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An Animal Model of Intrauterine Growth Retardation Induced by Synthetic Thromboxane A2

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Abstract

Objective

Intrauterine growth retardation (IUGR) is an important cause of prenatal and neonatal morbidity, and neurologic abnormalities. Although several animal models of IUGR have been developed for scientific investigation, few models approximate the pathophysiology in human fetal growth failure resulting from pregnancy-induced hypertension and preeclampsia. We developed an animal model of IUGR in which fetal growth restriction was induced by administering a synthetic thromboxane A2 analogue (STA2) to the mother.

Methods

Timed pregnant Sprague-Dawley rats were used in this study. STA2 was delivered into the peritoneal cavity of the pregnant female at a rate of 20 ng/h from day 13 of pregnancy. The effectiveness of this model was evaluated by monitoring the overall growth of the fetuses and neonates and measuring the weight and biochemical composition of individual organs.

Results

Fetuses and neonates from the STA2 group showed a highly significant weight reduction throughout the observation period from day 19 of gestation to postnatal day 7. Weight reduction near and at term exceeded 10% and became more pronounced during the first week after birth. Fetuses on the 20th gestational day exhibited a pattern of growth retardation characteristic of asymmetrical IUGR in which the weight reduction was prominent in the liver with relative sparing of the brain. However, the decrease in brain weight was more than 10%. The protein, DNA, and RNA contents of the liver were lower in the STA2 group. The protein content of the forebrain and brainstem also decreased significantly in the STA2 group compared with the control; however, the DNA content of the forebrain was higher in the STA2 group.

Conclusions

This animal model may mimic human IUGR more closely than previous models because the growth restriction is induced in a truly chronic manner.

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References

  1. Aucott SW, Donohue PK, Northington FJ. Increased morbidity in severe early intrauterine growth restriction. J Perinatol 2004;24;435–440.

    Article  Google Scholar 

  2. Bergvall N, Iliadou A, Johansson S, Tuvemo T, Cnattingius S. Risks for low intellectual performance related to being born small for gestational age are modified by gestational age. Pediatrics 2006;117:e460–e467.

    Article  Google Scholar 

  3. Martorell R, Ramakrishnan U, Schroeder DG, Melgar P, Neufeld L. Intrauterine growth retardation, body size, body composition and physical performance in adolescence. Eur J Clin Nutr 1998;52(Suppl 1):S43–S52.

    PubMed  Google Scholar 

  4. Strauss RS, Dietz WH. Effects of intrauterine growth retardation in premature infants on early childhood growth. J Pediatr 1997;130:95–102.

    Article  CAS  Google Scholar 

  5. Schreuder MF, Fodor M, van Wijk JA, Delemarre-van de Waal HA. Association of birth weight with cardiovascular parameters in adult rats during baseline and stressed conditions. Pediatr Res 2006;59:126–130.

    Article  Google Scholar 

  6. Simmons R. Developmental origins of adult metabolic disease: Concepts and controversies. Trends Endocrinol Metab 2005;16:390–394.

    Article  CAS  Google Scholar 

  7. Brodszki J, Lanne T, Marsal K, Ley D. Impaired vascular growth in late adolescence after intrauterine growth restriction. Circulation 2005;111;2623–2628.

    Article  CAS  Google Scholar 

  8. Wigglesworth JS. Experimental growth retardation in the foetal rat. J Pathol Bacteriol 1964;88:1–13.

    Article  CAS  Google Scholar 

  9. Roux JM, Tordet-Caridroit C, Chanez C. Studies on experimental hypotrophy in the rat. I. Chemical composition of the total body and some organs in the rat foetus. Biol Neonate 1970;15:342–347.

    Article  CAS  Google Scholar 

  10. Cha CJ, Gelar di NL, Oh W. Growth and cellular composition in rats with intrauterine growth retardation: Effects of postnatal nutrition. J Nutr 1987;117:1463–1468.

