Oxidative Stress and Neurodevelopmental Outcomes in Rat Offspring with Intrauterine Growth Restriction Induced by Reduced Uterine Perfusion

Marcelo E Rains, Colin B Muncie, Yi Pang, Lir-Wan Fan, Lu-Tai Tien, Norma B Ojeda, Marcelo E Rains, Colin B Muncie, Yi Pang, Lir-Wan Fan, Lu-Tai Tien, Norma B Ojeda

Abstract

Intrauterine growth restriction (IUGR) is a major cause of morbidity and mortality and is worldwide associated with delayed neurodevelopment. The exact mechanism involved in delayed neurodevelopment associated with IUGR is still unclear. Reduced uterine perfusion (RUP) is among the main causes of placental insufficiency leading to IUGR, which is associated with increases in oxidative stress. This study investigated whether oxidative stress is associated with delayed neurodevelopment in IUGR rat pups. Pregnant rats were exposed to RUP surgery on gestational day 14 to generate IUGR rat offspring. We evaluated offspring's morphometric at birth, and neurodevelopment on postnatal day 21 (PD21) as well as markers of oxidative stress in plasma and brain. Offspring from dams exposed to RUP showed significant (p < 0.05) lower birth weight compared to controls, indicating IUGR. Motor and cognitive deficits, and levels of oxidative stress markers, were significantly (p < 0.05) elevated in IUGR offspring compared to controls. IUGR offspring showed significant (p < 0.05) negative correlations between brain lipid peroxidation and neurocognitive tests (open field and novel object recognition) in comparison with controls. Our findings suggest that neurodevelopmental delay observed in IUGR rat offspring is associated with increased levels of oxidative stress markers.

Keywords: intrauterine growth restriction; motor and cognitive development; oxidative stress; reduced uterine perfusion.

Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Offspring’s body weights at birth (postnatal day 0 (PD0)) and at postnatal day 21 (PD21). Male and female offspring exposed to reduced uterine perfusion (RUP), presented in the black columns, show significant reductions in (A) birth weight (PD0), and (B) body weight at PD21 compared to offspring exposed to sham surgery presented in the white columns. All groups: n = 8/sex. *p < 0.0001 vs. control group. Graphs represented as mean ± SEM.
Figure 2
Figure 2
Motor behavioral assessment at PD7, PD14 and PD21. Male and female offspring exposed to RUP presented in the black columns as intrauterine growth restriction (IUGR), show significant reduction in (A) grip strength at PD7 and PD14, and (B) open field activity at PD21 compared to their counterparts exposed to sham surgery presented in the white columns as controls. All groups: n = 8/sex. *p < 0.0001 vs. control group. Graphs represented as mean ± SEM.
Figure 3
Figure 3
Cognitive behavior assessment at PD21. Male and female offspring exposed to RUP, presented in the black columns as IUGR, show significant reduction in novel object recognition compared to their counterparts exposed to sham surgery presented in the white columns as controls. All groups: n = 8/sex. *p < 0.0001 vs. control group. Graphs represented as mean ± SEM.
Figure 4
Figure 4
Pro-oxidation markers in plasma samples. Male and female offspring exposed to RUP, presented in the black columns as IUGR, show significant increase in pro-oxidation markers, (A) Superoxide Anion (O2−), and (B) Nicotinamide adenine dinucleotide phosphate-oxidase (NADPH-Ox) dependent O2− when compared to their counterparts exposed to sham surgery presented in the white columns as controls. All groups: n = 8/sex. *p < 0.0001 vs. control group. Graphs represented as mean ± SEM.
Figure 5
Figure 5
Markers of anti-oxidative stress in plasma samples. Male and female offspring exposed to RUP, presented in the black columns as IUGR, show significant decrease in antioxidant markers, (A) superoxide dismutase (SOD) activity, and (B) total antioxidant capacity when compared to their counterparts exposed to sham surgery presented in the white columns as controls. All groups: n = 8/sex. *p < 0.0001 vs. control group. Graphs represented as mean ± SEM.
Figure 6
Figure 6
Lipid peroxidation in plasma and brain samples. Male and female offspring exposed to RUP, presented in the black columns as IUGR, show significant increase in levels of lipid peroxidation in (A) plasma samples, and (B) brain tissues when compared to their counterparts exposed to sham surgery presented in the white columns as controls. All groups: n = 8/sex. *p < 0.0001 vs. control group. Graphs represented as mean ± SEM.
Figure 7
Figure 7
Correlations between levels of lipid peroxidation in brain and blood and neurodevelopment tests. There were negative correlations between brain lipid peroxidation and (A) open field activity (Pearson coefficient r = −0.7093; 95% CI = −0.8482 to −0.4791; p < 0.0001), and (B) novel object recognition (Pearson coefficient r = −0.7218; 95% CI = −0.8552 to −0.4986; p < 0.0001), and between blood lipid peroxidation and (C) open field activity (Pearson coefficient r = −0.6913; 95% CI = −0.8380 to −0.4515; p < 0.0001) and (D) novel object recognition (Pearson coefficient r = −0.6466; 95% CI = −0.8134 to −0.3876; p < 0.0001). Controls are presented as white dots and IUGR as black dots. All groups: n = 8/sex.

