妊娠期砷暴露对子代小鼠神经发育的影响及miRNA调控机制研究

doi:10.12183/j.scjpm.2026.0291

摘要/Abstract

摘要： 目的探讨妊娠期砷（As）暴露对子代小鼠神经发育的影响,并阐明其中miRNA的调控作用。方法通过孕鼠自由饮用亚砷酸钠溶液（按0.5 mg/kg体质量计算）构建妊娠期As暴露模型。采用悬尾、强迫游泳、旷场及Morris水迷宫等试验评估出生后30 d（Pnd 30）子代的神经行为学变化。取出生后1 d（Pnd 1）子代脑组织,通过HE染色观察海马区组织病理学改变,并利用miRNA测序筛选差异表达的miRNA,对其靶基因进行GO功能富集与KEGG通路分析。结果与对照组相比,As暴露组子代表现出显著的焦虑、抑郁样行为及学习记忆能力受损（均P<0.05）。组织病理学检查发现,其海马齿状回及CA3区神经元数量减少、排列紊乱。miRNA测序共筛选出69个差异表达的miRNA（27个上调,42个下调;P<0.05）。生物信息学分析提示,其靶基因主要富集于神经系统发育、生物学过程调控及钙离子转运等功能,参与神经发育、免疫调节、癌变及氧化应激等信号通路。结论妊娠期As暴露可通过调控子代miRNA表达异常,进而影响神经元发育及相关信号通路,最终导致神经行为异常。这些发现提示miRNA在As致神经毒性机制中具有关键调控作用。

关键词: 妊娠期砷暴露, 神经发育毒性, 转录组测序, miRNA

Abstract: Objective To investigate the influence of gestational arsenic (As) exposure on the neurodevelopment of offspring mice and to elucidate the regulatory role of microRNAs (miRNAs) therein. Methods A murine model of gestational As exposure was established by administering sodium arsenite to pregnant dams via drinking water (at a dose of 0.5 mg/kg body weight). Neurobehavioral alterations in the offspring at postnatal day 30 (Pnd 30) were assessed using the tail suspension test, forced swim test, open field test, and Morris water maze. On Pnd 1, brain tissues of the neonatal mice were collected for histopathological examination of the hippocampal region by hematoxylin and eosin (H&E) staining. MiRNA sequencing was performed to identify differentially expressed miRNAs, followed by Gene Ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses of their target genes. Results In comparison with the control group, offspring from the As-exposure group exhibited significant anxiety-and depression-like behaviors, alongside impaired learning and memory capabilities (all P<0.05). Histopathological analysis revealed a reduction in neuronal count and a disordered arrangement of neurons in the hippocampal dentate gyrus and CA3 region. MiRNA sequencing identified 69 differentially expressed miRNAs (27 upregulated, 42 downregulated; P<0.05). Bioinformatic analysis indicated that the target genes of these miRNAs were primarily enriched in functions related to nervous system development, regulation of biological processes, and calcium ion transport. These genes were implicated in signaling pathways crucial for neurogenesis, immune regulation, carcinogenesis, and oxidative stress. Conclusion Gestational exposure to arsenic may induce neurobehavioral abnormalities in offspring by modulating aberrant miRNA expression, which in turn affects neuronal development and associated signaling pathways. These findings suggest a pivotal regulatory role for miRNAs in the mechanisms of arsenic-induced neurotoxicity.

Key words: Gestational arsenic exposure, Neurodevelopmental toxicity, Transcriptome sequencing, miRNA

中图分类号:

R179

王梓同, 吕媛, 刘瑞刚, 王汇, 邰大鹏. 妊娠期砷暴露对子代小鼠神经发育的影响及miRNA调控机制研究[J]. 华南预防医学, 2026, 52(3): 291-298.

Wang Zitong, Lyu Yuan, Liu Ruigang, Wang Hui, Tai Dapeng. Effects of gestational arsenic exposure on neurodevelopment in mouse offspring and the underlying mirna-mediated regulatory mechanisms[J]. South China Journal of Preventive Medicine, 2026, 52(3): 291-298.

