Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Modulation of in utero total body irradiation induced newborn mouse growth retardation by maternal manganese superoxide dismutase-plasmid liposome (MnSOD-PL) gene therapy

Gene Therapy volume 18, pages 579–583 (2011)Cite this article

Subjects

Abstract

To determine the effects of manganese superoxide dismutase (MnSOD) plasmid liposome (PL) maternal radioprotection on fetal mice, timed pregnant female mice (E14 gestation) were irradiated to 3.0 Gy total body irradiation (TBI) dose, and the number, weight and growth and development over 6 months after birth of newborn mice was quantitated compared with irradiated controls. Maternal MnSOD-PL treatment at E13 improved pup survival at birth (5.4±0.9 per litter) compared with non-irradiated 3.0 Gy controls 4.9±1.1. There was no statistically significant difference in newborn abnormalities, male to female ratio in newborn litters, or other evidence of teratogenesis in surviving newborn mice from MnSOD-PL treated compared with irradiated controls. However, E14 3 Gy irradiated pups from gene therapy-treated mothers showed a significant increase in both growth and overall survival over 6 months after birth (P=0.0022). To determine if transgene product crossed the placenta pregnant E13 mice were injected intravenously with hemagglutinin-epitope-tagged MnSOD (100 μg plasmid in 100 μl liposomes), then after 24 h, fetal mice, placentas and maternal tissues were removed and tested by both immunohistochemistry and reverse transcriptase-PCR for transgene and product. There was no evidence of transgene or product in placenta or any fetal tissue while maternal liver was positive by both assays. The data provide evidence for fetal radioprotection by maternal MnSOD-PL gene therapy before irradiation, which is mediated by an indirect bystander effect and is associated with a significant improvement in both survival at birth and growth and development of newborn mice.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Naumburg E, Bellocco R, Cnattingius S, Hall P, Boice Jr JD, Ekbom A . Intrauterine exposure to diagnostic x rays and risk of childhood leukemia subtypes. Radiat Res 2001; 156: 718–723.

    Article  CAS  Google Scholar 

  2. Nakashima E . Relationship of five anthropometric measurements at age 18 to radiation dose among atomic bomb survivors exposed in utero. Radiat Res 1994; 138: 121–126.

    Article  CAS  Google Scholar 

  3. Benjamin A, Lee AC, Angleton GM, Saunders WJ, Keefe TJ, Mallinckrodt CH . Mortality in beagles irradiated during prenatal and postnatal development. I. Contribution of non-neoplastic diseases. Radiat Res 1998; 150: 316–329.

    Article  CAS  Google Scholar 

  4. Ohtaki K, Kodama Y, Nakano M, Itoh M, Awa AA, Cologne J et al. Human fetuses do not register chromosome damage inflicted by radiation exposure in lymphoid precursor cells except for a small but significant effect at low doses. Radiat Res 2004; 161: 373–379.

    Article  CAS  Google Scholar 

  5. Nakano M, Kodama Y, Ohtaki K, Nakashima E, Niwa O, Toyoshima M et al. Chromosome aberrations do not persist in the lymphocytes or bone marrow cells of mice irradiated in utero or soon after birth. Radiat Res 2007; 167: 693–702.

    Article  CAS  Google Scholar 

  6. Nakashima E, Carter RL, Neriishi K, Tanaka S, Funamoto S . Height reduction among prenatally exposed atomic-bomb survivors: a longitudinal study of growth. Health Phys 1995; 68: 766–772.

    Article  CAS  Google Scholar 

  7. Anderson LM . Predictive values of traditional animal bioassay studies for human perinatal carcinogenesis risk determination. Toxicol Appl Pharmacol 2004; 199: 162–174.

    Article  CAS  Google Scholar 

  8. Devi PU, Satyamitra M . Tracing radiation induced genomic instability in vivo in the haemopoietic cells from fetus to adult mouse. Br J Radiol 2005; 78: 928–933.

    Article  CAS  Google Scholar 

  9. Hossain M, Devi PU, Bisht KS . Effect of prenatal gamma irradiation during the late fetal period on the postnatal development of the mouse. Teratology 1999; 59: 133–138.

    Article  CAS  Google Scholar 

  10. Devi PU, Hossain M . Effect of early fetal irradiation on the postnatal development of the mouse. Teratology 2001; 64: 45–50.

    Article  CAS  Google Scholar 

  11. Preston DL, Cullings H, Suyama A, Funamoto S, Nishi N, Soda M et al. Solid cancer incidente in atomic bomb survivors exposed in utero or as young children. J Natl Cancer Inst 2008; 100: 428–436.

    Article  Google Scholar 

  12. Merianos DJ, Tiblad E, Santote MT, Todorow CA, Laje P, Endo M et al. Maternal alloantibodies induce a postnatal immune response that limits engraftment following in utero hematopoietic cell transplantation in mice. J Clin Invest 2009; 119: 2590–2598.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Meador KJ, Baker GA, Browning N, Clayton-Smith J, Combs-Cantrell DT, Cohen M et al. Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs. N Engl J Med 2009; 360: 1597–1605.

