Hostname: page-component-586b7cd67f-gb8f7 Total loading time: 0 Render date: 2024-11-26T03:21:45.822Z Has data issue: false hasContentIssue false
  • English
  • Français

Diverse ability of maternal immune stimulation to reduce birth defects in mice exposed to teratogens: a review

Published online by Cambridge University Press:  19 December 2011

T. C. Hrubec ,
M. R. Prater ,
M. K. Mallela ,
R. M. Gogal Jr ,
T. L. Guo  and
S. D. Holladay
T. C. Hrubec
Affiliation:
Department of Biomedical Sciences, E. Via College of Osteopathic Medicine, Blacksburg, VA, USA Department of Biomedical Sciences and Pathobiology, College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA
M. R. Prater
Affiliation:
Department of Biomedical Sciences, E. Via College of Osteopathic Medicine, Blacksburg, VA, USA Department of Biomedical Sciences and Pathobiology, College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA
M. K. Mallela
Affiliation:
Department of Biomedical Sciences, E. Via College of Osteopathic Medicine, Blacksburg, VA, USA
R. M. Gogal Jr
Affiliation:
Department of Anatomy and Radiology, College of Veterinary Medicine, University of Georgia, Athens, GA, USA
T. L. Guo
Affiliation:
Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA, USA
S. D. Holladay*
Affiliation:
Department of Anatomy and Radiology, College of Veterinary Medicine, University of Georgia, Athens, GA, USA
*
*Address for correspondence: Dr S. D. Holladay, Department of Anatomy and Radiology, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA. (Email [email protected])
Get access Rights & Permissions [Opens in a new window]

Abstract

Stimulating the maternal immune system before or during pregnancy can dramatically improve morphologic outcome in mice that have been exposed to teratogens. For example, maternal immune stimulation in mice reduced craniofacial and palate defects, heart defects, digit and limb defects, tail malformations and neural tube defects caused by diverse teratogens that included chemical agents, hyperthermia, X-rays and diabetes mellitus. Several different procedures of immune stimulation were effective and included footpad injection with Freund's Complete Adjuvant, intraperitoneal (IP) injection with inert particles or attenuated Bacillus Calmette–Guerin, intrauterine injection with allogenic or xenogenic lymphocytes, or intravascular, intrauterine or IP injection with immunomodulatory cytokines. Limited information is available regarding mechanisms by which such immune stimulation reduces fetal dysmorphogenesis; however, cytokines of maternal origin have been suggested as effector molecules that act on the placenta or fetus to improve development. These collective data raise novel questions about the possibility of unrecognized maternal immune system regulatory activity in normal fetal development. This manuscript reviews the literature showing maternal immune protection against morphologic birth defects. Potential operating mechanisms are discussed, and the possibility is considered that a suppressed maternal immune system may negatively impact fetal development.

Keywords

birth defectsfetal developmentmaternal immune stimulationteratogen
Type
Review
Information
Journal of Developmental Origins of Health and Disease , Volume 3 , Issue 3 , June 2012 , pp. 132 - 139
Copyright
Copyright © Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2012

