铅毒性的表观遗传学机制研究进展

doi:10.3969/j.issn.1674-8115.2025.04.013

摘要/Abstract

摘要：

铅是一种普遍存在于环境中的有毒重金属，也是人类历史上使用最早、应用最为广泛的重金属元素之一。由于铅在环境中不可降解，并且在人体内具有较长的生物累积效应（可长达30~50年），即使极低浓度的铅也能对人体造成健康损害，因而被世界卫生组织（World Health Organization，WHO）列为十大公共卫生关注化学品之一。铅进入人体后，通常会分布在脑、肝脏、肾脏、牙齿和骨骼等组织中，进而对全身各个系统、多种脏器和组织产生广泛的毒性作用。表观遗传学是研究基因表达在不改变核苷酸序列的情况下发生可遗传变化的学科，它揭示了基因表达修饰如何对细胞进行调控，导致具有相同DNA序列的细胞表现出不同形态与功能。尽管铅的毒性机制尚未完全明确，但近年来的研究表明，表观遗传学调控可能是铅毒性作用的重要机制之一。环境铅暴露可通过引发个体细胞的DNA甲基化、组蛋白修饰和微RNA（microRNA，miRNA）等表观遗传学改变，进而而诱发多种毒性反应。该文就铅毒性相关的表观遗传学机制研究现状，着重从DNA甲基化、组蛋白修饰和miRNA 3个方面进行综述，旨在从表观遗传学角度审视铅毒性，并为进一步探究铅的毒性机制提供理论基础。

关键词: 铅, DNA甲基化, 组蛋白修饰, 微RNA

Abstract:

Lead is a ubiquitous toxic heavy metal and one of the earliest and most widely used heavy metal elements in human history. Due to its non-degradable nature in the environment and its long biological accumulation effects (lasting up to 30‒50 years) in the human body, even trace amounts of lead can cause significant health damage. It has therefore been classified as one of the top ten public health concerns by the World Health Organization (WHO). Once absorbed into the body, lead is typically distributed in tissues such as the brain, liver, kidneys, teeth, and bones, thereby exerting widespread toxic effects on multiple organ systems. Epigenetics is the study of heritable changes in gene expression that occur without alterations in the nucleotide sequence. It reveals how modifications in gene expression regulate cellular functions, leading to diverse cellular phenotypes and functions despite identical DNA sequences. Although the toxic mechanisms of lead are not yet fully elucidated, recent studies suggest that epigenetic regulation may play a significant role in mediating lead toxicity. Environmental lead exposure can induce various epigenetic modifications in cells, such as DNA methylation, histone modifications, and microRNA (miRNA) alterations, which, in turn, can trigger multiple toxic responses. This paper presents a concise overview of current epigenetic investigations into lead toxicity, emphasizing DNA methylation, histone modifications, and miRNA dynamics. By adopting an epigenetic perspective, it offers a theoretical framework into understanding lead's toxic mechanisms comprehensively, facilitating further research in prevention and treatment strategies.

Key words: lead, DNA methylation (DNMT), histone modification, microRNA (miRNA)

中图分类号:

R114

张欣欣, 颜崇淮. 铅毒性的表观遗传学机制研究进展[J]. 上海交通大学学报（医学版）, 2025, 45(4): 500-507.

ZHANG Xinxin, YAN Chonghuai. Advances in epigenetic mechanisms of lead toxicity[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(4): 500-507.