    Article  CAS  Google Scholar 

  14. Tatsukawa Y, Nakashima E, Yamada M, Funamoto S, Hida A, Akahoshi M et al. Cardiovascular disease risk among atomic bomb survivors exposed in utero, 1978–2003. Radiat Res 2008; 170: 269–274.

    Article  CAS  Google Scholar 

  15. Epperly MW, Smith T, Wang H, Schlesselman J, Franicola D, Greenberger JS . Modulation of total body irradiation induced life shortening by systemic intravenous MnSOD-plasmid liposome gene therapy. Radiat Res 2008; 170: 437–444.

    Article  CAS  Google Scholar 

  16. Epperly MW, Guo HL, Bernarding M, Gretton J, Jefferson M, Greenberger JS . Delayed intratracheal injection of manganese superoxide dismutase (MnSOD)-plasmid/liposomes provides suboptimal protection against irradiation-induced pulmonary injury compared to treatment before irradiation. Gene Therapy Mol Biol 2003; 7: 61–68.

    Google Scholar 

  17. Epperly MW, Guo HL, Jefferson M, Wong S, Gretton J, Bernarding M et al. Cell phenotype specific duration of expression of epitope-tagged HA-MnSOD in cells of the murine lung following intratracheal plasmid liposome gene therapy. Gene Therapy 2003; 10: 163–171.

    Article  CAS  Google Scholar 

  18. Tarhini AA, Belani C, Luketich JD, Ramalingam SS, Argiris A, Gooding W et al. A phase I study of concurrent chemotherapy (Paclitaxel and Carboplatin) and thoracic radiotherapy with swallowed manganese superoxide dismutase (MnSOD) plasmid liposome (PL) protection in patients with locally advanced stage III non-small cell lung cancer. Human Gene Ther 2010, (in press).

  19. Greenberger JS, Epperly MW, Gretton J, Jefferson M, Nie S, Bernarding M et al. Radioprotective gene therapy. Current Gene Ther 2003; 3: 183–195.

    Article  CAS  Google Scholar 

  20. Epperly MW, Epstein CJ, Travis EL, Greenberger JS . Decreased pulmonary radiation resistance of manganese superoxide dismutase (MnSOD)-deficient mice is corrected by human manganese superoxide dismutase-plasmid liposome (SOD2-PL) intratracheal gene therapy. Radiat Res 2000; 154: 365–374.

    Article  CAS  Google Scholar 

  21. Epperly MW, Gretton JA, DeFilippi SJ, Sikora CA, Liggitt D, Koe G et al. Modulation of radiation-induced cytokine elevation associated with esophagitis and esophageal stricture by manganese superoxide dismutase-plasmid/liposome (SOD-PL) gene therapy. Radiat Res 2001; 155: 2–14.

    Article  CAS  Google Scholar 

  22. Guo HL, Seixas-Silva JA, Epperly MW, Gretton JE, Shin DM, Greenberger JS . Prevention of irradiation-induced oral cavity mucositis by plasmid/liposome delivery of the human manganese superoxide dismutase (MnSOD) transgene. Radiat Res 2003; 159: 361–370.

    Article  CAS  Google Scholar 

  23. Guo HL, Epperly MW, Bernarding M, Nie S, Gretton J, Jefferson M et al. Manganese superoxide dismutase-plasmid/liposome (MnSOD-PL) intratracheal gene therapy reduction of irradiation-induced inflammatory cytokines does not protect orthotopic lewis lung carcinomas. In Vivo 2003; 17: 13–22.

    CAS  PubMed  Google Scholar 

  24. Epperly MW, Travis EL, Sikora C, Greenberger JS . Magnesium superoxide dismutase (MnSOD) plasmid/liposome pulmonary radioprotective gene therapy: modulation of irradiation-induced mRNA for IL-1, TNF-α, and TGF-β correlates with delay of organizing alveolitis/fibrosis. Biol Blood Marrow Transplant 1999; 5: 204–214.

    Article  CAS  Google Scholar 

  25. Epperly MW, Bray JA, Esocobar P, Bigbee WL, Watkins S, Greenberger JS . Overexpression of the human MnSOD transgene in subclones of murine hematopoietic progenitor cell line 32D cl 3 decreases irradiation-induced apoptosis but does not alter G2/M or G1/S phase cell cycle arrest. Radiat Onco Inves Clin Basic Res 1999; 7: 331–342.

    Article  CAS  Google Scholar 

  26. Stickle RL, Epperly MW, Klein E, Bray JA, Greenberger JS . Prevention of irradiation-induced esophagitis by plasmid/liposome delivery of the human manganese superoxide dismutase (MnSOD) transgene. Radiat Oncol Invest Clin Basic Res 1999; 7: 204–217.