References

    1. Alberry M., Soothill P. Management of fetal growth restriction. Arch. Dis. Child. Fetal Neonatal Ed. 2007;92:F62–F67. doi: 10.1136/adc.2005.082297.
    1. Walker D.M., Marlow N. Neurocognitive outcome following fetal growth restriction. Arch. Dis. Child. Fetal Neonatal Ed. 2008;93:F322–F325. doi: 10.1136/adc.2007.120485.
    1. Levine T.A., Grunau R.E., McAuliffe F.M., Pinnamaneni R., Foran A., Alderdice F.A. Early childhood neurodevelopment after intrauterine growth restriction: A systematic review. Pediatrics. 2015;135:126–141. doi: 10.1542/peds.2014-1143.
    1. Krishna U., Bhalerao S. Placental insufficiency and fetal growth restriction. J. Obs. Gynaecol. India. 2011;61:505–511. doi: 10.1007/s13224-011-0092-x.
    1. Leitner Y., Fattal-Valevski A., Geva R., Bassan H., Posner E., Kutai M., Many A., Jaffa A.J., Harel S. Six-year follow-up of children with intrauterine growth retardation: Long-term, prospective study. J. Child. Neurol. 2000;15:781–786. doi: 10.1177/088307380001501202.
    1. Leitner Y., Fattal-Valevski A., Geva R., Eshel R., Toledano-Alhadef H., Rotstein M., Bassan H., Radianu B., Bitchonsky O., Jaffa A.J., et al. Neurodevelopmental outcome of children with intrauterine growth retardation: A longitudinal, 10-year prospective study. J. Child. Neurol. 2007;22:580–587. doi: 10.1177/0883073807302605.
    1. Beltrand J., Nicolescu R., Kaguelidou F., Verkauskiene R., Sibony O., Chevenne D., Claris O., Levy-Marchal C. Catch-up growth following fetal growth restriction promotes rapid restoration of fat mass but without metabolic consequences at one year of age. PLoS ONE. 2009;4:e5343. doi: 10.1371/journal.pone.0005343.
    1. Bellido-Gonzalez M., Diaz-Lopez M.A., Lopez-Criado S., Maldonado-Lozano J. Cognitive Functioning and academic achievement in children aged 6-8 years, born at term after intrauterine growth restriction and fetal cerebral redistribution. J. Pediatr. Psychol. 2017;42:345–354. doi: 10.1093/jpepsy/jsw060.
    1. Fushima T., Sekimoto A., Minato T., Ito T., Oe Y., Kisu K., Sato E., Funamoto K., Hayase T., Kimura Y., et al. Reduced uterine perfusion pressure (RUPP) model of preeclampsia in mice. PLoS ONE. 2016;11:e0155426. doi: 10.1371/journal.pone.0155426.
    1. Granger J.P., LaMarca B.B., Cockrell K., Sedeek M., Balzi C., Chandler D., Bennett W. Reduced uterine perfusion pressure (RUPP) model for studying cardiovascular-renal dysfunction in response to placental ischemia. Methods Mol. Med. 2006;122:383–392. doi: 10.1385/1-59259-989-3:381.
    1. Pijnenborg R., Bland J.M., Robertson W.B., Brosens I. Uteroplacental arterial changes related to interstitial trophoblast migration in early human pregnancy. Placenta. 1983;4:397–413. doi: 10.1016/S0143-4004(83)80043-5.
    1. Pardi G., Marconi A.M., Cetin I. Placental-fetal interrelationship in IUGR fetuses—A review. Placenta. 2002;23(Suppl. A):S136–S141. doi: 10.1053/plac.2002.0802.
    1. Regnault T.R., Galan H.L., Parker T.A., Anthony R.V. Placental development in normal and compromised pregnancies—A review. Placenta. 2002;23(Suppl. A):S119–S129. doi: 10.1053/plac.2002.0792.
    1. Stott D., Papastefanou I., Paraschiv D., Clark K., Kametas N.A. Longitudinal maternal hemodynamics in pregnancies affected by fetal growth restriction. Ultrasound Obs. Gynecol. 2017;49:761–768. doi: 10.1002/uog.17340.
    1. Regal J.F., Lillegard K.E., Bauer A.J., Elmquist B.J., Loeks-Johnson A.C., Gilbert J.S. Neutrophil depletion attenuates placental ischemia-induced hypertension in the rat. PLoS ONE. 2015;10:e0132063. doi: 10.1371/journal.pone.0132063.
