Epigenetic Basis of Lead-Induced Neurological Disorders
Abstract
:1. Introduction
2. Alzheimer’s Disease
2.1. AD and Risk Genes
2.2. AD and Lead Exposure
2.3. Epigenetic Basis of AD
2.4. Lead Exposure and Epigenetics
2.5. Epigenetic Mechanisms Linking Lead with AD
3. Parkinson’s Disease
3.1. PD and Risk Genes
3.2. Lead and PD Etiology
3.3. Epigenetics and Lead-Induced PD
4. Amyotrophic Lateral Sclerosis
5. Attention Deficit/Hyperactivity Disorder
6. Therapeutics for Neurological Disorders Based on Targeting Epigenetic Molecules
7. Conclusions and Future Perspective
Author Contributions
Funding
Conflicts of Interest
References
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Disease | Epigenetics | Observations | Associations with Lead |
---|---|---|---|
AD | Global DNA methylation | Reduced DNA methylation in human postmortem studies (n = 20) [33] | Global DNA methylation reprogrammed in ESCs (n = 7) [93] |
AD | CpG methylation at PSEN1, BACE1 | Deregulation of methylation status in cultured cells (n = 4) [39] | SERBP2-BACE1 pathway activated in rat brains (n = 40) [96] |
AD | CpG methylation at TREM2, BDNF | Differentially methylated in multiple models (n = 20; n = 30; n = 506, respectively) [46,47,48] | Positive relations between BDNF expression and umbilical cord blood lead level (n = 60) [97] |
AD | Global 5-hmC level | Elevated 5-hmC levels in preclinical AD subjects (n = 30) [53] | 5-hmC levels at a set of cluster CpG sites affected in umbilical cord blood DNA (n = 48) [98] |
AD | H4K12ac (acetylation of histone H4 at lysine 12) | Early increase in transgenic mouse model (n = 19) [56] | Latent increase of H4K12ac expression in aging primate brains (n = 5) [9] |
AD | H4 and H3 acetylation | Hypoacetylation of H4, not H3, in tg2576 mice [58] | H3 acetylation increased in developmentally exposed rats (n = 3) [99] |
AD | HDAC2 (histone deacetylase 2) | Elevated HDAC2 levels in AD patients (n = 6–9) [59] | HDAC2 aberrantly increased in developmentally exposed rats (n = 3) [100] |
AD | H3K9me (methylation of histone H3 at lysine 9) | Increase with age in the 3xTg-AD mouse model and AD model neurons (n = 6) [63] | Stable alteration depending on brain regions and genders in rats (n = 7–10) [5] |
AD | H3K4me3/H3K27me3 (trimethylation of histone H3 at lysine 4)/ trimethylation of histone H3 at lysine 27) | Identified DMRs overlapped promoters with bivalent markers in genome-wide methylation study in AD brains (n = 34) [33] | Bivalent regulation of Wnt9b and Wnt6 altered in hippocampal neuronal culture (n = 3) [101] |
AD | H3S10p (phosphorylation of H3S10) | Hyperphosphorylation in AD hippocampal neurons (n = 17) [66] | No direct link with lead was identified. |
AD | SUMOylation (SUMO, small ubiquitin-like modifiers) | SUMOylation of HDAC1 was a protective mechanism against Aβ toxicity in mouse model (n = 5) [67] | SUMOylation of EZH2 deregulated in lead-exposed PC-12 cells (unpublished data) |
AD | miR-29 | Reductions in AD patients, along with a increment of its target, BACE1 protein level (n = 5) [72] | MiR-29 elevated in short exposure period in developmentally exposed mice (n = 3) [102] |
AD | miR-132 | Deregulation of miR-132, targeting tau expression, in later stage of AD samples (n = 90; n = 7, respectively) [71,72] | miR-132 increased in short exposure period in developmentally exposed mice (n = 3) [102] |
AD | miR-146a | Deregulation of miR-146a, involved in neuroinflammation, in brain tissues from AD samples (n = 6) [77,78] | miR-146a negatively correlated with blood lead levels in 63 workers, but not significant (n = 63) [103] |
AD | BACE1-AS (BACE1 antisense RNA) | Aberrant elevation of BACE1-AS, promoting expression of BACE1, in AD subjects and APP transgenic mice [76,77] | No correlation of BACE1-AS with lead neurotoxicity was reported to date. |
AD | lncRNAL20992 | No information was given concerning importance of lncRNAL20992 in AD pathogenesis | lncRNAL20992 was aberrantly upregulated in a lead-induced neuronal injury model (n = 3) [104] |
AD | ciRS-7 (CDR1as) | Dysregulation in hippocampal CA1 region of AD patient, contributing to increased level of miR-7 and AD pathogenesis [87] | No associations were established. |
