle S, Rosenwalks Z, Witkin SS (2000) The role of heat shock proteins in reproduction. Hum Reprod Updat 6:149–159

    Article  CAS  Google Scholar 

  • Oglesbee MJ, Herdman AV, Passmore GG, Hoffman WH (2005) Diabetic ketoacidosis increases extracellular levels of the major inducible 70-kDa heat shock protein. J Biomed Biotechnol 38:900–904

    CAS  Google Scholar 

  • Oh W, Gelardi NL, Cha CJM (1991) The cross-generation effect of neonatal macrosomia in rat pups of streptozotocin-induced diabetes. Pediatr Res 29:606–610

    Article  PubMed  CAS  Google Scholar 

  • Ornoy A (2007) Embryonic oxidative stress as a mechanism of teratogenesis with special emphasis on diabetic embryopathy. Reprod Toxicol 24:31–41

    Article  PubMed  CAS  Google Scholar 

  • Portha B, Levacher C, Picon L, Rosselin G (1974) Diabetogenic effect of streptozotocin on the rat during the perinatal period. Diabetes 23:888–895

    Google Scholar 

  • Reece EA, Ma XD, Zhao Z, Wu YK, Dhanasekaran D (2005) Aberrant patterns of cellular communication in diabetes-induced embryopathy in rats: II, apoptotic pathways. Am J Obstet Gynecol 192:967–972

    Article  PubMed  Google Scholar 

  • Rudge MVC, Damasceno DC, Volpato GT, Almeida FCG, Calderon IMP, Lemonica IP (2007) Effect of Ginkgo biloba on the reproductive outcome and oxidative stress biomarkers of streptozotocin-induced diabetic rats. Braz J Med Biol Res 40:1095–1099

    Article  PubMed  CAS  Google Scholar 

  • Saito FH, Damasceno DC, Kempinas WG, Morceli G, Sinzato YK, Taylor KN, Rudge MV (2010) Repercussions of mild diabetes on pregnancy in Wistar rats and on the fetal development. Diabetol Metab Syndr 2:26

    Article  PubMed  Google Scholar 

  • Schaefer-Graf UM, Buchanan TA, Xiang A, Songster G, Montoro M, Kjos SL (2000) Patterns of congenital anomalies and relationship to initial maternal fasting glucose levels in pregnancies complicated by type 2 and gestational diabetes. Am J Obstet Gynecol 182:313–320

    Article  PubMed  CAS  Google Scholar 

  • Simán CM, Gittenberger-De Groot AC, Wisse B, Eriksson UJ (2000) Malformations in offspring of diabetic rats: morphometric analysis of neural crest-derived organs and effects of maternal vitamin E treatment. Teratology 61:355–367

    Article  PubMed  Google Scholar 

  • Sinzato YK, Lima PH, Campos KE, Kiss AC, Rudge MV, Damasceno DC (2009) Neonatally-induced diabetes: lipid profile outcomes and oxidative stress status in adult rats. Rev Assoc Med Bras 55:384–388

    Article  PubMed  Google Scholar 

  • Sinzato YK, Damasceno DC, Laufer-Amorim R, Rodrigues MM, Oshiiwa M, Taylor KN, Rudge MV (2011) Plasma concentrations and placental immunostaining of interleukin-10 and tumor necrosis factor-α as predictors of alterations in the embryo-fetal organism and the placental development of diabetic rats. Braz J Med Biol Res 44:206–211

    Article  PubMed  CAS  Google Scholar 

  • Sivan E, Lee YC, Wu YK, Reece EA (1997) Free radical scavenging enzymes in fetal dysmorphogenesis among off- spring of diabetic rats. Teratology 56:343–349

    Article  PubMed  CAS  Google Scholar 

  • Soulimane-Mokhtari NA, Guermouche B, Yessoufou A, Saker M, Moutairou K, Hichami A, Merzouk H, Khan NA (2005) Modulation of lipid metabolism by n-3 polyunsaturated fatty acids in gestational diabetic rats and their macrosomic offspring. Clinical Science (London) 109:287–295

    Article  CAS  Google Scholar 

  • Staples RE, Schnell VL (1964) Refinements in rapid clearing technic in the KOH-alizarin red S method for fetal bone. Stain Technol 39:61–63

