Long-term effects of maternal exposure to surgical stress at the earliest stage of pregnancy on blood pressure and behavior in offspring of OXYS rats

The use of some assisted reproductive technologies, in particular, embryo transfer, may cause various physiological and behavioral changes in the offspring. The purpose of our study was to study the effects of surgery (which is used for embryo transfer) done with pregnant dams on the weight, blood pressure and behavior in the open field and elevated plus­maze tests in adult offspring. Thus, long­term effects on the offspring after maternal exposure to surgical stress given to dams at the 4th day of pregnancy were studied in OXYS rats. OXYS females were mated in estrus with fertile males of the same strain. 96 hours after spermatozoa were found in vaginal smears the surgery (sham operation, imitating embryo transfer) was performed. Body weight (BW), systolic (SAP) and diastolic (DAP) arterial pressure as well as behavior in open field (OF) and elevated plus maze (EPM) tests were studied in the offspring of females exposed to surgical treatment during pregnancy (OXYS­PS) at the age of 3 mo. Untreated offspring of OXYS rats were used as controls. BW in naturally born OXYS rats did not differ from those of the OXYS­PS group. OXYS and OXYS­PS rats exhibited higher SAP (more than 150 mm Hg) and DAP; it is noteworthy that both SAP and DAP were higher in the OXYS­PS group than in the control group. The time spent in the center of arena, the area studied, the time and number of rearing were decreased in OXYS­PS rats in the OF test as compared to the OXYS controls. Moreover, OXYS­PS rats were characterized by the absence of grooming in the OF test. As was demonstrated by the EPM test, the duration and numbers of peeking out from closed arms were decreased in the OXYS­PS rats as compared to the OXYS controls. Thus, OXYS dams’ exposure to surgical stress at their early pregnancy led to such effects in the offspring as elevated SAP and DAP, decreased overall activity and increased anxiety.

OXYS rats, pregnancy, surgical treatment, long­term effects

1. Amstislavsky S.Y., Alekhina T.A., Barykina N.N., Chuguy V.F., Petrenko O.I., Kolpakov V.G. Effects of change of maternal environment during early postnatal development on behaviour in cataleptic rats. Behav. Proc. 2001;56(1):41-47. PMID: 11566236.

2. Amstislavsky S., Amstislavskaya T., Stein M., Maksimovsky L., Markel A., Ternov skaya Yu., Ternovsky D., Amstislavsky S. Embryo cryobanking for conserving laboratory and wild animal species. Scand. J. Lab. Anim. Sci. 1996;23:269-277.

3. Badache S., Bouslama S., Brahmia O., Baïri A.M., Tahraoui A.K., Ladjama A. Prenatal noise and restraint stress interact to alter exploratory behavior and balance in juvenile rats, and mixed stress reverses these effects. Stress. 2017;20:320-328. DOI 10.1080/10253890.2017. 1307962.

4. Barker D.J. In utero programming of cardiovascular disease. Theriogenology. 2000;53:555-574.

5. Belzung C., Griebel G. Measuring normal and pathological anxiety-like behaviour in mice: a review. Behav. Brain Res. 2001;125(1-2):141149. PMID: 11682105.

6. Brusentsev E.Yu., Igonina T.N., Amstislavsky S.Ya. Traditional and modern approaches to the culture of preimplantation mammalian embryos in vitro. Ontogenez = Ontogenesis (Moscow). 2014;45(2):7388. DOI 10.7868/S0475145014020037. (in Russian)

7. Carobrez A.P., Bertoglio L.J. Ethological and temporal analyses of anxiety-like behavior: the elevated plus-maze model 20 years on. Neuro sci. Biobehav. 2005;29:1193-1205. DOI 10.1016/j.neubiorev.2005.04.017.

8. Cruz A.P., Frei F., Graeff F.G. Ethopharmacological analysis of rat behavior on the elevated plus-maze. Pharmacol. Biochem. Behav. 1994;49(1):171-176. PMID: 7816869.

9. Dene H., Rapp J.P. Lack of effects of maternal salt intake on blood pressure of offspring in Dahl salt-sensitive rats. Clin. Exp. Hypertens. 1985;7:1121-1133.

10. Di Nicolantonio R., Koutsis K., Westcott K.T., Wlodek M.E. Relative contribution of the prenatal versus postnatal period on development of hypertension and growth rate of the spontaneously hypertensive rat. Clin. Exp. Pharm. Phys. 2006;33:9-16.

11. Gray S.D. Reciprocal embryo transfer between SHR and WKY. II. Effect on cardiovascular development. Clin. Exp. Hypertens. Part A. Theory Pract. 1991;13:963-969.

