Exposure to Metals, Pesticides, and Air Pollutants: Focus on Resulting DNA Methylation Changes in Neurodegenerative Diseases
Abstract
:1. Introduction
2. Metals, Pesticides, and Air Pollution as Risk Factors for Age-Related Neurodegenerative Diseases
3. DNA Methylation
4. DNA Methylation and Neurodegeneration
5. DNA Methylation Changes Induced by Metals, Pesticides, and Air Pollutants in Neurodegenerative Diseases
5.1. In Vitro and In Vivo Studies
5.2. Human Studies
6. Conclusions and Future Perspectives
Author Contributions
Funding
Conflicts of Interest
References
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Experimental Model | Disease Model | Epigenetic Target | Results | Reference |
---|---|---|---|---|
Metals | ||||
Cortical brain tissue of monkeys exposed to lead as infants, which later developed AD-like pathology by the age of 23 | AD | DNMT1 activity | Infantile exposure to lead induced increased expression of APP and BACE1 with concomitant decreased activity of DNMT1 in aged monkeys (23 years old) | [67] |
Cortical brain tissue of monkeys exposed to lead as infants, which later developed AD-like pathology by the age of 23 | AD | Dnmts, Mecp2, histone-modifying proteins | Infantile exposure to lead induced increased expression of neurobiology-related genes and decreased expression of Dnmts, MeCP2, and proteins involved in histone modifications | [99] |
Human neuroblastoma (SH-SY5Y) cells exposed to manganese as a model of idiopathic PD | PD | Genome-wide DNA methylation | DNA methylation alterations in genes involved in the onset of PD, including hypermethylation of PINK1, PARK2, and TH | [100] |
Substantia nigra samples of mice exposed to manganese as a model of PD | PD | Genome-wide DNA methylation | DNA methylation in the promoter region of 226 genes involved in mitochondrial function, cell cycle, DNA damage response, and ion transportation was found to be regulated (mainly hypermethylated) by manganese treatment | [101] |
Rat dopaminergic cells treated with manganese and MPP+ as models of PD | PD | Genome-wide DNA methylation | Manganese mainly induced hypermethylation in genes involved in cell differentiation and lipid metabolism. MPP+ mainly induced hypermethylation in genes involved in mitochondrial function, autophagy/mitophagy, and WNT signaling | [102] |
Hippocampal specimens from rats orally exposed to iron levels that cause memory impairment | Neurodegeneration | Global 5-mC and 5-hmC mtDNA content | Iron exposure during the neonatal period at doses that induced neurodegenerative processes led to decreased 5-mC and 5-hmC levels in mtDNA in adulthood | [103] |
Pesticides | ||||
Substantia nigra of mice developmentally exposed to dieldrin to model an early stage of PD | PD | Genome-wide DNA methylation | Developmental dieldrin exposure induced altered methylation levels in several genes, including hypermethylation of Nr4a2 and hypomethylation of Lmx1b which are involved in dopaminergic neuron development and maintenance | [105] |
Substantia nigra of mice developmentally exposed to dieldrin to model an early stage of PD | PD | Methyl-sequencing of targeted regions | Dieldrin induced DNA methylation changes in pup mice exposed to the pesticide in utero and after birth until 36 weeks of age in a sex-specific manner in loci associated with pathways related to neurodevelopment, dopaminergic neuron differentiation, synaptogenesis, and synaptic plasticity | [108] |
Human embryonic kidney cell with a neuronal lineage phenotype treated with rotenone as a model of PD | PD | Genome-wide DNA methylation | Rotenone treatment induced hypomethylation of genes involved in neuronal development and maturation, including HCN2 and NEFM | [109] |
Human embryonic kidney cell with a neuronal lineage phenotype treated with rotenone as a model of PD | PD | Genome-wide methylation | Altered methylation in 45 CpG sites (53% hypermethylated) surrounding CTCF binding sites in 7 PD-associated genes, including BMP4, UBOX5, GPRIN3, FER, CNKSR3, PARK2, and CHCHD2 | [113] |
Midbrain of mice exposed to fenpropathrin as a model of PD | PD | Genome-wide DNA methylation | Hypermethylation of the Ambra1 gene, which in turn was downregulated, led to dopaminergic neuron damage through the Ambra1/Parkin/LC3B-mediated mitophagy pathway | [114] |
Air pollution | ||||
Hippocampus samples of aged mice exposed to traffic-related air pollution which developed impairment in memory function | AD | Abca7 and Pyk2 genes | Increased methylation levels of Abca7 and decreased methylation of Pyk2 genes, together with altered mRNA expression levels | [116] |