图/表 3

参考文献 58

1	MEI Z Q, LIU G F, ZHAO B, et al. Emerging roles of epigenetics in lead-induced neurotoxicity[J]. Environ Int, 2023, 181: 108253.
2	APPLETON A A, JACKSON B P, KARAGAS M, et al. Prenatal exposure to neurotoxic metals is associated with increased placental glucocorticoid receptor DNA methylation[J]. Epigenetics, 2017, 12(8): 607-615.
3	RECILLAS-TARGA F. Cancer epigenetics: an overview[J]. Arch Med Res, 2022, 53(8): 732-740.
4	OKAMOTO Y, IWAI-SHIMADA M, NAKAI K, et al. Global DNA methylation in cord blood as a biomarker for prenatal lead and antimony exposures[J]. Toxics, 2022, 10(4): 157.
5	ZENG Z J, HUO X, ZHANG Y, et al. Differential DNA methylation in newborns with maternal exposure to heavy metals from an e-waste recycling area[J]. Environ Res, 2019, 171: 536-545.
6	BOZACK A K, RIFAS-SHIMAN S L, COULL B A, et al. Prenatal metal exposure, cord blood DNA methylation and persistence in childhood: an epigenome-wide association study of 12 metals[J]. Clin Epigenetics, 2021, 13(1): 208.
7	TUNG P W, KENNEDY E M, BURT A, et al. Prenatal lead (Pb) exposure is associated with differential placental DNA methylation and hydroxymethylation in a human population[J]. Epigenetics, 2022, 17(13): 2404-2420.
8	BRAUN J M. Early-life exposure to EDCs: role in childhood obesity and neurodevelopment[J]. Nat Rev Endocrinol, 2017, 13(3): 161-173.
9	RYGIEL C A, DOLINOY D C, PERNG W, et al. Trimester-specific associations of prenatal lead exposure with infant cord blood DNA methylation at birth[J]. Epigenet Insights, 2020, 13: 2516865720938669.
10	RYGIEL C A, DOLINOY D C, BAKULSKI K M, et al. DNA methylation at birth potentially mediates the association between prenatal lead (Pb) exposure and infant neurodevelopmental outcomes[J]. Environ Epigenet, 2021, 7(1): dvab005.
11	WANG K, LIU S Y, SVOBODA L K, et al. Tissue- and sex-specific DNA methylation changes in mice perinatally exposed to lead (Pb)[J]. Front Genet, 2020, 11: 840.
12	SVOBODA L K, NEIER K R, WANG K, et al. Tissue and sex-specific programming of DNA methylation by perinatal lead exposure: implications for environmental epigenetics studies[J]. Epigenetics, 2021, 16(10): 1102-1122.
13	SVOBODA L K, WANG K, JONES T R, et al. Sex-specific alterations in cardiac DNA methylation in adult mice by perinatal lead exposure[J]. Int J Environ Res Public Health, 2021, 18(2): 577.
14	SVOBODA L K, WANG K, GOODRICH J M, et al. Perinatal lead exposure promotes sex-specific epigenetic programming of disease-relevant pathways in mouse heart[J]. Toxics, 2023, 11(1): 85.
15	MORGAN R K, WANG K, SVOBODA L K, et al. Effects of developmental lead and phthalate exposures on DNA methylation in adult mouse blood, brain, and liver identifies tissue- and sex-specific changes with implications for genomic imprinting[J]. bioRxiv, 2023: 2023.09.29.560131.
16	MCCABE C, ANDERSON O S, MONTROSE L, et al. Sexually dimorphic effects of early-life exposures to endocrine disruptors: sex-specific epigenetic reprogramming as a potential mechanism[J]. Curr Environ Health Rep, 2017, 4(4): 426-438.
17	WARKOCKI Z. An update on post-transcriptional regulation of retrotransposons[J]. FEBS Lett, 2023, 597(3): 380-406.
18	WANG K, MENG Y, WANG T W, et al. Global and gene-specific promoter methylation, and micronuclei induction in lead-exposed workers: a cross-sectional study[J]. Environ Mol Mutagen, 2021, 62(7): 428-434.
19	WANG T W, MENG Y, TU Y T, et al. Associations between DNA methylation and genotoxicity among lead-exposed workers in China[J]. Environ Pollut, 2023, 316(Pt 1): 120528.
20	EL-SHETRY E S, MOHAMED A A, KHATER S I, et al. Synergistically enhanced apoptotic and oxidative DNA damaging pathways in the rat brain with lead and/or aluminum metals toxicity: expression pattern of genes OGG1 and P53[J]. J Trace Elem Med Biol, 2021, 68: 126860.