    PubMed  CAS  Google Scholar 

  • Sugimura Y, Murase T, Oyama K, Uchida A, Sato N, Hayasaka S, Kano Y, Takagishi Y, Hayashi Y, Oiso Y, Murata Y (2009) Prevention of neural tube defects by loss of function of inducible nitric oxide synthase in fetuses of a mouse model of streptozotocin-induced diabetes. Diabetologia 52:962–971

    Article  PubMed  CAS  Google Scholar 

  • Tan H, Xu Y, Xu J, Wang F, Nie S, Yang M, Yuan J, Tanguay RM, Wu T (2007) Association of increased heat shock protein 70 levels in the lymphocyte with high risk of adverse pregnancy outcomes in early pregnancy: a nested case-control study. Cell Stress Chaperones 12:230–236

    Article  PubMed  CAS  Google Scholar 

  • Toscano CM (2004) As campanhas nacionais para detecção das doenças crônicas não-transmissíveis: diabetes e hipertensão arterial. Ciências e Saúde Coletiva 9:885–895

    Article  Google Scholar 

  • Tsuji K, Taminato T, Usami M, Ishida H, Kitano N, Fukumoto H, Koh G, Kurose T, Yamada Y, Yano H, Seino Y, Imura H (1988) Characteristic features of insulin secretion in the streptozotocin- induced NIDDM rat model. Metabolism 37:1040–1044

    Article  PubMed  CAS  Google Scholar 

  • Vambergue A, Fajardy I (2011) Consequences of gestational and pregestational diabetes on placental function and birth weight. World J Diabetes 2:196–203

    PubMed  Google Scholar 

  • Volpato GT, Damasceno DC, Rudge MVC, Padovani CR, Calderon IMP (2008) Effect of Bauhinia forficata aqueous extract on the maternal-fetal outcome and oxidative stress biomarkers of streptozotocin-induced diabetic rats. J Ethnopharmacol 116:131–137

    Article  PubMed  CAS  Google Scholar 

  • Vomachka MS, Johnson DC (1982) Ovulation, ovarian 17 alpha-hydroxylase activity, and serum concentrations of luteinizing hormone, estradiol, and progesterone in immature rats with diabetes mellitus induced by streptozotocin. Proc Soc Exp Biol Med 171:207–213

    PubMed  CAS  Google Scholar 

  • Wilson JC (1965) Methods for administering agents and detecting malformations in experimental animal. In: Wilson JC, Warkany J (eds) Teratology: principles and techniques. Univ. of Chicago Press, Chicago

    Google Scholar 

  • Wittig S, Hensse S, Keitel C (1983) Heat shock gene expression is regulated during teratocarinoma cell differentiation and early embryo development. Dev Biol 96:507–514

    Article  PubMed  CAS  Google Scholar 

  • Yabunaka N, Ohtsuka Y, Watanabe I, Noro H, Fujisawa H, Agishi Y (1995) Elevated levels of heat-shock protein 70 (HSP70) in the mononuclear cells of patients with non-insulin-dependent diabetes mellitus. Diabetes Res Clin Pract 30:143–147

    Article  PubMed  CAS  Google Scholar 

  • Zhong X, Wang T, Zhang X, Li W (2011) Heat shock protein 70 is upregulated in the intestine of intrauterine growth retardation piglets. Cell Stress Chaperones 15:335–342

    Article  Google Scholar 

  • Zhu Y, Ren C, Wan X, Zhu Y, Zhu J, Zhou H, Zhang T (2012) Gene expression of Hsp70, Hsp90 and Hsp110 families in normal palate and cleft palate during mouse embryogenesis. Toxicol Ind Health. doi:10.1177/0748233712446720

Download references

Acknowledgments

We are grateful to Dr. Maria Terezinha Serrão Peraçoli for assistance and helpful discussions. We would also like to thank to Talísia Moreto, technician in the Laboratory of Experimental Research on Gynecology and Obstetrics. The financial support of CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior) is gratefully acknowledged.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Steven S. Witkin.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Saito, F.H., Damasceno, D.C., Dallaqua, B. et al. Heat shock protein production and immunity and altered fetal development in diabetic pregnant rats. Cell Stress and Chaperones 18, 25–33 (2013). https://doi.org/10.1007/s12192-012-0353-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12192-012-0353-3

Keywords

Navigation