Infant exposure to lead (Pb) and epigenetic modifications in the aging primate brain: implications for Alzheimer’s disease
Abstract
The beginnings of late onset Alzheimer's disease (LOAD) are still unknown; however, the progressive and latent nature of neurodegeneration suggests that the triggering event occurs earlier in life. Aging primates exposed to lead (Pb) as infants exhibited an overexpression of the amyloid-β protein precursor (AβPP), amyloid-β (Aβ) and enhanced pathologic neurodegeneration. In this study, we measured the latent expression of a wide array of brain-specific genes and explored whether epigenetic pathways mediated such latent molecular and pathological changes. We analyzed the levels of proteins associated with DNA methylation, i.e., DNA methyltransferase 1 (Dnmt1), DNA methyltransferase3a (Dnmt3a), methyl-CpG binding protein-2 (MeCP2) and those involved in histone modifications (acetylated and methylated histones). We monitored the expression profiles of these intermediates across the lifespan and analyzed their levels in 23-year-old primate brains exposed to Pb as infants. Developmental Pb exposure altered the gene expression of the arrayed genes, which were predominately repressed, with fewer upregulated genes. The latent induction and repression of genes was accompanied by a significant decrease in the protein levels of Dnmts, MeCP2, and proteins involved in histone modifications. The attenuation of DNA methylation enzymes is consistent with hypomethylating effects, which promote upregulation of the genes, while the alterations in the histone modifiers are associated with the repression of genes. Hence, we deduce that early life exposure to Pb can reprogram gene expression resulting in both upregulation and down-regulation of genes through alternate epigenetic pathways contributing to an enhancement in neurodegeneration in old age.
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There is evidence to implicate DNA methylation as a potential mechanism by which developmental lead exposure alters neurodevelopment and function throughout life.
“There is evidence to implicate DNA methylation as a potential mechanism by which developmental lead exposure alters neurodevelopment and function throughout life [ 121 , 122 ].”
From DNA methylation: a mechanism linking environmental chemical exposures to risk of autism spectrum disorders? (2016) · cites this paper as [121]
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- Authors
- Bihaqi, S. W., Huang, H., Wu, J., & Zawia, N. H.
- Affiliations
- University of Rhode Island (US)
- Zhengzhou University (CN)
- Venue
- Journal of Alzheimer’s Disease
- Publisher
- SAGE Publications
- Published
- 2011-12-12
- Volume
- 27
- Issue
- 4
- Pages
- 819-833
- ISSN
- 1387-2877 (ISSN-L)
- 1875-8908
- OpenAlex
- W1693568153
- Cited by
- 162
- References
- 60
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 7 · 2023: 8 · 2022: 6 · 2021: 10 · 2020: 14 · 2019: 14 · 2018: 10 · 2017: 12 · 2016: 15 · 2015: 12 · 2014: 19 · 2013: 14 · 2012: 10
- FWCI
- 5.72
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Alzheimer s Disease (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute for Health and Care Research
- Institute of Environmental Science and Research
- National Institute of Environmental Research
- National Institutes of Health
- National Institute of Environmental Health Sciences (R01ES015867)
- National Center for Research Resources (P20RR016457)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Heavy Metal Exposure and Toxicity
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- lead exposure
- MeSH terms
- Age Factors, Aging, Animals, Animals, Newborn, Disease Models, Animal, Female, Humans, Lead, Lead Poisoning, Macaca fascicularis, Nerve Tissue Proteins, RNA, Messenger, Transcription Factors, DNA Modification Methylases, Cohort Studies, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, DNA Methylation, rab5 GTP-Binding Proteins, Epigenesis, Genetic, Methyl-CpG-Binding Protein 2
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