21	YOHANNES Y B, NAKAYAMA S M, YABE J, et al. Blood lead levels and aberrant DNA methylation of the ALAD and p16 gene promoters in children exposed to environmental-lead[J]. Environ Res, 2020, 188: 109759.
22	CARDELLI M. The epigenetic alterations of endogenous retroelements in aging[J]. Mech Ageing Dev, 2018, 174: 30-46.
23	GOKHMAN D, MALUL A, CARMEL L. Inferring past environments from ancient epigenomes[J]. Mol Biol Evol, 2017, 34(10): 2429-2438.
24	COLICINO E, JUST A, KIOUMOURTZOGLOU M A, et al. Blood DNA methylation biomarkers of cumulative lead exposure in adults[J]. J Expo Sci Environ Epidemiol, 2021, 31(1): 108-116.
25	PAUL K C, HORVATH S, DEL ROSARIO I, et al. DNA methylation biomarker for cumulative lead exposure is associated with Parkinson's disease[J]. Clin Epigenetics, 2021, 13(1): 59.
26	LIEBERMAN-CRIBBIN W, DOMINGO-RELLOSO A, NAVAS-ACIEN A, et al. Epigenetic biomarkers of lead exposure and cardiovascular disease: prospective evidence in the strong heart study[J]. J Am Heart Assoc, 2022, 11(23): e026934.
27	HOCHER A, WARNECKE T. Nucleosomes at the dawn of eukaryotes[J]. Genome Biol Evol, 2024, 16(3): evae029.
28	SÁNCHEZ O F, LIN L F, XIE J K, et al. Lead exposure induces dysregulation of constitutive heterochromatin hallmarks in live cells[J]. Curr Res Toxicol, 2022, 3: 100061.
29	GU X Z, XU Y, XUE W Z, et al. Interplay of miR-137 and EZH2 contributes to the genome-wide redistribution of H3K27me3 underlying the Pb-induced memory impairment[J]. Cell Death Dis, 2019, 10(9): 671.
30	XIAO J, WANG T, XU Y, et al. Long-term probiotic intervention mitigates memory dysfunction through a novel H3K27me3-based mechanism in lead-exposed rats[J]. Transl Psychiatry, 2020, 10(1): 25.
31	EID A, BIHAQI S W, RENEHAN W E, et al. Developmental lead exposure and lifespan alterations in epigenetic regulators and their correspondence to biomarkers of Alzheimer's disease[J]. Alzheimers Dement (Amst), 2016, 2: 123-131.
32	VARMA G, SOBOLEWSKI M, CORY-SLECHTA D A, et al. Sex- and brain region- specific effects of prenatal stress and lead exposure on permissive and repressive post-translational histone modifications from embryonic development through adulthood[J]. Neurotoxicology, 2017, 62: 207-217.
33	SNIGDHA S, ALEPH PRIETO G, PETROSYAN A, et al. H3K9me3 inhibition improves memory, promotes spine formation, and increases BDNF levels in the aged hippocampus[J]. J Neurosci, 2016, 36(12): 3611-3622.
34	LIN L F, XIE J K, SÁNCHEZ O F, et al. Low dose lead exposure induces alterations on heterochromatin hallmarks persisting through SH-SY5Y cell differentiation[J]. Chemosphere, 2021, 264(Pt 1): 128486.
35	KUMAR K, ANJALI S, SHARMA S. Effect of lead exposure on histone modifications: a review[J]. J Biochem Mol Toxicol, 2024, 38(1): e23547.
36	LUO M, XU Y, CAI R, et al. Epigenetic histone modification regulates developmental lead exposure induced hyperactivity in rats[J]. Toxicol Lett, 2014, 225(1): 78-85.
37	XU L H, MU F F, ZHAO J H, et al. Lead induces apoptosis and histone hyperacetylation in rat cardiovascular tissues[J]. PLoS One, 2015, 10(6): e0129091.
38	KIRAN G S, KUMAR P K, MITRA P, et al. Unravelling blood-based epigenetic mechanisms: the impact of hsa-miR-146a and histone H3 acetylation in lead-induced inflammation among occupational workers[J]. Int Arch Occup Environ Health, 2023, 96(9): 1257-1266.
39	WANG Y W, HU Y Z, WU Z T, et al. Latent role of in vitro Pb exposure in blocking Aβ clearance and triggering epigenetic modifications[J]. Environ Toxicol Pharmacol, 2019, 66: 14-23.