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. Brough, L, Rees, GA, Crawford, MA, Morton, RH, Dorman, EK. Effect of multiple-micronutrient supplementation on maternal nutrient status, infant birth weight and gestational age at birth in a low-income, multi-ethnic population. Br J Nutr. 2010; 104, 437–445.CrossRefGoogle Scholar
2. Nomura, T. Comparative inhibiting effects of methylxanthines on urethane-induced tumors, malformations, and presumed somatic mutations in mice. Cancer Res. 1983; 43, 1342–1349.Google Scholar
3. Kurishita, A. Histological study of cell death in digital malformations induced by 5-azacytidine: suppressive effect of caffeine. Teratology. 1989; 39, 163–170.CrossRefGoogle ScholarPubMed
4. Torchinsky, A, Gongadze, M, Orenstein, H, et al. . TNF-α acts to prevent occurrence of malformed fetuses in diabetic mice. Diabetologia. 2004; 47, 132–139.CrossRefGoogle ScholarPubMed
5. Toriello, HV. Policy statement on folic acid and neural tube defects. Genet Med. 2011; 13, 593–596.CrossRefGoogle ScholarPubMed
6. Nomura, T, Hata, S, Kusafuka, T. Suppression of developmental anomalies by maternal macrophages in mice. J Exp Med. 1990; 172, 1325–1330.CrossRefGoogle ScholarPubMed
7. Holladay, SD, Sharova, LV, Smith, BJ, et al. . Non-specific stimulation of the maternal immune system: I. Effects on teratogen-induced fetal malformations. Teratology. 2000; 62, 413–419.3.0.CO;2-B>CrossRefGoogle Scholar
8. Holladay, SD, Sharova, LV, Punareewattana, K, et al. . Maternal immune stimulation in mice decreases fetal malformations caused by teratogens. Int Immunopharmacol. 2002; 2, 325–332.CrossRefGoogle ScholarPubMed
9. Abbott, BD, Probst, MR, Perdew, GH, Buckalew, AR. Ah receptor, ARNT, glucocorticoid receptor, EGF receptor, EGF, TGFα, TGFβ1, TGFβ2, and TGFβ3 expression in human embryonic palate, and effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Teratology. 1988; 58, 30–43.3.0.CO;2-4>CrossRefGoogle Scholar
10. Abbott, BD, Birnbaum, LS. TCDD-induced altered expression of growth factors may have a role in producing cleft palate and enhancing the incidence of clefts after coadministration of retinoic acid and TCDD. Toxicol Appl Pharmacol. 1990; 106, 418–432.CrossRefGoogle ScholarPubMed
11. Sharova, LV, Sura, P, Smith, BJ, et al. . Non-specific stimulation of the maternal immune system: I. Effects on fetal gene expression. Teratology. 2000; 62, 420–428.3.0.CO;2-8>CrossRefGoogle Scholar
12. Roth, P, Dominguez, MG, Stanley, ER. The effects of colony-stimulating factor-1 on the distribution of mononuclear phagocytes in the developing osteopetrotic mouse. Blood. 1998; 91, 3773–3783.CrossRefGoogle ScholarPubMed
13. Calhoun, DA, Posa, C, Christensen, RE. Transplacental passage of recombinant human granulocyte colony-stimulating factor in women with an imminent preterm delivery. Am J Obstet Gynecol. 1996; 174, 1306–1311.CrossRefGoogle ScholarPubMed
14. Zdravkovic, M, Knudson, HJ, Liu, X, et al. . High interferon alpha levels in placenta, maternal, and cord blood suggest a protective effect against intrauterine herpes simplex virus infection. J Med Virol. 1997; 51, 210–213.3.0.CO;2-O>CrossRefGoogle ScholarPubMed
15. Hrubec, TC, Prater, MA, Toops, KA, Holladay, SD. Reduction in diabetes-induced defects by maternal immune stimulation. Birth Defects Res B Dev Reprod Toxicol. 2006; 77, 1–9.CrossRefGoogle ScholarPubMed
16. Hrubec, TC, Toops, KA, Holladay, SD. Modulation of diabetes-induced palate defects by maternal immune stimulation. Anat Rec. 2009; 292, 271–276.CrossRefGoogle ScholarPubMed
17. Lale, S, Yu, S, Ahmed, A. Complex congenital heart defects in association with maternal diabetes and partial deletion of the A2BP1 gene. Fetal Pediatr Pathol. 2011; 30, 161–166.CrossRefGoogle ScholarPubMed
18. Gutierrez, CJ, Prater, MR, Hrubec, TC, et al. . Heart changes in 17-day-old fetuses of diabetic ICR (Institute for Cancer Research) mothers: improvement with maternal immune stimulation. Congenit Anom. 2009; 49, 1–7.CrossRefGoogle Scholar
