With social development and increased life pressures, prenatal stress has become a significant physical and mental challenge for women during the perinatal period. Research indicates that prenatal stress may affect fetal developmental programming through epigenetic regulatory mechanisms, thereby interfering with neurodevelopment and increasing the risk of emotional disturbances, behavioral abnormalities, and cognitive impairments in offspring. Epigenetic modifications such as DNA methylation (DNAm), histone modifications, and non-coding RNAs (ncRNAs) are likely to mediate the long-term effects of prenatal stress on offspring cognitive function. This article summarizes the mechanisms of epigenetic regulation in prenatal stress-induced cognitive impairments in offspring, with a focus on analyzing the associations of DNAm, histone modifications, and ncRNAs with cognitive deficits in offspring, aiming to provide references for the development of relevant clinical intervention strategies.

1.Clayborne ZM, Zou R, Gilman SE, et al. Associations between prenatal maternal stress, maternal inflammation during pregnancy, and children's internalizing and externalizing symptoms throughout childhood[J]. Brain Behav Immun, 2023, 114: 165-172. DOI: 10.1016/j.bbi.2023.08.017.

2.McCarthy M, Houghton C, Matvienko-Sikar K. Women's experiences and perceptions of anxiety and stress during the perinatal period: a systematic review and qualitative evidence synthesis[J]. BMC Pregnancy Childbirth, 2021, 21(1): 811. DOI: 10.1186/s12884-021-04271-w.

3.Kassotaki I, Valsamakis G, Mastorakos G, et al. Placental CRH as a signal of pregnancy adversity and impact on fetal neurodevelopment[J]. Front Endocrinol (Lausanne), 2021, 12: 714214. DOI: 10.3389/fendo.2021.714214.

4.O'Donnell MG, Stumpp L, Gallaher MJ, et al. Pre-pregnancy stress induces maternal vascular dysfunction during pregnancy and postpartum[J]. Reprod Sci, 2023, 30(11): 3197-3211. DOI: 10.1007/s43032-023-01248-2.

5.Adeline Dorothy PD, Rajan KE. Prenatal maternal life adversity impacts on learning and memory in offspring: implication to transgenerational epigenetic inheritance[J]. Front Neurosci, 2025, 19: 1518046. DOI: 10.3389/fnins.2025.1518046.

6.Andrawus M, Sharvit L, Atzmon G. Epigenetics and pregnancy: conditional snapshot or rolling event[J]. Int J Mol Sci, 2022, 23(20): 12698. DOI: 10.3390/ijms232012698.

7.Li L, Chen R, Zhang H, et al. The epigenetic modification of DNA methylation in neurological diseases[J]. Front Immunol, 2024, 15: 1401962. DOI: 10.3389/fimmu.2024.1401962.

8.Camerota M, Lester BM, McGowan EC, et al. Contributions of prenatal risk factors and neonatal epigenetics to cognitive outcome in children born very preterm[J]. Dev Psychol, 2024, 60(9): 1606-1619. DOI: 10.1037/dev0001709.

9.Stroud LR, Jao NC, Ward LG, et al. Differential impact of prenatal PTSD symptoms and preconception trauma exposure on placental NR3C1 and FKBP5 methylation[J]. Stress, 2024, 27(1): 2321595. DOI: 10.1080/10253890.2024.2321595.

10.Cao-Lei L, van den Heuvel MI, Huse K, et al. Epigenetic modifications associated with maternal anxiety during pregnancy and children's behavioral measures[J]. Cells, 2021, 10(9): 2421. DOI: 10.3390/cells10092421.

11.Dieckmann L, Czamara D. Epigenetics of prenatal stress in humans: the current research landscape[J]. Clin Epigenetics, 2024, 16(1): 16. DOI: 10.1186/s13148-024-01635-9.

12.Zhang Y, Liu C. Evaluating the challenges and reproducibility of studies investigating DNA methylation signatures of psychological stress[J]. Epigenomics, 2022, 14(7): 405-421. DOI: 10.2217/epi-2021-0190.

13.Wadji DL, Tandon T, Ketcha Wanda GJM, et al. Child maltreatment and NR3C1 exon 1(F) methylation, link with deregulated hypothalamus-pituitary-adrenal axis and psychopathology: a systematic review[J]. Child Abuse Negl, 2021, 122: 105304. DOI: 10.1016/j.chiabu.2021.105304.

14.Bajbouj K, Al-Ali A, Ramakrishnan RK, et al. Histone modification in NSCLC: molecular mechanisms and therapeutic targets[J]. Int J Mol Sci, 2021, 22(21): 11701. DOI: 10.3390/ijms222111701.

15.Wu D, Shi Y, Zhang H. Epigenetic mechanisms of immune remodeling in sepsis: targeting histone modification[J]. Cell Death Dis, 2023, 14(2): 112. DOI: 10.1038/s41419-023-05656-9.

