Skip to main content

Advertisement

Log in

Evaluation of Maternal Reproductive Outcomes and Biochemical Analysis from Wistar Audiogenic Rats (WAR) and Repercussions in Their Offspring

  • Original Article
  • Published:
Reproductive Sciences Aims and scope Submit manuscript

Abstract

The objective of the present study was to evaluate maternal reproductive performance, body weight, and frequency of external and internal anomalies of newborns of Wistar Audiogenic Rat (WAR) females as compared with Wistar rats. The adult WAR and Wistar rats were mated within their respective strains. After confirming the pregnancy, the body weights were weekly evaluated. On day 21 of pregnancy, the female rats were anesthetized and sacrificed to evaluate the maternal reproductive outcomes and biochemical profile, newborn weight, and external and internal anomalies. The WAR strain gained less weight during the pregnancy and presented hyperproteinemia, hypertriglyceridemia, and embryonic losses concerning Wistar rats, suggesting an inadequate intrauterine condition for embryonic development and fetal viability. WAR also presented a higher percentage of newborns classified as small for gestational age related to intrauterine growth restriction, which was confirmed by the lower number of ossification centers. There was a higher percentage of skeletal anomalies compared with fetuses of the Wistar dams, confirming their greater susceptibility during the formation and development of their skeletal system. Thus, the WAR presents physiological alterations compromising the viability of their embryos and fetuses, leading to impaired development of the newborns.

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.

Fig. 1

Similar content being viewed by others

References

  1. Beghi E. The epidemiology of epilepsy. Neuroepidemiology. 2019;54:185–91. https://doi.org/10.1159/000503831.

    Article  Google Scholar 

  2. Kandratavicius L, Balista PA, Lopes-Aguiar C, Ruggiero R, Umeoka E, Garcia-Cairasco N, et al. Animal models of epilepsy: use and limitations. Neuropsychiatr Dis Treat. 2014;10:1693–705. https://doi.org/10.2147/NDT.S50371.

    Article  Google Scholar 

  3. Brazilian Association of Neurology. Epilepsia. 2019. http://www.cadastro.abneuro.org/site/publico_epilepsia.asp.

  4. Kanner AM, Barry J. Why do neurologists and psychiatrists not talk to each other? In: Kanner AM, Schachter SC, Kanemoto K, Tadokoro Y, Oshima T, editors. Psychiatric controversies in epilepsy. Boston: Academic Press; 2008. p. 19–31.

    Chapter  Google Scholar 

  5. Dechandt CRP, Vicentini TM, Lanfredi GP, Silva-Jr RMP, Espreafico EM, de Oliveira JAC, et al. The highly efficiente powerhouse in the Wistar audiogenic rat, an epileptic rat strain. Am J Phys Regul Integr Comp Phys. 2019;16:R243–54. https://doi.org/10.1152/ajpregu.00254.2018.

    Article  CAS  Google Scholar 

  6. Doretto MC, Fonseca CG, Lobo RB, Terra VC, Oliveira JAC, Garcia-Cairasco N. Quantitative study of the response to generic selection of the Wistar audiogenic rat strain (WAR). Behav Genet. 2003;33:33–42. https://doi.org/10.1023/a:1021099432759.

    Article  CAS  Google Scholar 

  7. Garcia-Cairasco N, Umeoka EHL, Oliveira JAC. The Wistar Audiogenic Rat (WAR) strain and its contributions to epileptology and related comorbities: history and perspectives. Epilepsy Behav. 2017;71:250–73. https://doi.org/10.1016/j.yebeh.2017.04.001.

    Article  Google Scholar 

  8. Frings H, Frings M, Kivert A. Behaviour patterns of the laboratory mouse under audiotory stress. J Mammal. 1951;32:60–76. https://doi.org/10.2307/1375413.

    Article  Google Scholar 

  9. Skradski SI, Clark AM, Jiang H, White HS, Fu YH, Ptácek IJ. A novel gene causing a mendelian audiogenic mouse epilepsy. Neuron. 2001;31:537–44. https://doi.org/10.1016/s0896-6273(01)00397-x.