    Article  CAS  Google Scholar 

  27. Epperly MW, Defilippi S, Sikora C, Gretton J, Kalend K, Greenberger JS . Intratracheal injection of manganese superoxide dismutase (MnSOD) plasmid/liposomes protects normal lung but not orthotopic tumors from irradiation. Gene Therapy 2000; 7: 1011–1018.

    Article  CAS  Google Scholar 

  28. Epperly MW, Epstein CJ, Travis EL, Greenberger JS . Decreased pulmonary radiation resistance of manganese superoxide dismutase (MnSOD)-deficient mice is corrected by human manganese Superoxide dismutase-plasmid/liposome (SOD2-PL) intratracheal gene therapy. Radiat Res 2000; 154: 365–374.

    Article  CAS  Google Scholar 

  29. Epperly MW, Travis EL, Whitsett JA, Epstein CJ, Greenberger JS . Overexpression of manganese superoxide dismutase (MnSOD) in whole lung or alveolar type II (AT-II) cells of MnSOD transgenic mice does not provide intrinsic lung irradiation protection. Radiat Oncol Invest 2001; 96: 11–21.

    CAS  Google Scholar 

  30. Epperly MW, Kagan VE, Sikora CA, Gretton JE, Defilippi SJ, Bar-Sagi D et al. Manganese superoxide dismutase-plasmid/liposome (MnSOD-PL) administration protects mice from esophagitis associated with fractionated irradiation. Int J Cancer (Radiat Oncol Invest) 2001; 96: 221–233.

    Article  CAS  Google Scholar 

  31. Epperly MW, Sikora CA, Defilippi SJ, Gretton JE, Bar-Sagi D, Carlos T et al. Pulmonary irradiation-induced expression of VCAM-1 and ICAM-1 is decreased by MnSOD-PL gene therapy. Biol Blood Bone Marrow Transplant 2002; 8: 175–187.

    Article  CAS  Google Scholar 

  32. Epperly MW, Sikora C, Defilippi S, Gretton J, Zhan Q, Kufe DW et al. MnSOD inhibits irradiation-induced apoptosis by stabilization of the mitochondrial membrane against the effects of SAP kinases p38 and Jnk1 translocation. Radiat Res 2002; 157: 568–577.

    Article  CAS  Google Scholar 

  33. Hall EJ, Gacca A . Radiobiology for the Radiologist, 6th edn. Lippincott, William & Wilkins: New York, 2008.

    Google Scholar 

  34. Greenberger JS . Perspectives/opinion ‘Radioprotection’. In Vivo 2009; 23: 323–336.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Derradji H, Bekaert S, De Meyer T, Jacques P, Abou-El-Ardat K, Garrid M et al. Ionizing radiation-induced gene modulations, cytokine content changes and telomere shortening in mouse fetuses exhibiting forelimb defects. Dev Biol 2008; 322: 302–313.

    Article  CAS  Google Scholar 

  36. Streffer C . Bystander effects, adaptive response and genomic instability induced by prenatal irradiation. Mutat Res 2004; 568: 79–87.

    Article  CAS  Google Scholar 

  37. Rajagopalan MS, Stone B, Rwigema JC, Salimi U, Epperly MW, Goff J et al. Total body and thoracic irradiation sensitivity of homologous deletion recombinant negative nitric oxide synthase-1 (NOS-1−/−) mice. Rad Res 2010; 174: 297–312.

    Article  CAS  Google Scholar 

  38. Mader SL, Libal NL, Pritchett-Corning K, Yang R, Murphy SJ . Refining timed pregnancies in two strains of genetically engineered mice. Lab Animal 2009; 38: 305–310.

    Article  Google Scholar 

Download references

Acknowledgements

This project was supported by award number U19A1068021by the National Institute of Allergy and Infectious Diseases.

Author information

Authors and Affiliations

  1. Department of Radiation Oncology, UPCI Cancer Institute, Pittsburgh, PA, USA

    M W Epperly, T Smith, X Zhang, J P Goff, D Franicola, B Greenberger, P Komanduri, H Wang & J S Greenberger

Authors
  1. M W Epperly
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. T Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. X Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J P Goff
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. D Franicola
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. B Greenberger
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. P Komanduri
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. H Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. J S Greenberger
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J S Greenberger.

Ethics declarations

Competing interests

The authors declare no conflicts of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Epperly, M., Smith, T., Zhang, X. et al. Modulation of in utero total body irradiation induced newborn mouse growth retardation by maternal manganese superoxide dismutase-plasmid liposome (MnSOD-PL) gene therapy. Gene Ther 18, 579–583 (2011). https://doi.org/10.1038/gt.2010.178

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/gt.2010.178

Keywords

This article is cited by

Search

Advanced search

Quick links