19. Gutierrez, CJ, Prater, MR, Smith, BJ, et al. . Late-gestation ventricular myocardial reduction in fetuses of hyperglycemic CD1 mice is associated with increased apoptosis. Birth Defects Res B Dev Reprod Toxicol. 2009; 86, 409–415.CrossRefGoogle ScholarPubMed
20. Punareewattana, K, Sharova, LV, Li, W, Ward, DL, Holladay, SD. Reduced birth defects caused by maternal immune stimulation may involve increased expression of growth promoting genes and cytokine GM-CSF in the spleen of diabetic ICR mice. Int Immunopharmacol. 2003; 3, 1639–1655.CrossRefGoogle ScholarPubMed
21. Sharova, LV, Gogal, RM Jr, Sharova, AA, Crisman, MV, Holladay, SD. Immune stimulation in urethane-exposed pregnant mice increases expression of level of spleen leukocyte genes for TGFβ3, GM-CSF and other cytokines that may play a role in reduced chemical-induced birth defects. Int Immunopharmacol. 2002; 2, 1477–1489.CrossRefGoogle ScholarPubMed
22. Savion, S, Brengauz-Breitmann, M, Torchinsky, A, Toder, VA. A possible role for granulocyte macrophage colony-stimulating factor in modulating teratogen-induced effects. Teratog Carcinog Mutagen. 1999; 19, 171–182.3.0.CO;2-S>CrossRefGoogle ScholarPubMed
23. Toder, V, Carp, H, Fein, A, Torchinsky, A. The role of pro- and anti-apoptotic molecular interactions in embryonic maldevelopment. Am J Reprod Immunol. 2002; 48, 235–244.CrossRefGoogle ScholarPubMed
24. Savion, S, Zeldich, E, Orenstein, H. Cytokine expression in the uterus of mice with pregnancy loss: effect of maternal immunopotentiation with GM-CSF. Reproduction. 2002; 123, 399–409.CrossRefGoogle ScholarPubMed
25. Gjerset, RA, Lebedeva, S, Haghighi, A, Turla, ST, Mercola, D. Inhibition of the Jun kinease pathway blocks DNA repair, enhances p53-mediated apoptosis and promotes gene amplification. Cell Growth Differ. 1999; 25, 545–554.Google Scholar
26. Ninomiya, M, Numakawa, T, Adachi, N, et al. . Cortical neurons from intrauterine growth retardation rats exhibit lower response to neurotrophin BDNF. Neurosci Lett. 2010; 476, 104–109.CrossRefGoogle ScholarPubMed
27. Zhang, X, Tang, N, Hadden, TJ, Rishi, AK. Akt, FoxO and regulation of apoptosis. Biochem Biophys Acta. 2011; 1813, 1978–1986.CrossRefGoogle ScholarPubMed
28. Coutinho, I, Pereira, C, Pereira, G, et al. . Distinct regulation of p53-mediated apoptosis by protein kinase Cα, δ, ε and ζ: evidence in yeast for transcription-dependent and -independent p53 apoptotic mechanisms. Exp Cell Res. 2011; 317, 1147–1158.CrossRefGoogle ScholarPubMed
29. Savion, S, Lepsky, E, Orenstein, H. Apoptosis in the uterus of mice with pregnancy loss. Am J Reprod Immunol. 2002; 47, 118–127.CrossRefGoogle ScholarPubMed
30. Elledge, RM, Lee, WH. Life and death by p53. Bioassays. 1995; 17, 923–930.CrossRefGoogle ScholarPubMed
31. Korsmeyer, SJ. Bcl2 initiates a new category of oncogenes: regulators of cell death. Blood. 1992; 80, 879–886.CrossRefGoogle ScholarPubMed
32. Savion, S, Kamshitsky-Feldman, A, Ivnitsky, I, et al. . Potentiation of the maternal immune system may modify the apoptotic process in embryos exposed to development toxicants. Am J Reprod Immunol. 2003; 49, 30–41.CrossRefGoogle Scholar
33. Torchinsky, A, Gongadze, M, Zaslavsky, Z, et al. . Maternal immunopotentiation affects caspase activation and NF-kappaB DNA-binding activity in embryos responding to an embryopathic stress. Am J Reprod Immunol. 2006; 55, 36–44.CrossRefGoogle Scholar
34. Savion, S, Aroch, I, Mammon, K, et al. . Effect of maternal immunopotentiation on apoptosis-associated molecules expression in teratogen-treated embryos. Am J Reprod Immunol. 2009; 62, 400–411.CrossRefGoogle ScholarPubMed
35. Bennett, GD, Wlodarczyk, B, Calvin, JA, Craig, JC, Finnell, RH. Valproic acid-induced alterations in growth and neurotrophic factor. Reprod Toxicol. 2000; 1, 1–11.CrossRefGoogle Scholar
36. Craig, JC, Bennett, GD, Miranda, RC, Mackler, SA, Finnell, RH. Ribonucleotide reductase subunit R1: a gene conferring sensitivity to valproic acid induced neural tube defects in mice. Teratology. 2000; 61, 305–313.3.0.CO;2-8>CrossRefGoogle ScholarPubMed
37. Martin, ML, Regan, CM. The anticonvulsant valproate teratogen restricts the glial cell cycle at a defined point in the mid-G1 phase. Brain Res. 1991; 554, 223–228.CrossRefGoogle Scholar
