Journal of Basic and Clinical Pathophysiology

Journal of Basic and Clinical Pathophysiology

Effect of prenatal stress on cytokine profile in rodent fetus and offspring: A systematic review and meta-analysis

Document Type : Research Paper

Authors
Hossein Hassanpour 1
Leila Nasiri 2
Marzieh Mojtahed 3
Aziz A. Fallah 4
Tahereh Karimi shayan 5
Zahra Changaniyan-Khorasgani 1
1 Department of Basic Sciences, Faculty of Veterinary Medicine, Shahrekord University, Shahrekord, Iran
2 Health Equity Research Center, Shahed University, Tehran, Iran
3 Department of Cellular and Molecular Biology, Faculty of Advanced Sciences and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
4 Department of Food Hygiene and Quality Control, Faculty of Veterinary Medicine, Shahrekord University, Shahrekord, Iran
5 Department of Biology, Faculty of Science, University of Mohaghegh Ardabili, Ardabil, Iran
10.22070/jbcp.2025.20258.1199
Abstract
Background and Objective: Prenatal stress can lead to alterations in cytokine secretion in the offspring, which may enhance inflammatory processes. We conducted a meta-analysis of rodent studies to evaluate the effects of prenatal stress exposure on the pro- and anti-inflammatory cytokines in the fetus and offspring.
Materials and Methods: Data were extracted, and effect size and heterogeneity were assessed using random-effects models, Cochrane Q, and I2 statistics.
Results: Prenatal stress consistently increased most pro-inflammatory cytokines (IFN-ϒ, IL-1β, IL-6, IL-18, and TNF-α), while decreasing the level of anti-inflammatory cytokine (IL-10). Most of the cytokines (IL-1β, IL-6, IL-18, and TNF-α) increased in the short term after prenatal stress (≤ 24 hours), except for IL-10, which decreased in long-term stress (P < 0.05). Challenges in offspring following prenatal stress had no significant effect on IL-10, IL-5, IL-6, and TNF-α levels. Meta-analysis of the species subgroup indicated that significant changes in most cytokines (IFN-ϒ, IL-1β, IL-6, and TNF-α) only occurred in the rat fetus and offspring following prenatal stress. In contrast, only IL-10 significantly changed in both rats and mice.
Conclusions: This meta-analysis indicates important biological differences in the response to prenatal stress based on species, duration, and challenges faced by the offspring in immune response studies.
Keywords
Interleukin
Interferon
Stress type
Stress duration
1.         Marco EM, Macrì S, Laviola G. Critical age windows for neurodevelopmental psychiatric disorders: evidence from animal models. Neurotoxicity Research. 2011;19:286-307.
2.         Gollwitzer ES, Marsland BJ. Impact of early-life exposures on immune maturation and susceptibility to disease. Trends in Immunology. 2015;36(11):684-96.
3.         Ygberg S, Nilsson A. The developing immune system–from foetus to toddler. Acta Paediatrica. 2012;101(2):120-7.
4.         Khosrotehrani K, Leduc M, Bachy Vr, Huu SN, Oster M, Abbas A, et al. Pregnancy allows the transfer and differentiation of fetal lymphoid progenitors into functional T and B cells in mothers. The Journal of Immunology. 2008;180(2):889-97.
5.         Strunk T, Temming P, Gembruch U, Reiss I, Bucsky P, Schultz C. Differential maturation of the innate immune response in human fetuses. Pediatric Research. 2004;56(2):219-26.
6.         Mold JE, Michaëlsson J, Burt TD, Muench MO, Beckerman KP, Busch MP, et al. Maternal alloantigens promote the development of tolerogenic fetal regulatory T cells in utero. Science. 2008;322(5907):1562-5.
7.         de Marco R, Pesce G, Girardi P, Marchetti P, Rava M, Ricci P, Marcon A. Foetal exposure to maternal stressful events increases the risk of having asthma and atopic diseases in childhood. Pediatric Allergy and Immunology. 2012;23(8):724-9.
8.         Fernandes SB, Patil ND, Meriaux S, Theresine M, Muller CP, Leenen FA, et al. Unbiased screening identifies functional differences in NK cells after early life psychosocial stress. Frontiers in Immunology. 2021;12:674532.
9.         O’Connor TG, Winter MA, Hunn J, Carnahan J, Pressman EK, Glover V, et al. Prenatal maternal anxiety predicts reduced adaptive immunity in infants. Brain, Behavior, and Immunity. 2013;32:21-8.
10.     Creutzberg KC, Sanson A, Viola TW, Marchisella F, Begni V, Grassi-Oliveira R, Riva MA. Long-lasting effects of prenatal stress on HPA axis and inflammation: A systematic review and multilevel meta-analysis in rodent studies. Neuroscience and Biobehavioral Reviews. 2021;127:270-83.
11.     Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ (Clinical Research Ed.). 2003;327(7414):557-60.
12.     Jafari T, Rostampour N, Fallah AA, Hesami A. The association between mercury levels and autism spectrum disorders: a systematic review and meta-analysis. Journal of Trace Elements in Medicine and Biology. 2017;44:289-97.