    Article  CAS  Google Scholar 

  11. Hayashi TT, Dorko ME. A rat model for the study of intrauterine growth retardation. Am J Obstet Gynecol 1988;158:1203–1207.

    Article  CAS  Google Scholar 

  12. Lueder FL, Ogata ES. Uterine artery ligation in the maternal rat alters fetal tissue glucose utilization. Pediatr Res 1990;28:464–468.

    Article  CAS  Google Scholar 

  13. Van Geijn HP, Kaylor WM Jr, Nico la KR, Zuspan FP. Induction of severe intrauterine growth retardation in the Sprague-Dawley rat. Am J Obstet Gynecol 1980;137:43–47.

    Article  Google Scholar 

  14. Rosso P. Maternal-fetal exchange during protein malnutrition in the rat. Placental transfer of alpha-amino isobutyric acid. J Nutr 1977;107:2002–2005.

    Article  CAS  Google Scholar 

  15. McKenzie JM, Fosmire GJ, Sandstead HH. Zinc deficiency during the latter third of pregnancy: Effects on fetal rat brain, liver, and placenta. J Nutr 1975;105:1466–1475.

    Article  CAS  Google Scholar 

  16. Streissguth AP, Landesman-Dwyer S, Martin JC, Smith DW. Teratogenic effects of alcohol in humans and laboratory animals. Science 1980;209:353–361.

    Article  CAS  Google Scholar 

  17. Chaube S, Swinyard CA. Cellular and biochemical aspects of growth retardation in rat fetuses induced by maternal administration of selected anticancer agents. Teratology 1975;12:259–270.

    Article  CAS  Google Scholar 

  18. Wallenburg HC, Rotmans N. Prevention of recurrent idiopathic fetal growth retardation by low-dose aspirin and dipyridamole. Am J Obstet Gynecol 1987;157:1230–1235.

    Article  CAS  Google Scholar 

  19. Magness RR, Mitchell MD, Rosenfeld CR. Uteroplacental production of eicosanoids in ovine pregnancy. Prostaglandins 1990;39:75–88.

    Article  CAS  Google Scholar 

  20. Sibai BM. An aspirin a day to prevent prematurity. Clin Perinatol 1992;19:305–317.

    Article  CAS  Google Scholar 

  21. Mills JL, DerSimonian R, Raymond E, et al. Prostacyclin and thromboxane changes predating clinical onset of preeclampsia: A multicenter prospective study. JAMA 1999;282:356–362.

    Article  CAS  Google Scholar 

  22. Rocca B, Loeb AL, Strauss JF 3rd, et al. Directed vascular expression of the thromboxane A2 receptor results in intrauterine growth retardation. Nat Med 2000;6:219–221.

    Article  CAS  Google Scholar 

  23. Pradelles P, Grassi J, Maclouf J. Enzyme immunoassays of eicosanoids using acetylcholine esterase as label: An alternative to radioimmunoassay. Anal Chem 1985;57:1170–1173.

    Article  CAS  Google Scholar 

  24. Slot C. Plasma creatinine determination. A new and specific Jaffe reaction method. Scand J Clin Lab Invest 1965;17:381–387.

    Article  CAS  Google Scholar 

  25. Schmidt G, Thannhauser SJ. A method for determination of deoxyribonucleic acid, ribonucleic acid, and phosphoproteins in animal tissues. J Biol Chem 1945;161:83–89.

    CAS  PubMed  Google Scholar 

  26. Zamenhof S, Bursztyn H, Rich K, Zamenhof PJ. The determination of deoxyribonucleic acid and of cell number in brain. J Neurochem 1964;11:505–509.

    Article  CAS  Google Scholar 

  27. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem 1951;193:265–275.

    CAS  Google Scholar 

  28. Ergaz Z, Avgil M, Ornoy A. Intrauterine growth restriction-etiology and consequences: What do we know about the human situation and experimental animal models? Reprod Toxicol 2005;20:301–322.