AD | circHOMER1 | Significant associations with AD diagnosis, as measured in an RNA-sequencing study. circHOMER1 contained five predicted binding sites for miR-651, which is predicted to target PSEN1 and PSEN2 (n = 77) [105] | No associations were established. |
AD | circCORO1C | Significant associations with AD diagnosis, as measured in an RNA-sequencing study. circCORO1C contained two predicted binding sites for miR-105, which is predicted to target APP and SCNA (n = 77) [105] | No associations were established. |
AD | MeCP2 (Methyl-CpG Binding Protein 2), DNMT1, DNMT3a (DNMT, DNA (cytosine-5)-methyltransferase), H3K4me2, H3K9ac, H4K8ac, H4K12ac | In a cohort of female monkeys randomly grouped and exposed with 1.5 mg/kg/d of lead acetate from birth till 400 d of age, cerebral cortex was sampled from 23-year-old primates, which exhibited AD symptoms. Developmental lead exposure led to a decreased expression of MeCP2 (p < 0.05), DNMT1 (p < 0.001) and DNMT3a (p < 0.001), along with marked increase in the expression of H3K4me2 (p < 0.01), as well as H3K9ac, H4K8ac and H4K12ac (p < 0.001) (n = 5; n = 4, respectively) [9,31] | |
AD | H3K9ac | Male C57BL/6 mice received 0.2% lead acetate from PND 1 through PND 20, and subsequently brain samples were collected across the lifespan till PND 700. Global downregulation of H3K9ac was observed, and chromatin immunoprecipitation sequencing revealed distinct subsets of H3K9ac-enriched genes (n = 5) [106] | |
PD | DNA methylation at HLA-DQA1 (Major Histocompatibility Complex, Class II, DQ Alpha 1) | Deregulation of methylation levels at HLA-DQA1 in blood and brain measurement of PD patients. HLA-DQA1 was also regulated by HDAC1 (n = 5) [107] | Developmental lead exposure changes the function of HDAC1/2 complex in rats and PC-12 cells (n = 3) [100] |
PD | H3 acetylation | Reduced acetyltransferase activity and H3Ac level in a Drosophila model of PD [108]; net hyperacetylation of histone H3 in human primary motor cortex (n = 3) [109] | H3 acetylation increased in developmentally exposed rats (n = 3) [99] |
PD | H3K9ac | Decreased H3K9ac level in human primary motor cortex (n = 9) [109] | H3K9ac decreased in lead-exposed PC-12 cell and rat hippocampus (n = 3) [100] |
PD | DNA methylation at SCNA promoter | Hypomethylation at SCNA promotor in brains of PD patients (n = 12) [110] | Lead increased PD odds only among subjects carrying non-deleterious SCNA allele (n = 328) [111] |
ALS | DNMT/5-mC | Upregulation of DNMTs and 5-mC in cellular models of ALS, as well as human ALS motor neurons (n = 5) [9] | Protein levels of DNMTs significantly affected in a 23-year-old primate with early life exposure of lead (n = 5) [9] |
ALS | miR-142 | Upregulation of miR-142 levels in the spinal cords of ALS patients, possibly by targeting cell death or brain development-related pathway [112] | miR-142 exhibited a positive correlation with increasing tibia lead levels in the cervix tissue (n = 45) [113] |
ADHD | CpG 1 methylation at DRD4 (dopamine receptor 4) promoter, HDAC1, Myst4 (histone acetyltransferase 4), p300 | In a case-control study towards Chinese children, ADHD was associated with a specific CpG site methylation at the promoter of DRD4 gene, as well as with expression levels of histone acetylation-related genes: HDAC1, Myst4 and p300. Among the same population, blood lead levels in ADHD children were significantly higher than age/gender-matched controls (n = 50) [114] | |
ADHD | MeCP2 | Reduced MeCP2 expression in ADHD frontal cortex samples (n = 5) [115] | Lead exposure altered DNMT and MeCP2 levels in the hippocampus of exposed dams (n = 6–8) [116] |
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Wang, T.; Zhang, J.; Xu, Y. Epigenetic Basis of Lead-Induced Neurological Disorders. Int. J. Environ. Res. Public Health 2020, 17, 4878. https://doi.org/10.3390/ijerph17134878
Wang T, Zhang J, Xu Y. Epigenetic Basis of Lead-Induced Neurological Disorders. International Journal of Environmental Research and Public Health. 2020; 17(13):4878. https://doi.org/10.3390/ijerph17134878
Chicago/Turabian StyleWang, Tian, Jie Zhang, and Yi Xu. 2020. "Epigenetic Basis of Lead-Induced Neurological Disorders" International Journal of Environmental Research and Public Health 17, no. 13: 4878. https://doi.org/10.3390/ijerph17134878