40	WU Y L, XU Y, HUANG X Y, et al. Regulatory roles of histone deacetylases 1 and 2 in Pb-induced neurotoxicity[J]. Toxicol Sci, 2018, 162(2): 688-701.
41	CHESHMAZAR N, HAMZEH-MIVEHROUD M, NOZAD CHAROUDEH H, et al. Current trends in development of HDAC-based chemotherapeutics[J]. Life Sci, 2022, 308: 120946.
42	ZHOU R Q, ZHAO J, LI D Y, et al. Combined exposure of lead and cadmium leads to the aggravated neurotoxicity through regulating the expression of histone deacetylase 2[J]. Chemosphere, 2020, 252: 126589.
43	GU X Z, HUANG X Y, LI D Y, et al. Nuclear accumulation of histone deacetylase 4 (HDAC4) by PP1-mediated dephosphorylation exerts neurotoxicity in Pb-exposed neural cells[J]. Neurotoxicology, 2020, 81: 395-405.
44	GU X Z, SHEN N, HUANG C Q, et al. Pb inhibited C2C12 myoblast differentiation by regulating HDAC2[J]. Toxicology, 2023, 499: 153639.
45	XU M, YU Z M, HU F F, et al. Identification of differential plasma miRNA profiles in Chinese workers with occupational lead exposure[J]. Biosci Rep, 2017, 37(5): BSR20171111.
46	OCHOA-MARTÍNEZ Á C, VARELA-SILVA J A, ORTA-GARCÍA S T, et al. Lead (Pb) exposure is associated with changes in the expression levels of circulating miRNAS (miR-155, miR-126) in Mexican women[J]. Environ Toxicol Pharmacol, 2021, 83: 103598.
47	WEN Q F, VERHEIJEN M, WITTENS M M J, et al. Lead-exposure associated miRNAs in humans and Alzheimer's disease as potential biomarkers of the disease and disease processes[J]. Sci Rep, 2022, 12(1): 15966.
48	MITRA P, GOYAL T, SINGH P, et al. Assessment of circulating miR-20b, miR-221, and miR-155 in occupationally lead-exposed workers of North-Western India[J]. Environ Sci Pollut Res Int, 2021, 28(3): 3172-3181.
49	XUE C, KANG B P, SU P, et al. microRNA-106b-5p participates in lead (Pb²⁺)-induced cell viability inhibition by targeting XIAP in HT-22 and PC12 cells[J]. Toxicol In Vitro, 2020, 66: 104876.
50	WANG W X, SHI F, CUI J M, et al. miR-378a-3p/SLC7A11 regulate ferroptosis in nerve injury induced by lead exposure[J]. Ecotoxicol Environ Saf, 2022, 239: 113639.
51	HAN L, ZOU Y F, YU C. Targeting CC chemokine ligand (CCL) 20 by miR-143-5p alleviate lead poisoning-induced renal fibrosis by regulating interstitial fibroblasts excessive proliferation and dysfunction[J]. Bioengineered, 2022, 13(4): 11156-11168.
52	MASOUD A M, BIHAQI S W, ALANSI B, et al. Altered microRNA, mRNA, and protein expression of neurodegeneration-related biomarkers and their transcriptional and epigenetic modifiers in a human tau transgenic mouse model in response to developmental lead exposure[J]. J Alzheimers Dis, 2018, 63(1): 273-282.
53	DASH M, EID A, SUBAIEA G, et al. Developmental exposure to lead (Pb) alters the expression of the human tau gene and its products in a transgenic animal model[J]. NeuroToxicology, 2016, 55: 154-159.
54	NUNOMURA A, PERRY G. RNA and oxidative stress in Alzheimer's disease: focus on microRNAs[J]. Oxid Med Cell Longev, 2020, 2020: 2638130.
55	WANG R K, WU Z T, LIU R D, et al. Age-related miRNAs dysregulation and abnormal BACE1 expression following Pb exposure in adolescent mice[J]. Environ Toxicol, 2022, 37(8): 1902-1913.
56	LIU R D, WANG Y W, BAI L, et al. Time-course miRNA alterations and SIRT1 inhibition triggered by adolescent lead exposure in mice[J]. Toxicol Res (Camb), 2021, 10(4): 667-676.
57	YANG C H, KANG B P, CAO Z P, et al. Early-life Pb exposure might exert synapse-toxic effects via inhibiting synapse-associated membrane protein 2 (VAMP2) mediated by upregulation of miR-34b[J]. J Alzheimers Dis, 2022, 87(2): 619-633.
58	WANG T, GUAN R L, ZOU Y F, et al. miR-130/SNAP-25 axis regulate presynaptic alteration in anterior cingulate cortex involved in lead induced attention deficits[J]. J Hazard Mater, 2023, 443(Pt B): 130249.