    Article  CAS  Google Scholar 

  29. Ishimitsu T, Uehara Y, Ishii M, Sugimoto T. Enhanced generation of vascular thromboxane A2 in spontaneously hypertensive rats and its role in the rapid proliferation of vascular smooth muscle cells. Am J Hypertens 1988;1:38S–40S.

    Article  CAS  Google Scholar 

  30. Yusuf K, Smith SD, Levy R, et al. Thromboxane A(2) limits differentiation and enhances apoptosis of cultured human trophoblasts. Pediatr Res 2001;50:203–209.

    Article  CAS  Google Scholar 

  31. Younoszai MK, Peloso J, Haworth JC. Fetal growth retardation in rats exposed to cigarette smoke during pregnancy. Am J Obstet Gynecol 1969;104:1207–1213.

    Article  CAS  Google Scholar 

  32. Nitzan M, Orloff S, Chrzanowska BL, Schulman JD. Intrauterine growth retardation in renal insufficiency: An experimental model in the rat. Am J Obstet Gynecol 1979;133:40–43.

    Article  CAS  Google Scholar 

  33. de Grauw TJ, Myers R E, Scott WJ. Fetal growth retardation in rats from different levels of hypoxia. Biol Neonate 1986;49:85–89.

    Article  Google Scholar 

  34. Jacobson M. Histogenesis and morphogenesis of cortical stuctures. In: Jacobson M, ed. Developmental Neurobiology. 3rd ed. New York: Plenum, 1991:401—52.

    Chapter  Google Scholar 

  35. Hill DE, Myers RE, Holt AB, Scott RE, Cheek DB. Fetal growth retardation produced by experimental placental insufficiency in the rhesus monkey. II. Chemical composition of the brain, liver, muscle and carcass. Biol Neonate 1971;19:68–82.

    Article  CAS  Google Scholar 

  36. O W, Guy JA. Cellular growth in experimental intrauterine growth retardation in rats. J Nutr 1971;101:1631–1633.

    Article  Google Scholar 

  37. Bernal A, Morales M, Feria-Velasco A, Chew S, Rosado A. Effect of intrauterine growth retardation on the biochemical maturation of brain synaptosomes in the rat. J Nutr 1974;104:1157–1164.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Maternity and Perinatal Care Center, Nagoya University Hospital, 65 Tsurumai-cho, Showa-ku Nagoya, 466-8550, Japan

    Masahiro Hayakawa MD, PhD, Koji Takemoto MD, Atsushi Nakayama MD, Akiko Saito MD, Yoshiaki Sato MD, Masayuki Hasegawa MD, Kuniko Ieda MD & Shunji Mimura MD, PhD

  2. Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Masahiro Hayakawa MD, PhD, Koji Takemoto MD, Atsushi Nakayama MD, Akiko Saito MD, Yoshiaki Sato MD, Masayuki Hasegawa MD, Kuniko Ieda MD & Shunji Mimura MD, PhD

  3. Department of Pediatrics, Tousei General Hospital, Seto, Japan

    Masahiro Hayakawa MD, PhD, Koji Takemoto MD, Atsushi Nakayama MD, Akiko Saito MD, Yoshiaki Sato MD, Masayuki Hasegawa MD, Kuniko Ieda MD & Shunji Mimura MD, PhD

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  1. Masahiro Hayakawa MD, PhD
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  2. Koji Takemoto MD
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  3. Atsushi Nakayama MD
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  4. Akiko Saito MD
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  6. Masayuki Hasegawa MD
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  7. Kuniko Ieda MD
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  8. Shunji Mimura MD, PhD
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Corresponding author

Correspondence to Masahiro Hayakawa MD, PhD.

Additional information

Supported by a Grant-in-Aid (No. 17591139) for Scientific Research from the Japan Society for the Promotion of Science.

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Hayakawa, M., Takemoto, K., Nakayama, A. et al. An Animal Model of Intrauterine Growth Retardation Induced by Synthetic Thromboxane A2. Reprod. Sci. 13, 566–572 (2006). https://doi.org/10.1016/j.jsgi.2006.09.007

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