Model | Exposure | Disease | Epigenetic Target | Results | Reference |
---|---|---|---|---|---|
Metals | |||||
Peripheral blood of PD (n = 1528) and control subjects (n = 1169) | Lead | PD | Genome-wide DNA methylation | PD patients had increased DNA methylation-predicted lead levels in tibial bone | [118] |
Peripheral blood of 366 Al potroom workers, including 43 MCI | Aluminium | MCI | Global DNA methylation | Increased aluminum serum levels were inversely correlated with global DNA methylation and MMSE | [119] |
Peripheral blood of 201 workers, including 49 with parkinsonism | Manganese | PD | NOS2 gene methylation | Workers with parkinsonism had lower mean methylation levels of NOS2, a gene involved in inflammation | [120] |
Peripheral blood samples of 45 PD patients and 52 control subjects | Heavy metal mining | PD | Global 5-mC | Decrease in global DNA methylation in PD patients either exposed or not exposed to mining activity. No difference between exposed and non-exposed PD patients | [121] |
Peripheral blood samples of 438 ALS cases and 417 controls | Cadmium, mercury, and metallurgy | ALS | Genome-wide DNA methylation | Self-reported cadmium, mercury, and metallurgy exposure was associated with methylation levels of seven CpG sites across the genome in ALS, including hypermethylation of GNRHR2, PEX11B, ZFR2, LINGO1, and PRKG1-AS1 and hypomethylation of P2RY6 and KSR2 genes | [122] |
Peripheral blood of 61 ALS patients and 61 controls | Various chemicals, metals, pesticides, and air pollutants | ALS | Genome-wide DNA methylation | ALS epigenetic signature associated with exposure to various metals, including sodium arsenite and nickel, air pollutants, including PM, and pesticides, including rotenone | [123] |
Pesticides | |||||
Brain tissue from a pair of monozygotic twins discordant for AD | Pesticides | AD | Global DNA methylation | Global DNA hypomethylation in the AD twin who worked in contact with pesticides | [124] |
Peripheral blood DNA of 237 individuals | Pesticide (pyrethroid) | Control subjects | Genome-wide DNA methylation | Several CpG sites were associated with pyrethroid exposure, some in genes related to AD, PD, and ALS pathology, including the RTN3 and TMOD3 genes | [125] |
Peripheral blood samples of 342 PD patients and 238 controls | Pesticides (organophosphate insecticides) | PD | Genome-wide DNA methylation | 70 CpG sites were associated with pesticide exposure, of which 7 were specific to PD patients, such as the MYH15, MFAP2, and KIAA0319 genes | [126] |
Matched peripheral blood and post-mortem brain in 20 PD cases | Pesticides | PD | Genome-wide DNA methylation | By comparing individuals exposed more than 10 years and 0 years, 7 and 123 DML in brain and blood DNA, respectively, were identified. DML were mainly associated with genes involved in neurotoxic and neuropathologic pathways | [127] |
Peripheral blood of agricultural workers, including 71 early-stage PD cases and 147 control subjects | Pesticides | PD | Genome-wide DNA methylation | Pesticide exposure influenced blood DNA methylation in females at the early stages of PD, in various genes including the NFATC1 and DLGAP1 genes | [128] |
Air pollution | |||||
Prefrontal cortex tissue of 159 donors evaluated for AD-related neuropathological markers | PM2.5 | AD | Genome-wide DNA methylation | PM2.5 exposure induced altered DNA methylation of twenty-four CpG sites that were associated with neuropathology markers of AD. Several CpG sites were located in genes related to neuroinflammation, including SORBS2, PDE11A, and GABBR1 | [129] |
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Stoccoro, A.; Coppedè, F. Exposure to Metals, Pesticides, and Air Pollutants: Focus on Resulting DNA Methylation Changes in Neurodegenerative Diseases. Biomolecules 2024, 14, 1366. https://doi.org/10.3390/biom14111366
Stoccoro A, Coppedè F. Exposure to Metals, Pesticides, and Air Pollutants: Focus on Resulting DNA Methylation Changes in Neurodegenerative Diseases. Biomolecules. 2024; 14(11):1366. https://doi.org/10.3390/biom14111366
Chicago/Turabian StyleStoccoro, Andrea, and Fabio Coppedè. 2024. "Exposure to Metals, Pesticides, and Air Pollutants: Focus on Resulting DNA Methylation Changes in Neurodegenerative Diseases" Biomolecules 14, no. 11: 1366. https://doi.org/10.3390/biom14111366