    Article  CAS  Google Scholar 

  10. Seyfried TN, Yu RK, Glaser GH. Genetic analysis of audiogenic seizure susceptibility in C57BL/6J X DBA/2J recombinant inbred strains of mice. Genetics. 1980;94:701–18.

    CAS  Google Scholar 

  11. Schreiber RA, Graham JM. Audiogenic priming in DBA/2J and C57 BL/6J mice: interactions among age, prime-to-test interval, and index of seizure. Dev Psychobiol. 1976;9:57–66. https://doi.org/10.1002/dev.420090109.

    Article  CAS  Google Scholar 

  12. Krushinsky LV. Etude physiologique des differents types de crise convulsives de l'epilepsie audiogene du rat. In: Busnel RG, editor. Psychophysiologie, Neuropharmacologie et Biechemie de la Crise Audiogene. Paris: CNRS; 1963. p. 71–92.

    Google Scholar 

  13. Jobe PC, Picchioni AL, Chin L. Role of brain norepinephrine in audiogenic seizure in the rat. J Pharmacol Exp Ther. 1973;184:1–10. https://doi.org/10.1111/j.2042-7158.1973.tb09952.x.

    Article  CAS  Google Scholar 

  14. Ko KH, Dailey JW, Jobe PC. Effect of increments in norepinephrine concentrations on seizure intensity in the genetically epilepsy-prone rat. J Pharmacol Exp Ther. 1982;222:662–9.

    CAS  Google Scholar 

  15. Jobe PC, Laird HE, Ko KH, Ray T, Dailey JW. Abnormalities in monoamine levels in the central nervous system of the genetically epilepsy-prone rat. Epilepsia. 1982;23:359–66. https://doi.org/10.1111/j.1528-1157.1982.tb05421.x.

    Article  CAS  Google Scholar 

  16. Zhao DY, Wu XR, Pei YQ, Zuo QH. Kindling phenomenon of hyperthermic seizures in the epilepsy-prone versus the epilepsy-resistant rat. Brain Res. 1985;358:390–3. https://doi.org/10.1016/0006-8993(85)90991-6.

    Article  CAS  Google Scholar 

  17. van Luijtelaar EL, Coenen AM. Two types of electrocortical paroxysms in an inbred strain of rats. Neurosci Lett. 1986;70:393–7. https://doi.org/10.1016/0304-3940(86)90586-0.

    Article  Google Scholar 

  18. Marescaux C, Vergnes M, Kiesmann M, Depaulis A, Micheletti G, Warter JM. Kindling of audiogenic seizures in Wistar rats: an EEG study. Exp Neurol. 1987;97:160–8. https://doi.org/10.1016/0014-4886(87)90290-1.

    Article  CAS  Google Scholar 

  19. Carballosa-Gonzalez MM, Muñoz LJ, López-Alburquerque T, Pardal-Fernández JM, Nava E, de Cabo C, et al. EEG characterization of audiogenic seizures in the hamster strain GASH:Sal. Epilepsy Res. 2013;106:318–25. https://doi.org/10.1016/j.eplepsyres.2013.07.001.

    Article  Google Scholar 

  20. Prieto-Martín AI, Aroca-Aguilar JD, Sánchez-Sánchez F, Muñoz LJ, López DE, Escribano J, et al. Molecular and neurochemical substrates of the audiogenic seizure strains: the GASH:Sal model. Epilepsy Behav. 2017;71:218–25. https://doi.org/10.1016/j.yebeh.2015.05.025.

    Article  Google Scholar 

  21. Garcia-Cairasco N. A critical review on the participation of inferior colliculus in acoustic-motor and acoustic-limbic networks involved in the expression of acute and kindled audiogenic seizures. Hear Res. 2002;168:208–22. https://doi.org/10.1016/s0378-5955(02)00371-4.