13.     Chandler J, Cumpston M, Li T. Cochrane Handbook for Systematic Reviews of Interventions.
14.     Dowdy A, Hantula DA, Travers JC, Tincani M. Meta-analytic methods to detect publication bias in behavior science research. Perspectives on Behavior Science. 2022;45(1):37-52.
15.     Hooijmans CR, Rovers MM, De Vries RB, Leenaars M, Ritskes-Hoitinga M, Langendam MW. SYRCLE’s risk of bias tool for animal studies. BMC Medical Research Methodology. 2014;14:1-9.
16.     Amani M, Houwing DJ, Homberg JR, Salari A-A. Perinatal fluoxetine dose-dependently affects prenatal stress-induced neurobehavioural abnormalities, HPA-axis functioning and underlying brain alterations in rat dams and their offspring. Reproductive Toxicology. 2021;104:27-43.
17.     Baratta AM, Kanyuch NR, Cole CA, Valafar H, Deslauriers J, Pocivavsek A. Acute sleep deprivation during pregnancy in rats: rapid elevation of placental and fetal inflammation and kynurenic acid. Neurobiology of Stress. 2020;12:100204.
18.     Bolton JL, Huff NC, Smith SH, Mason SN, Foster WM, Auten RL, Bilbo SD. Maternal stress and effects of prenatal air pollution on offspring mental health outcomes in mice. Environmental Health Perspectives. 2013;121(9):1075-82.
19.     Chen M-X, Liu Q, Cheng S, Lei L, Lin A-J, Wei R, et al. Interleukin-18 levels in the hippocampus and behavior of adult rat offspring exposed to prenatal restraint stress during early and late pregnancy. Neural Regeneration Research. 2020;15(9):1748.
20.     de los Ángeles Aldirico M, Giorgio FM, Soto A, Sibilia MDP, Sánchez VR, Picchio MS, et al. Maternal stress increases risk of allergic lung inflammation in adult mice. Immunobiology. 2023;228(3):152395.
21.     Ho H, Lhotak S, Solano M, Karimi K, Pincus M, Austin R, Arck P. Prenatal stress enhances severity of atherosclerosis in the adult apolipoprotein E-deficient mouse offspring via inflammatory pathways. Journal of Developmental Origins of Health and Disease. 2013;4(1):90-7.
22.     Kohman RA, Tarr AJ, Day CE, McLinden KA, Boehm GW. Influence of prenatal stress on behavioral, endocrine, and cytokine responses to adulthood bacterial endotoxin exposure. Behavioural Brain Research. 2008;193(2):257-68.
23.     Li Y, Yao G, Wang R, Zhu J, Li H, Yang D, et al. Maternal immune activation mediated prenatal chronic stress induces Th17/Treg cell imbalance may relate to the PI3K/Akt/NF-κB signaling pathway in offspring rats. International Immunopharmacology. 2024;126:111308.
24.     Lopes NA, Falkenberg EA, Wiley C, Patel V, Serrano-Lomelin J, Fang X, et al. Social isolation stress modulates pregnancy outcomes and the inflammatory profile of rat uterus. International Journal of Molecular Sciences. 2022;23(11):6169.
25.     Mkhize NVP, Qulu L, Mabandla MV. The effect of quercetin on pro-and anti-inflammatory cytokines in a prenatally stressed rat model of febrile seizures. Journal of Experimental Neuroscience. 2017;11:1179069517704668.
26.     Nemati S, Edalatmanesh MA. Effects of trichostatin A on pre-and anti-inflammatory cytokines of the hippocampus in rats of the prenatally restraint stressed model. Medical Science Journal of Islamic Azad University. 2020;30(3):244-52.
27.     Pascuan CG, Di Rosso ME, Pivoz-Avedikian JE, Wald MR, Zubilete MZ, Genaro AM. Alteration of neurotrophin and cytokine expression in lymphocytes as novel peripheral markers of spatial memory deficits induced by prenatal stress. Physiology & Behavior. 2017;173:144-55.
28.     Pavlov D, Gorlova A, Haque A, Cavalcante C, Svirin E, Burova A, et al. Maternal Chronic Ultrasound Stress Provokes Immune Activation and Behavioral Deficits in the Offspring: A Mouse Model of Neurodevelopmental Pathology. International Journal of Molecular Sciences. 2023;24(14):11712.
29.     Pincus-Knackstedt MK, Joachim RA, Blois SM, Douglas AJ, Orsal AS, Klapp BF, et al. Prenatal stress enhances susceptibility of murine adult offspring toward airway inflammation. The Journal of Immunology. 2006;177(12):8484-92.
30.     Qulu L, Daniels WM, Mabandla MV. Exposure to prenatal stress enhances the development of seizures in young rats. Metabolic Brain Disease. 2012;27:399-404.
31.     Qulu L, Daniels WM, Russell V, Mabandla MV. Searsia chirindensis reverses the potentiating effect of prenatal stress on the development of febrile seizures and decreased plasma interleukin-1β levels. Neuroscience Research. 2016;103:54-8.