    1. Burton G.J., Yung H.W., Cindrova-Davies T., Charnock-Jones D.S. Placental endoplasmic reticulum stress and oxidative stress in the pathophysiology of unexplained intrauterine growth restriction and early onset preeclampsia. Placenta. 2009;30(Suppl. A):S43–S48. doi: 10.1016/j.placenta.2008.11.003.
    1. Cobley J.N., Fiorello M.L., Bailey D.M. 13 reasons why the brain is susceptible to oxidative stress. Redox Biol. 2018;15:490–503. doi: 10.1016/j.redox.2018.01.008.
    1. Ferreira D.J.S., da Silva Pedroza A.A., Braz G.R.F., da Silva-Filho R.C., Lima T.A., Fernandes M.P., Doi S.Q., Lagranha C.J. Mitochondrial bioenergetics and oxidative status disruption in brainstem of weaned rats: Immediate response to maternal protein restriction. Brain Res. 2016;1642:553–561. doi: 10.1016/j.brainres.2016.04.049.
    1. Wang X., Michaelis E.K. Selective neuronal vulnerability to oxidative stress in the brain. Front. Aging Neurosci. 2010;2:12. doi: 10.3389/fnagi.2010.00012.
    1. Soleimani E., Goudarzi I., Abrari K., Lashkarbolouki T. The combined effects of developmental lead and ethanol exposure on hippocampus dependent spatial learning and memory in rats: Role of oxidative stress. Food Chem. Toxicol. 2016;96:263–272. doi: 10.1016/j.fct.2016.07.009.
    1. Abdel-Salam O.M., Salem N.A., El-Shamarka M.E., Hussein J.S., Ahmed N.A., El-Nagar M.E. Studies on the effects of aspartame on memory and oxidative stress in brain of mice. Eur. Rev. Med. Pharm. Sci. 2012;16:2092–2101.
    1. Xiaoli F., Junrong W., Xuan L., Yanli Z., Limin W., Jia L., Longquan S. Prenatal exposure to nanosized zinc oxide in rats: Neurotoxicity and postnatal impaired learning and memory ability. Nanomed. (Lond.) 2017;12:777–795. doi: 10.2217/nnm-2016-0397.
    1. Merzoug S., Toumi M.L., Boukhris N., Baudin B., Tahraoui A. Adriamycin-related anxiety-like behavior, brain oxidative stress and myelotoxicity in male Wistar rats. Pharm. Biochem. Behav. 2011;99:639–647. doi: 10.1016/j.pbb.2011.06.015.
    1. Borkum J.M. The migraine attack as a homeostatic, neuroprotective response to brain oxidative stress: Preliminary evidence for a theory. Headache. 2018;58:118–135. doi: 10.1111/head.13214.
    1. Stigger F., Lovatel G., Marques M., Bertoldi K., Moyses F., Elsner V., Siqueira I.R., Achaval M., Marcuzzo S. Inflammatory response and oxidative stress in developing rat brain and its consequences on motor behavior following maternal administration of LPS and perinatal anoxia. Int. J. Dev. Neurosci. 2013;31:820–827. doi: 10.1016/j.ijdevneu.2013.10.003.
    1. Dias J.P., Gariepy Hde B., Ongali B., Couture R. Brain kinin B1 receptor is upregulated by the oxidative stress and its activation leads to stereotypic nociceptive behavior in insulin-resistant rats. Peptides. 2015;69:118–126. doi: 10.1016/j.peptides.2015.04.022.
    1. Reus G.Z., Becker I.R.T., Scaini G., Petronilho F., Oses J.P., Kaddurah-Daouk R., Ceretta L.B., Zugno A.I., Dal-Pizzol F., Quevedo J., et al. The inhibition of the kynurenine pathway prevents behavioral disturbances and oxidative stress in the brain of adult rats subjected to an animal model of schizophrenia. Prog. Neuropsychopharmacol. Biol. Psychiatry. 2018;81:55–63. doi: 10.1016/j.pnpbp.2017.10.009.
    1. Coles L.D., Tuite P.J., Oz G., Mishra U.R., Kartha R.V., Sullivan K.M., Cloyd J.C., Terpstra M. Repeated-dose oral n-acetylcysteine in Parkinson’s disease: Pharmacokinetics and effect on brain glutathione and oxidative stress. J. Clin. Pharm. 2018;58:158–167. doi: 10.1002/jcph.1008.