Gene	Expression change	Sample type	Effect	Reference
miR-155/miR-221	Upregulated	Peripheral blood samples from adults	Cell apoptosis, cell proliferation, and cytokine production	PMID: 32902755
miR-146a	Upregulated	Peripheral blood samples from adults	Inhibition of inflammatory factor release and cell apoptosis	PMID: 36274319
miR-106b-56p	Upregulated	HT-22 and PC12 cell lines	Decreased XIAP levels and cell viability	PMID: 32344020
miR-378a-3p	Upregulated	HT-22 cell line	Reduced GSH and increased lipid ROS levels	PMID: 35588615
miR-143-5p	Downregulated	Fibroblast samples	Regulation of dysfunction of interstitial fibroblasts	PMID: 35485286
miR-106b/miR-124/miR-34c	Upregulated	Cerebral cortex tissue samples	Induced neurotoxicity and learning/memory impairment	PMID: 29614648/27293183
miR-34b	Upregulated	Hippocampal tissue samples	Induced developmental neuropsychiatric dysfunction	PMID: 35367965

Gene	Expression change	Sample type	Effect	Reference
miR-155/miR-221	Upregulated	Peripheral blood samples from adults	Cell apoptosis, cell proliferation, and cytokine production	PMID: 32902755
miR-146a	Upregulated	Peripheral blood samples from adults	Inhibition of inflammatory factor release and cell apoptosis	PMID: 36274319
miR-106b-56p	Upregulated	HT-22 and PC12 cell lines	Decreased XIAP levels and cell viability	PMID: 32344020
miR-378a-3p	Upregulated	HT-22 cell line	Reduced GSH and increased lipid ROS levels	PMID: 35588615
miR-143-5p	Downregulated	Fibroblast samples	Regulation of dysfunction of interstitial fibroblasts	PMID: 35485286
miR-106b/miR-124/miR-34c	Upregulated	Cerebral cortex tissue samples	Induced neurotoxicity and learning/memory impairment	PMID: 29614648/27293183
miR-34b	Upregulated	Hippocampal tissue samples	Induced developmental neuropsychiatric dysfunction	PMID: 35367965

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