32.     Ślusarczyk J, Trojan E, Głombik K, Budziszewska B, Kubera M, Lasoń W, et al. Prenatal stress is a vulnerability factor for altered morphology and biological activity of microglia cells. Frontiers in Cellular Neuroscience. 2015;9:82.
33.     Ślusarczyk J, Trojan E, Wydra K, Głombik K, Chamera K, Kucharczyk M, et al. Beneficial impact of intracerebroventricular fractalkine administration on behavioral and biochemical changes induced by prenatal stress in adult rats: possible role of NLRP3 inflammasome pathway. Biochemical Pharmacology. 2016;113:45-56.
34.     Sun Q, Jia N, Ren F, Li X. Grape seed proanthocyanidins improves depression-like behavior by alleviating oxidative stress and NLRP3 activation in the hippocampus of prenatally-stressed female offspring rats. Journal of Histotechnology. 2021;44(2):90-8.
35.     Suwaluk A, Chutabhakdikul N. Long-term effects of prenatal stress on the development of prefrontal cortex in the adolescent offspring. Journal of Chemical Neuroanatomy. 2022;125:102169.
36.     Szczesny E, Basta-Kaim A, Slusarczyk J, Trojan E, Glombik K, Regulska M, et al. The impact of prenatal stress on insulin-like growth factor-1 and pro-inflammatory cytokine expression in the brains of adult male rats: the possible role of suppressors of cytokine signaling proteins. Journal of Neuroimmunology. 2014;276(1-2):37-46.
37.     Trojan E, Chamera K, Bryniarska N, Kotarska K, Leśkiewicz M, Regulska M, Basta-Kaim A. Role of chronic administration of antidepressant drugs in the prenatal stress-evoked inflammatory response in the brain of adult offspring rats: involvement of the nlrp3 inflammasome-related pathway. Molecular Neurobiology. 2019;56:5365-80.
38.     Trojan E, Curzytek K, Cieślik P, Wierońska JM, Graff J, Lasoń W, et al. Prenatal stress aggravates age-dependent cognitive decline, insulin signaling dysfunction, and the pro-inflammatory response in the APPNL-F/NL-F mouse model of Alzheimer's disease. Neurobiology of Disease. 2023;184:106219.
39.     Vanbesien-Mailliot CC, Wolowczuk I, Mairesse J, Viltart O, Delacre M, Khalife J, et al. Prenatal stress has pro-inflammatory consequences on the immune system in adult rats. Psychoneuroendocrinology. 2007;32(2):114-24.
40.     Vargas MHM, Campos NE, de Souza RG, da Cunha AA, Nuñez NK, Pitrez PM, Donadio MVF. Protective effect of early prenatal stress on the induction of asthma in adult mice: Sex-specific differences. Physiology & Behavior. 2016;165:358-64.
41.     Zheng X, Cheng Y, Chen Y, Yue Y, Li Y, Xia S, et al. Ferulic acid improves depressive-like behavior in prenatally-stressed offspring rats via anti-inflammatory activity and HPA axis. International Journal of Molecular Sciences. 2019;20(3):493.
42.     Diz-Chaves Y, Astiz M, Bellini MJ, Garcia-Segura LM. Prenatal stress increases the expression of proinflammatory cytokines and exacerbates the inflammatory response to LPS in the hippocampal formation of adult male mice. Brain, Behavior, and Immunity. 2013;28:196-206.
43.     Kim Y-K, Na K-S, Myint A-M, Leonard BE. The role of pro-inflammatory cytokines in neuroinflammation, neurogenesis and the neuroendocrine system in major depression. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2016;64:277-84.
44.     Alizadeh A, Dyck SM, Karimi-Abdolrezaee S. Traumatic spinal cord injury: an overview of pathophysiology, models and acute injury mechanisms. Frontiers in Neurology. 2019;10:282.
45.     Haley PJ. Species differences in the structure and function of the immune system. Toxicology. 2003;188(1):49-71.
46.     Dhabhar FS. Enhancing versus suppressive effects of stress on immune function: implications for immunoprotection and immunopathology. Neuroimmunomodulation. 2009;16(5):300-17.
47.     Kemme K, Kaiser S, Sachser N. Prenatal stress does not impair coping with challenge later in life. Physiology & Behavior. 2008;93(1-2):68-75.
48.     Serpeloni F, Radtke KM, Hecker T, Sill J, Vukojevic V, Assis SGd, et al. Does prenatal stress shape postnatal resilience?–an epigenome-wide study on violence and mental health in humans. Frontiers in Genetics. 2019;10:269.
49.     Wu S, Gennings C, Wright RJ, Wilson A, Burris HH, Just AC, et al. Prenatal stress, methylation in inflammation-related genes, and adiposity measures in early childhood: the progress cohort study. Psychosomatic Medicine. 2018;80(1):34.
50.     Mlinarić A, Horvat M, Šupak Smolčić V. Dealing with the positive publication bias: Why you should really publish your negative results. Biochemia Medica. 2017;27(3):447-52.
Journal of Basic and Clinical Pathophysiology
Volume 14, Issue 2
January 2026
Pages 31-44