16.Wu MS, Li XJ, Liu CY, et al. Effects of histone modification in major depressive disorder[J]. Curr Neuropharmacol, 2022, 20(7): 1261-1277. DOI: 10.2174/1570159X19666210922150043.

17.Chen YZ, Zhu XM, Lyu P, et al. Association of histone modification with the development of schizophrenia[J]. Biomed Pharmacother, 2024, 175: 13. DOI: 10.1016/j.biopha.2024.116747.

18.张瑶, 邹蔓姝, 韩远山, 等.表观遗传学在抑郁症发病机制中的研究进展[J].中国临床药理学与治疗学, 2025, 30(4): 517-525. [Zhang Y, Zou MS, Han YS, et al. Research progress of epigenetics in the pathogenesis of depression[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2025, 30(4): 517-525.] DOI: 10.12092/j.issn.1009-2501.2025.04.010.

19.Wang H, Helin K. Roles of H3K4 methylation in biology and disease[J]. Trends Cell Biol, 2025, 35(2): 115-128. DOI: 10.1016/j.tcb.2024.06.001.

20.Sun N, Qin S, Zhang L, et al. Roles of noncoding RNAs in preeclampsia[J]. Reprod Biol Endocrinol, 2021, 19(1): 100. DOI: 10.1186/s12958-021-00783-4.

21.Mucha M, Skrzypiec AE, Kolenchery JB, et al. miR-483-5p offsets functional and behavioural effects of stress in male mice through synapse-targeted repression of Pgap2 in the basolateral amygdala[J]. Nat Commun, 2023, 14(1): 2134. DOI: 10.1038/s41467-023-37688-2.

22.Schell G, Roy B, Prall K, et al. miR-218: a stress-responsive epigenetic modifier[J]. Noncoding RNA, 2022, 8(4): 55. DOI: 10.3390/ncrna8040055.

23.Rinne GR, Hartstein J, Guardino C, et al. Stress before conception and during pregnancy and maternal cortisol during pregnancy: a scoping review[J]. Psychoneuroendocrinology, 2023, 153: 106115. DOI: 10.1016/j.psyneuen.2023.106115.

24.Haq SU, Bhat UA, Kumar A. Prenatal stress effects on offspring brain and behavior: mediators, alterations and dysregulated epigenetic mechanisms[J]. J Biosci, 2021, 46(2): 1-16. DOI: 10.1007/s12038-021-00153-7.

25.Mandl S, Alexopoulos J, Doering S, et al. The effect of prenatal maternal distress on offspring brain development: a systematic review[J]. Early Hum Dev, 2024, 192: 106009. DOI: 10.1016/j.earlhumdev.2024.106009.

26.Abrishamcar S, Zhuang BC, Thomas M, et al. Association between maternal perinatal stress and depression and infant DNA methylation in the first year of life[J]. Transl Psychiatry, 2024, 14(1): 445. DOI: 10.1038/s41398-024-03148-8.

27.Chalfun G, Reis MM, de Oliveira MBG, et al. Perinatal stress and methylation of the NR3C1 gene in newborns: systematic review[J]. Epigenetics, 2022, 17(9): 18. DOI: 10.1080/15592294.2021.1980691.

28.Hyder N, Abbas G, Ahmed A, et al. Post-natal antibiotic exposure in mother rat (F0) induces anxiety like behavior in adult rat offspring (F1) by activating HPA axis and down-regulating the Nr3c1 gene[J]. Braz J Biol, 2024, 84: e286928. DOI: 10.1590/1519-6984.286928.

29.Castro-Quintas A, Palma-Gudiel H, Eixarch E, et al. Placental epigenetic signatures of maternal distress in glucocorticoid-related genes and newborn outcomes: a study of Spanish primiparous women[J]. Eur Neuropsychopharmacol, 2025, 90: 36-37. DOI: 10.1016/j.euroneuro.2024.10.001.

30.Wiley KS, Camilo C, Gouveia G, et al. Maternal distress, DNA methylation, and fetal programing of stress physiology in Brazilian mother-infant pairs[J]. Dev Psychobiol, 2023, 65(1): e22352. DOI: 10.1002/dev.22352.

31.Sammallahti S, Cortes Hidalgo AP, Tuominen S, et al. Maternal anxiety during pregnancy and newborn epigenome-wide DNA methylation[J]. Mol Psychiatry, 2021, 26(6): 1832-1845. DOI: 10.1038/s41380-020-00976-0.

32.Chalfun G, Araújo Brasil A, Paravidino VB, et al. NR3C1 gene methylation and cortisol levels in preterm and healthy full-term infants in the first 3 months of life[J]. Epigenomics, 2022, 14(24): 1545-1561. DOI: 10.2217/epi-2022-0444.