    Article  Google Scholar 

  22. Tsutsui J, Terra VC, Garcia-Cairasco N. Neuroethological evaluation of audiogenic seizures and audiogenic-like seizures induced by microinjection of bicuculline into the inferior colliculus. II. Effects of nigral clobazam microinjections. Behav Brain Res. 1992;52:19–28. https://doi.org/10.1016/s0166-4328(05)80320-1.

    Article  Google Scholar 

  23. Botion LM, Doretto MC. Changes in peripheral energy metabolism during audiogenic seizures in rats. Physiol Behav. 2003;78:535–41. https://doi.org/10.1016/S0031-9384(03)00061-1.

    Article  CAS  Google Scholar 

  24. Pereira FKS, Neves MJ, Lima MP, Braga AA, Pesquero JL, Doretto MC, et al. Peripheral glucose metabolism is altered by epileptic seizures. Metab Brain Dis. 2008;23:105–14. https://doi.org/10.1007/s11011-007-9075-0.

    Article  CAS  Google Scholar 

  25. Umeoka EH, Garcia SB, Antunes-Rodrigues J, Elias LL, Garcia-Cairasco N. Functional characterization of the hypothalamic-pituitary-adrenal axis of the Wistar Audiogenic Rat (WAR) strain. Brain Res. 2011;1381:141–7. https://doi.org/10.1016/j.brainres.2011.01.042.

    Article  CAS  Google Scholar 

  26. Umeoka EH, Eiras MC, Viana IG, Giorgi VS, Bueno A, Damasceno DC, et al. Maternal reproductive performance and fetal development of the Wistar Audiogenic Rat (WAR) strain. Syst Biol Reprod Med. 2019;65:87–94. https://doi.org/10.1080/19396368.2018.1483443.

    Article  Google Scholar 

  27. Moraes-Souza RQ, Reinaque AP, Soares TS, Silva ALT, Giunchetti RC, Takano MAS, et al. Safety evaluation of a vaccine: effect in maternal reproductive outcome and fetal anomaly frequency in rats using a leishmanial vaccine as a model. PLoS One. 2017;12:e0172525. https://doi.org/10.1371/journal.pone.0172525.

    Article  CAS  Google Scholar 

  28. Salewski E. Färbemethode zum makroskopischen nachweis von implantationsstellen am uterus der ratte. Naunyn-Schmiedebergs Arch. 1964;247:367. https://doi.org/10.1007/BF02308461.

    Article  Google Scholar 

  29. Soares TS, Damasceno DC, Kempinas WG, et al. Effect of Himatanthus sucuuba in maternal reproductive outcome and fetal anomaly frequency in rats. Birth Defects Res B Dev Reprod Toxicol. 2015;104:190–5. https://doi.org/10.1002/bdrb.21152.

    Article  CAS  Google Scholar 

  30. Damasceno DC, Silva HP, Vaz GF, Vasques-Silva FA, Calderon IMP, Rudge MVC, et al. Diabetic rats exercised prior to and during pregnancy: maternal reproductive outcome, biochemical profile, and frequency of fetal anomalies. Reprod Sci. 2013;20:730–8. https://doi.org/10.1177/1933719112461186.

    Article  Google Scholar 

  31. Young DS. Effects of drugs on clinical laboratory tests. 5th ed. London: AACC Press; 2000.

    Google Scholar 

  32. Knopfholz J, Disserol CC, Pierin AJ, et al. Validation of the friedewald formula in patients with metabolic syndrome. Cholesterol. 2014;2014:261878–5. https://doi.org/10.1155/2014/261878.

    Article  CAS  Google Scholar 

  33. Wilson JG. Methods for administering agents and detecting malformations in experimental animal. In: Wilson JG, Warkany J, editors. Teratology: principles and techniques. Chicago: University of Chicago Press; 1965. p. 262–77.

    Google Scholar 

  34. Staples RE, Schnell VL. Refinements in rapid clearing technique in the KOHalizarin red S method for fetal bone. Stain Technol. 1964;39:61–3.