参考文献

[1] Hu HB, Xie BZ, Lu YT, et al.Advances in electrochemical detection electrodes for As(III)[J]. Nanomaterials, 2022, 12(5): 781.
[2] 吴兆明, 刘琪, 谭焕腾. 砷暴露和糖尿病发病关系的研究进展[J]. 糖尿病新世界, 2024, 27(20): 188-190.
[3] Liu XD, Zhang R, Fan JJ, et al.The role of ROS/p38 MAPK/NLRP3 inflammasome cascade in arsenic-induced depression-/anxiety-like behaviors of mice[J]. Ecotoxicol Environ Saf, 2023, 261: 115111.
[4] Dai YM, Lu HY, Zhang JM, et al.Sex-specific associations of maternal and childhood urinary arsenic levels with emotional problems among 6-year-old children: Evidence from a longitudinal cohort study in China[J]. Ecotoxicol Environ Saf, 2023, 267: 115658.
[5] Rahaman MS, Rahman MM, Mise N, et al.Environmental arsenic exposure and its contribution to human diseases, toxicity mechanism and management[J]. Environ Pollut, 2021, 289: 117940.
[6] Wang JZ, Zhu S, Meng N, et al.ncRNA-encoded peptides or proteins and cancer[J]. Mol Ther, 2019, 27(10): 1718-1725.
[7] Dong JC, Hu Y, Liu S, et al.Arsenic induces ferroptosis in HTR-8/SVneo cells and placental damage[J]. Sci Total Environ, 2024, 955: 176885.
[8] Zhang B, Chen JH, Wang JJ, et al.Arsenic exposure induces neural cells senescence and abnormal lipid droplet accumulation leading to social memory impairment in mice[J]. Environ Pollut, 2025, 368: 125779.
[9] Chen L, Heikkinen L, Wang CL, et al.Trends in the development of miRNA bioinformatics tools[J]. Brief Bioinform, 2019, 20(5): 1836-1852.
[10] Thapa R, Afzal M, Goyal A, et al.Exploring ncRNA-mediated regulation of EGFR signalling in glioblastoma: From mechanisms to therapeutics[J]. Life Sci, 2024, 343: 122613.
[11] Hill M, Tran N. miRNA interplay: Mechanisms and consequences in cancer[J]. Dis Model Mech, 2021, 14(4): dmm047662.
[12] Banerjee M, Lykoudi A, Hwang JY, et al.Dysregulation of mRNA expression by hsa-miR-186 overexpression in arsenic-induced skin carcinogenesis[J]. Toxicol Appl Pharmacol, 2025, 495: 117209.
[13] Zhang MY, Li LZ, Li SG.The role of miR-150-5p/SOCS1 pathway in arsenic-induced pyroptosis of LX-2 cells[J]. Biol Trace Elem Res, 2025, 203(2): 822-834.
[14] Li WD, Li ZY, Ma JX, et al.Circulating microRNAs in association with urinary arsenic: A community-based multi-center study in China[J]. Environ Res, 2025, 274: 121354.
[15] Wang HH, Liu XD, Chen Y, et al.The regulatory role of miR-21 in ferroptosis by targeting FTH1 and the contribution of microglia-derived miR-21 in exosomes to arsenic-induced neuronal ferroptosis[J]. J Hazard Mater, 2024, 478: 135580.
[16] Wang DJ, Wang XD, Liu XF, et al.Inhibition of miR-219 alleviates arsenic-induced learning and memory impairments and synaptic damage through up-regulating CaMKII in the hippocampus[J]. Neurochem Res, 2018, 43(4): 948-958.
[17] Hughes MF, Kenyon EM, Edwards BC, et al.Strain-dependent disposition of inorganic arsenic in the mouse[J]. Toxicology, 1999, 137(2): 95-108.
[18] 张维福. Welch检验及Games-Howell法在单因素方差分析中的应用[J]. 中国卫生统计, 2025, 42(2): 297-300.
[19] Yang H, Liu YF, Chen LQ, et al.miRNA-based therapies for lung cancer: opportunities and challenges?[J]. Biomolecules, 2023, 13(6): 877.
[20] 杜艾家, 张曼, 陈鹤, 等. 微小RNA-1270靶向调控血管生成素样蛋白7抑制巨噬细胞炎症和脂质蓄积[J]. 山东大学学报(医学版), 2025, 63(2): 1-9, 20.
[21] Ferragut Cardoso AP, Banerjee M, Nail AN, et al.miRNA dysregulation is an emerging modulator of genomic instability[J]. Semin Cancer Biol, 2021, 76: 120-131.