38. Wlodarczyk, BC, Craig, JC, Bennett, GD, Calvin, JA, Finnell, RH. Valproic acid-induced changes in gene expression during neurulation in a mouse model. Teratology. 1996; 54, 284–297.3.0.CO;2-Z>CrossRefGoogle ScholarPubMed
39. Tohyama, M, Hanakawa, Y, Shirakata, Y, et al. . IL-17 and IL-22 mediate IL-20 subfamily cytokine production in cultured keratinocytes via increased IL-22 receptor expression. Eur J Immunol. 2009; 39, 2779–2788.CrossRefGoogle ScholarPubMed
40. Diaugustine, RP, Rosch, MJ, Lannon, DE, Walker, MP, Pratt, RM. Evaluation of murine placental degradation and transfer of [125]Iodo-epidermal growth factor. Endocrinology. 2011; 120, 1190–1200.CrossRefGoogle Scholar
41. Gorivodsky, M, Torchinsky, A, Shepshelovich, J, et al. . Colony stimulating factor 1 (CSF-1) expression in the uteroplacental unit of mice with spontaneous and induced pregnancy loss. Clin Exp Immunol. 1999; 117, 540–549.CrossRefGoogle ScholarPubMed
42. Gorivodsky, M, Torchinsky, A, Zemliak, I, et al. . TGFβ2 mRNA expression and pregnancy failure in mice. Am J Reprod Immunol. 1999; 42, 124–133.CrossRefGoogle Scholar
43. Fein, A, Kostina, E, Savion, S, et al. . Expression of tumor necrosis factor-a in the pregnant uterus of diabetic mice: effect of maternal immunopotentiation. Am J Reprod Immunol. 2001; 46, 161–168.CrossRefGoogle Scholar
44. Fein, A, Magid, N, Savion, S, et al. . Diabetes teratogenicity in mice is accompanied with distorted expression of TGFβ2 in the uterus. Teratog Carcinog Mutagen. 2002; 22, 59–71.CrossRefGoogle ScholarPubMed
45. Garcia-Lloret, MI, Morrish, DW, Wegmann, TG, et al. . Demonstration of functional cytokine-placental interactions: CSF-1 and GM-CSF stimulate human cytotrophoblast differentiation and peptide hormone secretion. Exp Cell Res. 1994; 214, 46–54.CrossRefGoogle ScholarPubMed
46. Robertson, SA, O'Connell, AC, Hudson, SN, Seamark, RF. Granulocyte-macrophage colony-stimulating factor (GM-CSF) targets myeloid leukocytes in the uterus during the post-mating inflammatory response in mice. J Reprod Immunol. 2000; 46, 131–154.CrossRefGoogle ScholarPubMed
47. Robertson, SA, Seamark, RF, Guilbert, LJ, Wegmann, TG. The role of cytokines in gestation. Crit Rev Immunol. 1994; 14, 239–292.CrossRefGoogle ScholarPubMed
48. Sharova, LV, Sharova, AA, Sura, P, et al. . Maternal immune stimulation reduces both placental morphologic damage and down-regulated placental growth factor and cell cycle gene expression caused by urethane: are these events related to reduced teratogenesis? Int Immunopharmacol. 2003; 3, 945–955.CrossRefGoogle ScholarPubMed
49. Athanassakis, I, Aifantis, Y, Ranella, A, Vassiliadis, S. Production of embryotoxic IgG antibodies during IFN-gamma treatment of pregnant mice. Am J Reprod Immunol. 1996; 36, 111–117.CrossRefGoogle ScholarPubMed
50. Tsoukatos, D, Skarpelis, G, Athanassakis, I. Placenta-specific growth factor production by splenic cells during pregnancy. Placenta. 1994; 15, 467–476.CrossRefGoogle ScholarPubMed
51. Thaxton, JE, Sharma, S. Interleukin-10: a multi-faceted agent of pregnancy. Am J Reprod Immunol. 2010; 63, 482–491.CrossRefGoogle ScholarPubMed
52. Prater, MR, Strahl, ED, Zimmerman, KL, Ward, DL, Holladay, SD. Reduced birth defects caused by maternal immune stimulation in methylnitrosourea-exposed mice: association with placental improvement. Birth Defects Res A Clin Molec Teratol. 2004; 70, 862–869.CrossRefGoogle ScholarPubMed
53. Prater, MR, Laudermilch, CL, Holladay, SD. Does immune stimulation or antioxidant therapy reduce MNU-induced placental damage via activation of Jak-STAT and NFkappaB signaling pathways? Placenta. 2007; 28, 566–570.CrossRefGoogle ScholarPubMed
54. Baizhuang, X, Pekkanen, J, Jarvelin, M-R, Olsen, P, Hartikainen, A-L. Maternal infections in pregnancy and the development of asthma among offspring. Int J Epidemiol. 1999; 28, 723–727.Google Scholar
55. Torchinsky, A, Toder, V, Savion, S, et al. . Immunostimulation increases the resistance of mouse embryos to the teratogenic effect of diabetes mellitus. Diabetologia. 1997; 40, 635–640.CrossRefGoogle Scholar