    CAS  Google Scholar 

  35. Aliverti V, Bonanomi L, Giavini E, Leone VG, Mariani L. The extent of fetal ossification as an index of delayed development in teratogenic studies on the rat. Teratology. 1979;20:237–42. https://doi.org/10.1002/tera.1420200208.

    Article  CAS  Google Scholar 

  36. Dallaqua B, Saito FH, Rodrigues T, Calderon IMP, Rudge MVC, Volpato GT, et al. Azadirachta indica treatment on the congenital malformations of fetuses from rats. J Ethnopharmacol. 2013;150:1109–13. https://doi.org/10.1016/j.jep.2013.10.046.

    Article  CAS  Google Scholar 

  37. Damasceno DD, Savergnini SQ, Gomes ER, et al. Cardiac dysfunction in rats prone to audiogenic epileptic seizures. Seizure. 2013;22:259–66. https://doi.org/10.1016/j.seizure.2013.01.006.

    Article  Google Scholar 

  38. Thorn M. Neuropathologic findings in postmortem studies of sudden death in epilepsy. Epilepsia. 1997;38:S32–4. https://doi.org/10.1111/j.1528-1157.1997.tb06123.x.

    Article  CAS  Google Scholar 

  39. Linzer M, Grubb BP, Ho S, Ramakrishnan L, Bromfield E, Estes NA. Cardiovascular causes of loss of consciousness in patients with presumed epilepsy: a cause of the increased sudden death rate in people with epilepsy? Am J Med. 1994;96:146–54. https://doi.org/10.1016/0002-9343(94)90135-x.

    Article  CAS  Google Scholar 

  40. Asano Y, Susami M, Honda K, Serikawa T. Haematological and serum biochemical values in spontaneously epileptic male rats and related rat strains. Lab Anim. 1998;32:214–8. https://doi.org/10.1258/002367798780600052.

    Article  CAS  Google Scholar 

  41. Islam NAF, Chowdhury MAR, Kibria GM, Akhter S. Study of serum lipid profile in pre-eclampsia and eclampsia. Faridpur Med Coll J. 2010;5(2):56–9. https://doi.org/10.3329/fmcj.v5i2.6823.

    Article  Google Scholar 

  42. Kaneko JJ. Serum proteins and the dysproteinemias. In: Kaneko JJ, editor. Clinical biochemistry of domestic animals. San Diego: Academic Press; 1997. p. 117–38.

    Chapter  Google Scholar 

  43. Bersinger NA, Smárason AK, Muttukrishna S, Groome NP, Redman CW. Women with preeclampsia have increased serum levels of pregnancy-associated plasma protein A (PAPP-A), inhibin A, activin A and soluble E-selectin. Hypertens Pregnancy. 2003;22(1):45–55. https://doi.org/10.1081/PRG-120016794.

    Article  CAS  Google Scholar 

  44. Muller F, Savey L, Le Fiblec B, et al. Maternal serum human chorionic gonadotropin level at fifteen weeks is a predictor for preeclampsia. Am J Obstet Gynecol. 1996;175(1):37–40. https://doi.org/10.1016/s0002-9378(96)70247-8.

    Article  CAS  Google Scholar 

  45. Bersinger NA, Odegard RA. Second- and third-trimester serum levels of placental proteins in preeclampsia and small-for-gestational age pregnancies. Acta Obstet Gynecol Scand. 2004;83:37–45.

    Article  Google Scholar 

  46. Audibert F, Benchimol Y, Benattar C, Champagne C, Frydman R. Prediction of preeclampsia or intrauterine growth restriction by second trimester serum screening and uterine Doppler velocimetry. Fetal Diagn Ther. 2005;20:48–53. https://doi.org/10.1159/000081369.

    Article  Google Scholar 

  47. Venkatesha S, Toporsian M, Lam C, Hanai JI, Mammoto T, Kim YM, et al. Soluble endoglin contributes to the pathogenesis of preeclampsia. Nat Med. 2006;12:642–9. https://doi.org/10.1038/nm1429.