    1. Ojeda N.B., Hennington B.S., Williamson D.T., Hill M.L., Betson N.E., Sartori-Valinotti J.C., Reckelhoff J.F., Royals T.P., Alexander B.T. Oxidative stress contributes to sex differences in blood pressure in adult growth-restricted offspring. Hypertension. 2012;60:114–122. doi: 10.1161/HYPERTENSIONAHA.112.192955.
    1. Ojeda N., Hall S., Lasley C.J., Rudsenske B., Dixit M., Arany I. Prenatal nicotine exposure augments renal oxidative stress in embryos of pregnant rats with reduced uterine perfusion pressure. Vivo. 2016;30:219–224.
    1. Campbell L.R., Pang Y., Ojeda N.B., Zheng B., Rhodes P.G., Alexander B.T. Intracerebral lipopolysaccharide induces neuroinflammatory change and augmented brain injury in growth-restricted neonatal rats. Pediatr. Res. 2012;71:645–652. doi: 10.1038/pr.2012.26.
    1. Eder D.J., McDonald M.T. A role for brain angiotensin II in experimental pregnancy-induced hypertension in laboratory rats. Clin. Exp. Hypertens. Part B Hypertens. Pregnancy. 1987;6:431–451. doi: 10.3109/10641958709023492.
    1. Altman J., Sudarshan K., Das G.D., McCormick N., Barnes D. The influence of nutrition on neural and behavioral development. 3. Development of some motor, particularly locomotor patterns during infancy. Dev. Psychobiol. 1971;4:97–114. doi: 10.1002/dev.420040202.
    1. Rodriguez-Porcel F., Green D., Khatri N., Harris S.S., May W.L., Lin R.C., Paul I.A. Neonatal exposure of rats to antidepressants affects behavioral reactions to novelty and social interactions in a manner analogous to autistic spectrum disorders. Anat. Rec. (Hoboken) 2011;294:1726–1735. doi: 10.1002/ar.21402.
    1. Hsieh C.T., Lee Y.J., Lee J.W., Lu S., Tucci M.A., Dai X., Ojeda N.B., Lee H.J., Fan L.W., Tien L.T. Interleukin-1 receptor antagonist ameliorates the pain hypersensitivity, spinal inflammation and oxidative stress induced by systemic lipopolysaccharide in neonatal rats. Neurochem. Int. 2020;135:104686. doi: 10.1016/j.neuint.2020.104686.
    1. Salminen L.E., Paul R.H. Oxidative stress and genetic markers of suboptimal antioxidant defense in the aging brain: A theoretical review. Rev. Neurosci. 2014;25:805–819. doi: 10.1515/revneuro-2014-0046.
    1. Scandalios J.G. Oxidative stress: Molecular perception and transduction of signals triggering antioxidant gene defenses. Braz. J. Med. Biol. Res. 2005;38:995–1014. doi: 10.1590/S0100-879X2005000700003.
    1. Coats L.E., Davis G.K., Newsome A.D., Ojeda N.B., Alexander B.T. Low birth weight, blood pressure and renal susceptibility. Curr. Hypertens. Rep. 2019;21:62. doi: 10.1007/s11906-019-0969-0.
    1. Peleg D., Kennedy C.M., Hunter S.K. Intrauterine growth restriction: Identification and management. Am. Fam. Physician. 1998;58:453–467.
    1. Prut L., Belzung C. The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: A review. Eur. J. Pharm. 2003;463:3–33. doi: 10.1016/S0014-2999(03)01272-X.
    1. Altafaj X., Dierssen M., Baamonde C., Marti E., Visa J., Guimera J., Oset M., Gonzalez J.R., Florez J., Fillat C., et al. Neurodevelopmental delay, motor abnormalities and cognitive deficits in transgenic mice overexpressing Dyrk1A (minibrain), a murine model of Down’s syndrome. Hum. Mol. Genet. 2001;10:1915–1923. doi: 10.1093/hmg/10.18.1915.
    1. Sestakova N., Puzserova A., Kluknavsky M., Bernatova I. Determination of motor activity and anxiety-related behaviour in rodents: Methodological aspects and role of nitric oxide. Interdiscip. Toxicol. 2013;6:126–135. doi: 10.2478/intox-2013-0020.
