Table 1.
Summary of studies of epigenetics involved in lead-induced neurological disorders.
| 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against Aβ toxicity in mouse model (n = 5) [67] | SUMOylation of EZH2 deregulated in lead-exposed PC-12 cells (unpublished data) |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] |
AD, Alzheimer’s disease; PD, Parkinson’s disease; ALS, Amyotrophic lateral sclerosis; ADHD, Attention deficit/hyperactivity disorder.