    Article  CAS  Google Scholar 

  48. Baumann MU, Bersinger NA, Surbek DV. Serum markers for predicting pre-eclampsia. Mol Asp Med. 2007;28:227–44. https://doi.org/10.1016/j.mam.2007.04.002.

    Article  CAS  Google Scholar 

  49. Teixeira PG, Cabral AC, Andrade SP, et al. Placental growth factor (PlGF) is a surrogate marker in preeclamptic hypertension. Hypertens Pregnancy. 2008;27:65–73. https://doi.org/10.1080/10641950701825937.

    Article  CAS  Google Scholar 

  50. Antsaklis P, Fasoulakis Z, Theodora M, Diakosavvas M, Kontomanolis EN. Association of low maternal pregnancy-associated plasma protein a with adverse perinatal outcome. Cureus. 2019;11(6):e4912. https://doi.org/10.7759/cureus.4912.

    Article  Google Scholar 

  51. Tomson T, Perucca E, Battino D. Navigating toward fetal and maternal health: the challenge of treating epilepsy in pregnancy. Epilepsia. 2004;45:1171–5. https://doi.org/10.1111/j.0013-9580.2004.15104.x.

    Article  Google Scholar 

  52. Viinikainen K, Heinonen S, Eriksson K, Kälviäinen R. Community-based, prospective, controlled study of obstetric and neonatal outcome of 179 pregnancies in women with epilepsy. Epilepsia. 2006;47:186–92. https://doi.org/10.1111/j.1528-1167.2006.00386.x.

    Article  Google Scholar 

  53. Meador K, Reynolds MW, Crean S, Fahrbach K, Probst C. Pregnancy outcomes in women with epilepsy: a systematic review and meta-analysis of published pregnancy registries and cohorts. Epilepsy Res. 2008;81:1–13. https://doi.org/10.1016/j.eplepsyres.2008.04.022.

    Article  Google Scholar 

Download references

Acknowledgments

The authors thank Mr. Danilo Chaguri, the technician responsible for the Laboratory of Experimental Research in Gynecology and Obstetrics, for the handling of the animals and assistance in the surgeries.

Funding

This study was financed by the CNPq for the fellowship to B.T. Antunes. N. Garcia-Cairasco, and CAPES and FAPESP for grants associated with the WAR selection and maintenance. D.C. Damasceno and N. Garcia-Cairasco hold CNPq Research Fellowships.

Author information

Authors and Affiliations

Authors

Contributions

Rafaianne Queiroz Moraes-Souza, Yuri Karen Sinzato, Gustavo Tadeu Volpato, and Débora Cristina Damasceno designed the study. Rafaianne Queiroz Moraes-Souza and Beatriz Tambasco Antunes collected the data. Norberto Garcia-Cairasco and José Antônio C. Oliveira donated WAR strain for the study. Rafaianne Queiroz Moraes-Souza, Yuri Karen Sinzato, Gustavo Tadeu Volpato, and Débora Cristina Damasceno performed all statistical analyses and interpreted the data. All authors drafted the work and performed final revision of the intellectual content. All authors were responsible for critical revisions and approved the final version of the manuscript.

Corresponding author

Correspondence to Débora Cristina Damasceno.

Ethics declarations

The animals were maintained following the principles of Guide for Care and Use of Experimental Animals. All experimental procedures performed in this study were approved by the Ethics Committee in Animal Experimentation of UNESP-Botucatu, São Paulo State, Brazil (Protocol number 1123/2015).

Conflict of Interest

The authors declare that they have no conflict of interest.

Code Availability

Not applicable.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Moraes-Souza, R.Q., Sinzato, Y.K., Antunes, B.T. et al. Evaluation of Maternal Reproductive Outcomes and Biochemical Analysis from Wistar Audiogenic Rats (WAR) and Repercussions in Their Offspring. Reprod. Sci. 27, 2223–2231 (2020). https://doi.org/10.1007/s43032-020-00236-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s43032-020-00236-0

Keywords

Navigation