    1. Simon P., Dupuis R., Costentin J. Thigmotaxis as an index of anxiety in mice. Influence of dopaminergic transmissions. Behav. Brain Res. 1994;61:59–64. doi: 10.1016/0166-4328(94)90008-6.
    1. Antunes M., Biala G. The novel object recognition memory: Neurobiology, test procedure, and its modifications. Cogn. Process. 2012;13:93–110. doi: 10.1007/s10339-011-0430-z.
    1. Sun G.Y., MacQuarrie R.A. Deacylation-reacylation of arachidonoyl groups in cerebral phospholipidsa. Ann. N. Y. Acad. Sci. 1989;559:37–55. doi: 10.1111/j.1749-6632.1989.tb22597.x.
    1. Yang B., Fritsche K.L., Beversdorf D.Q., Gu Z., Lee J.C., Folk W.R., Greenlief C.M., Sun G.Y. Yin-Yang mechanisms regulating lipid peroxidation of docosahexaenoic acid and arachidonic acid in the central nervous system. Front. Neurol. 2019;10 doi: 10.3389/fneur.2019.00642.
    1. Shoji H., Ikeda N., Hosozawa M., Ohkawa N., Matsunaga N., Suganuma H., Hisata K., Tanaka K., Shimizu T. Oxidative stress early in infancy and neurodevelopmental outcome in very low-birthweight infants. Pediatr. Int. 2014;56:709–713. doi: 10.1111/ped.12332.
    1. Bharadwaj S.K., Vishnu Bhat B., Vickneswaran V., Adhisivam B., Bobby Z., Habeebullah S. Oxidative stress, antioxidant status and neurodevelopmental outcome in neonates born to pre-eclamptic mothers. Indian J. Pediatr. 2018;85:351–357. doi: 10.1007/s12098-017-2560-5.
    1. Padilla N., Junque C., Figueras F., Sanz-Cortes M., Bargallo N., Arranz A., Donaire A., Figueras J., Gratacos E. Differential vulnerability of gray matter and white matter to intrauterine growth restriction in preterm infants at 12 months corrected age. Brain Res. 2014;1545:1–11. doi: 10.1016/j.brainres.2013.12.007.
    1. Jantzie L.L., Getsy P.M., Denson J.L., Firl D.J., Maxwell J.R., Rogers D.A., Wilson C.G., Robinson S. Prenatal hypoxia–ischemia induces abnormalities in Ca3 microstructure, potassium chloride Co-transporter 2 expression and inhibitory tone. Front. Cell. Neurosci. 2015;9 doi: 10.3389/fncel.2015.00347.
    1. Jantzie L.L., Robinson S. Preclinical models of encephalopathy of prematurity. Dev. Neurosci. 2015;37:277–288. doi: 10.1159/000371721.
    1. Coq J.O., Delcour M., Ogawa Y., Peyronnet J., Castets F., Turle-Lorenzo N., Montel V., Bodineau L., Cardot P., Brocard C., et al. Mild intrauterine hypoperfusion leads to lumbar and cortical hyperexcitability, spasticity, and muscle dysfunctions in rats: Implications for prematurity. Front. Neurol. 2018;9:423. doi: 10.3389/fneur.2018.00423.
    1. Delcour M., Russier M., Amin M., Baud O., Paban V., Barbe M.F., Coq J.O. Impact of prenatal ischemia on behavior, cognitive abilities and neuroanatomy in adult rats with white matter damage. Behav. Brain Res. 2012;232:233–244. doi: 10.1016/j.bbr.2012.03.029.
    1. Ushida T., Kotani T., Tsuda H., Imai K., Nakano T., Hirako S., Ito Y., Li H., Mano Y., Wang J., et al. Molecular hydrogen ameliorates several characteristics of preeclampsia in the reduced uterine perfusion pressure (RUPP) rat model. Free Radic. Biol. Med. 2016;101:524–533. doi: 10.1016/j.freeradbiomed.2016.10.491.
    1. Mano Y., Kotani T., Ito M., Nagai T., Ichinohashi Y., Yamada K., Ohno K., Kikkawa F., Toyokuni S. Maternal molecular hydrogen administration ameliorates rat fetal hippocampal damage caused by in utero ischemia-reperfusion. Free Radic. Biol. Med. 2014;69:324–330. doi: 10.1016/j.freeradbiomed.2014.01.037.

Source: PubMed

Sponzoři a spolupracovníci

Zdravotní podmínky

Drogové intervence

3
Předplatit