[22] Bayraktar R, Fontana B, Calin GA, et al.miRNA biology in chronic lymphocytic leukemia[J]. Semin Hematol, 2024, 61(3): 181-193.
[23] Ayyanar MP, Vijayan M.A review on gut microbiota and miRNA crosstalk: implications for Alzheimer's disease[J]. GeroScience, 2025, 47(1): 339-385.
[24] Cogoni C, Ruberti F, Barbato C.MicroRNA landscape in Alzheimer's disease[J]. CNS Neurol Disord Drug Targets, 2015, 14(2): 168-175.
[25] Kyi-Tha-Thu C, Htway SM, Suzuki T, et al. Gestational arsenic exposure induces anxiety-like behaviors in F1 female mice by dysregulation of neurological and immunological markers[J]. Environ Health Prev Med, 2023, 28: 43.
[26] 万君, 柯红, 王磊, 等. 低含量含砷水暴露对子代鼠生长和发育的影响[J]. 中国现代医学杂志, 2019, 29(4): 9-13.
[27] Chen H, Zhang HL, Wang X, et al.Prenatal arsenic exposure, arsenic metabolism and neurocognitive development of 2-year-old children in low-arsenic areas[J]. Environ Int, 2023, 174: 107918.
[28] Bartos M, Gallegos CE, Mónaco N, et al.Developmental exposure to arsenic reduces anxiety levels and leads to a depressive-like behavior in female offspring rats: Molecular changes in the prefrontal cortex[J]. Neurotoxicology, 2024, 104: 85-94.
[29] Li S, Li J, Chen K, et al.Chronic arsenic exposure causes Alzheimer's disease characteristic effects and the intervention of fecal microbiota transplantation in rats[J]. J Appl Toxicol, 2025, 45(8): 1476-1486.
[30] Karat BG, Köhler S, Khan AR.Diffusion MRI of the hippocampus[J]. J Neurosci, 2024, 44(23): e1705232024.
[31] Flannery JC, Tirrell PS, Baumgartner NE, et al.Neuroestrogens, the hippocampus, and female cognitive aging[J]. Horm Behav, 2025, 170: 105710.
[32] Szymkowicz DB, Sims KC, Schwendinger KL, et al.Exposure to arsenic during embryogenesis impairs olfactory sensory neuron differentiation and function into adulthood[J]. Toxicology, 2019, 420: 73-84.
[33] Chu F, Yang WJ, Li Y, et al.Subchronic arsenic exposure induces behavioral impairments and hippocampal damage in rats[J]. Toxics, 2023, 11(12): 970.
[34] Li LP, Li SQ. miR-205-5p inhibits cell migration and invasion in prostatic carcinoma by targeting ZEB1[J]. Oncol Lett, 2018, 16(2): 1715-1721.
[35] Chen SY, Xie CP, Hu XR. lncRNA SNHG6 functions as a ceRNA to up-regulate c-Myc expression via sponging let-7c-5p in hepatocellular carcinoma[J]. Biochem Biophys Res Commun, 2019, 519(4): 901-908.
[36] Gao P, He M, Zhang CL, et al.Integrated analysis of gene expression signatures associated with colon cancer from three datasets[J]. Gene, 2018, 654: 95-102.
[37] Ma XB, Liu Y, Ding B, et al.Anthocyanins from blueberry ameliorated arsenic-induced memory impairment, oxidative stress, and mitochondrial-biosynthesis imbalance in rat hippocampal neurons[J]. Cell Signal, 2024, 119: 111177.
[38] Manthari RK, Tikka C, Ommati MM, et al.Arsenic induces autophagy in developmental mouse cerebral cortex and hippocampus by inhibiting PI3K/Akt/mTOR signaling pathway: Involvement of blood-brain barrier's tight junction proteins[J]. Arch Toxicol, 2018, 92(11): 3255-3275.
[39] Yamauchi H, Hitomi T, Takata A.Evaluation of arsenic metabolism and tight junction injury after exposure to arsenite and monomethylarsonous acid using a rat in vitro blood-brain barrier model[J]. PLoS One, 2023, 18(11): e0295154.
[40] Rao G, Zhong GL, Hu T, et al.Arsenic trioxide triggers mitochondrial dysfunction, oxidative stress, and apoptosis via Nrf2/caspase-3 signaling pathway in heart of ducks[J]. Biol Trace Elem Res, 2023, 201(3): 1407-1417.