12. Igonina T.N., Ragaeva D.S., Prokudina O.I., Brusentsev E.Yu., Rozhkova I.N., Abramova T.O., Amstislavsky S.Ya. Effects of in vitro culture and embryo transfer on arterial blood pressure, body weight and behaviour in ISIAH rats. Rossiyskiy fiziologicheskiy zhurnal im. I.M. Sechenova = I.M. Sechenov Physiological Journal. 2016; 102(9):1089-1098. (in Russian)

13. Kolosova N.G., Stefanova N.A., Korbolina E.E., Fursova A.Zh., Kozhevnikova O.S. Senescence-accelerated OXYS rats: A genetic model of premature aging and age-related diseases. Adv. Gerontol. 2014;4:294-298.

14. Kubisch H.M., Gomez-Sanchez E.P. Embryo transfer in the rat as a tool to determine genetic components of the gestational environment. Lab. Anim. Sci. 1999;49(1):90-94. PMID: 10090101.

15. Kulikov A.V., Tikhonova M.A., Kulikov V.A. Automated measurement of spatial preference in the open field test with transmitted lighting. J. Neurosci. Meth. 2008;170(2):345-351. DOI 10.1016/j.jneumeth.2008.01.024.

16. Kwong W.Y., Wild A.E., Roberts P., Willis A.C., Fleming T.P. Maternal undernutrition during the preimplantation period of rat development causes blastocyst abnormalities and programming of postnatal hypertension. Development. 2000;127:4195-4202.

17. Lee B., Sur B., Cho S.G., Yeom M., Shim I., Lee H., Hahm D.H. Ginsenoside Rb1 rescues anxiety-like responses in a rat model of posttraumatic stress disorder. J. Nat. Med. 2016;70(2):133-144. DOI 10.1007/s11418-015-0943-3.

18. Lee J.Y., Azar S.H. Wistar-Kyoto and spontaneously hypertensive rat blood pressure after embryo transfer into different wombs and crosssuckling. Exp. Biol. Med. (Maywood). 2010;235:1375-1384.

19. Ragaeva D.S., Abramova T.O., Rozhkova I.N., Brusentsev E.Yu., Kalinichenko E.V., Igonina T.N., Amstislavsky S.Ya. Effects of reproductive technologies and the SPF status on some physiological and behavioral characteristics in rats with arterial hypertension (ISIAH strain). Vavilovskii Zhurnal Genetiki i Selektsii = Vavilov Journal of Genetics and Breeding. 2015;19(4):383-387. DOI 10.18699/ VJ15.048. (in Russian)

20. Ragaeva D.S., Brusentsev E.Yu., Amstislavsky S.Ya. Assisted reproductive technologies and arterial hypertension. Ontogenez = Ontogenesis (Moscow). 2014;45(5):299-313 DOI 10.7868/ S0475145014050085. (in Russian)

21. Rodgers R.J., Cole J.C. Anxiolytic-like effect of (S)-WAY 100135, a 5-HT1A receptor antagonist, in the murine elevated plus-maze test. Eur. J. Pharmacol. 1994;261(3):321-325. PMID: 7813555.

22. Said N., Lakehayli S., Battas O., Hakkou F., Tazi A. Effects of prenatal stress on anxiety-like behavior and nociceptive response in rats. J. Integr. Neurosci. 2015;14:223-234. DOI 10.1142/S0219635215500107.

23. Scherrer U., Rimold S.F., Rexhaj E., Stuber T., Duplain H., Garcin S., de Marchi S.F., Nicod P., Germond M., Allemann Y., Sartori C. Systemic and pulmonary vascular dysfunction in children conceived by assisted reproductive technologies. Circulation. 2012;125:1890-1896.

24. Schieve L.A., Meikle S.F., Ferre C., Peterson H.B., Jeng G., Wilcox L.S. Low and very low birth weight in infants conceived with use of assisted reproductive technology. N. Engl. J. Med. 2002;346:731-737.

25. Shteklina T.A., Kolosova N.G., Terner A.Ia. Hypertensive syndrome and changes of water-salt metabolism in the OXYS rats with early ageing. Ross. Fiziol. Zh. 2005;91:1213-1220.

26. Sjoblom C., Roberts C.T., Wikland M., Robertson S.A. Granulocytemacrophage colony-stimulating factor alleviates adverse consequences of embryo culture on fetal growth trajectory and placental morphogenesis. Endocrinology. 2005;146:2142-2153.

27. Wilson C.A., Vazdarjanova A., Terry A.V. Jr. Exposure to variable prenatal stress in rats: effects on anxiety-related behaviors, innate and contextual fear, and fear extinction. Behav. Brain Res. 2013;238: 279-288. DOI 10.1016/j.bbr.2012.10.003.