33.Noble AJ, Adams AT, Satsangi J, et al. Prenatal cannabis exposure is associated with alterations in offspring DNA methylation at genes involved in neurodevelopment, across the life course[J]. Mol Psychiatry, 2025, 30(4): 1418-1429. DOI: 10.1038/s41380-024-02752-w.

34.Saavedra K, Salazar LA. Epigenetics: a missing link between early life stress and depression[J]. Adv Exp Med Biol, 2021, 1305(1). DOI: 10.1007/978-981-33-6044-0_8.

35.曾伟,罗佛全. 表观遗传调控在阿尔茨海默病相关认知功能障碍中的作用[J]. 神经损伤与功能重建, 2024, 19(5): 285-290. [Zeng W, Luo FQ. Role of epigenetic regulation in cognitive dysfunction associated with Alzheimer's disease[J]. Neural Injury and Functional Reconstruction, 2024, 19(5): 285-290.] DOI: 10.16780/j.cnki.sjssgncj.20230083.

36.汪紫微,梁艳,王运良,等. 运动调节组蛋白去乙酰化改善阿尔茨海默病的研究进展[J]. 生命的化学, 2024, 44(5): 786-794. [Wang ZW, Lang Y, Wang YL, et al. Research progress in the improvement of motion-regulated histone deacetylation in Alzheimer's disease[J]. Chemistry of life, 2024, 44(5): 786-794.] DOI: 10.13488/j.smhx.20240052.

37.Liu YR, Wang JQ, Huang ZG, et al. Histone deacetylase2: a potential regulator and therapeutic target in liver disease (Review) [J]. Int J Mol Med, 2021, 48(1): 131. DOI: 10.3892/ijmm.2021.4964.

38.Kumar V, Kundu S, Singh A, et al. Understanding the role of histone deacetylase and their inhibitors in neurodegenerative disorders: current targets and future perspective[J]. Curr Neuropharmacol, 2022, 20(1): 158-178. DOI: 10.2174/1570159X19666210609160017.

39.Feng Y, Qin J, Lu Y, et al. Suberoylanilide hydroxamic acid attenuates cognitive impairment in offspring caused by maternal surgery during mid-pregnancy[J]. PLoS One, 2024, 19(3): e0295096. DOI: 10.1371/journal.pone.0295096.

40.De Plano LM, Saitta A, Oddo S, et al. Epigenetic changes in Alzheimer's disease: DNA methylation and histone modification[J]. Cells, 2024, 13(8). DOI: 10.3390/cells13080719.

41.Abay-Nørgaard S, Tapia MC, Zeijdner M, et al. Inter and transgenerational impact of H3K4 methylation in neuronal homeostasis[J]. Life Sci Alliance, 2023, 6(8): e202301970. DOI: 10.26508/lsa.202301970.

42.Xu L, Zheng Y, Li X, et al. Abnormal neocortex arealization and sotos-like syndrome-associated behavior in Setd2 mutant mice[J]. Sci Adv, 2021, 7(1): eaba1180. DOI: 10.1126/sciadv.aba1180.

43.Soutschek M, Schratt G. Non-coding RNA in the wiring and remodeling of neural circuits[J]. Neuron, 2023, 111(14): 2140-2154. DOI: 10.1016/j.neuron.2023.04.031.

44.Islam MR, Kaurani L, Berulava T, et al. A microRNA signature that correlates with cognition and is a target against cognitive decline[J]. EMBO Mol Med, 2021, 13(11): e13659. DOI: 10.15252/emmm.202013659.

45.Beversdorf DQ, Shah A, Jhin A, et al. microRNAs and gene-environment interactions in autism: effects of prenatal maternal stress and the SERT gene on maternal microRNA expression[J]. Front Psychiatry, 2021, 12: 668577. DOI: 10.3389/FPSYT.2021.668577.

46.Torres-Berrío A, Morgunova A, Giroux M, et al. miR-218 in adolescence predicts and mediates vulnerability to stress[J]. Biol Psychiatry, 2021, 89(9): 911-919. DOI: 10.1016/J.BIOPSYCH.2020.10.015.

47.Yoshino Y, Roy B, Dwivedi Y. Corticosterone-mediated regulation and functions of miR-218-5p in rat brain[J]. Sci Rep, 2022, 12(1): 1-12. DOI: 10.1038/s41598-021-03863-y.

48.Ke X, Huang Y, Fu Q, et al. Adverse maternal environment alters microRNA-10b-5p expression and its epigenetic profile concurrently with impaired hippocampal neurogenesis in male mouse hippocampus[J]. Dev Neurosci, 2021, 43(2): 1-11. DOI: 10.1159/000515750.

49.Foley HB, Howe CG, Eckel SP, et al. Depression, perceived stress, and distress during pregnancy and EV-associated miRNA profiles in MADRES[J]. J Affect Disord, 2023, 323: 799-808. DOI: 10.1016/j.jad.2022.12.039.