Review

Advances in epigenetic mechanisms of lead toxicity

  • ZHANG Xinxin ,
  • YAN Chonghuai
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  • 1.Shanghai Jiao Tong University School of Public Health, Shanghai 200025, China
    2.Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
YAN Chonghuai, E-mail: yanchonghuai@xinhuamed.com.cn.

Received date: 2024-11-10

  Accepted date: 2024-12-19

  Online published: 2025-04-21

Supported by

National Natural Science Foundation of China(81973062)

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.

Cite this article

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 . DOI: 10.3969/j.issn.1674-8115.2025.04.013

References

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.
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