Alzheimer’s Disease and Environmental Exposure to Lead: The Epidemiologic Evidence and Potential Role of Epigenetics
University of Michigan, School of Public Health, Department of Environmental Health Sciences, MI, USA.Current Alzheimer research (Impact Factor: 3.89). 01/2012; 9(5):563-73. DOI: 10.2174/156720512800617991
Several lines of evidence indicate that the etiology of late-onset Alzheimer's disease (LOAD) is complex, with significant contributions from both genes and environmental factors. Recent research suggests the importance of epigenetic mechanisms in defining the relationship between environmental exposures and LOAD. In epidemiologic studies of adults, cumulative lifetime lead (Pb) exposure has been associated with accelerated declines in cognition. In addition, research in animal models suggests a causal association between Pb exposure during early life, epigenetics, and LOAD. There are multiple challenges to human epidemiologic research evaluating the relationship between epigenetics, LOAD, and Pb exposure. Epidemiologic studies are not well-suited to accommodate the long latency period between exposures during early life and onset of Alzheimer's disease. There is also a lack of validated circulating epigenetics biomarkers and retrospective biomarkers of Pb exposure. Members of our research group have shown bone Pb is an accurate measurement of historical Pb exposure in adults, offering an avenue for future epidemiologic studies. However, this would not address the risk of LOAD attributable to early-life Pb exposures. Future studies that use a cohort design to measure both Pb exposure and validated epigenetic biomarkers of LOAD will be useful to clarify this important relationship.
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- "For instance, epigenetic marks are associated with brain functions and methylation patterns differ in patients with Alzheimer (M. Bakulski et al., 2012; Woldemichael et al., 2014). "
ABSTRACT: Modified epigenetic programming early in life is proposed to underlie the development of an adverse adult phenotype, known as the Developmental Origins of Health and Disease (DOHaD) concept. Several environmental contaminants have been implicated as modifying factors of the developing epigenome. This underlines the need to investigate this newly recognized toxicological risk and systematically screen for the epigenome modifying potential of compounds. In this study, we examined the applicability of the zebrafish embryo as a screening model for DNA methylation modifications. Embryos were exposed from 0 to 72h post fertilization (hpf) to bisphenol-A (BPA), diethylstilbestrol, 17α-ethynylestradiol, nickel, cadmium, tributyltin, arsenite, perfluoroctanoic acid, valproic acid, flusilazole, 5-azacytidine (5AC) in subtoxic concentrations. Both global and site-specific methylation was examined. Global methylation was only affected by 5AC. Genome wide locus-specific analysis was performed for BPA exposed embryos using Digital Restriction Enzyme Analysis of Methylation DREAM, which showed minimal wide scale effects on the genome, whereas potential informative markers were not confirmed by pyrosequencing. Site-specific methylation was examined in the promoter regions of three selected genes vasa, vtgI and cyp19a2, of which vasa (ddx4) was the most responsive. This analysis distinguished estrogenic compounds from metals by direction and sensitivity of the effect compared to embryotoxicity. In conclusion, the zebrafish embryo is a potential screening tool to examine DNA methylation modifications after xenobiotic exposure. The next step is to examine the adult phenotype of exposed embryos and to analyze molecular mechanisms that potentially link epigenetic effects and altered phenotypes, to support the DOHaD hypothesis.
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- "Next-generation sequencing will be the next step to identify additional variants with less frequency (rare variants) but large effects . Besides DNA variation, there is accumulating evidence of epigenetic effect contributing to AD, which implies the complex interplay between genetic and environmental factors   . However, most epigenetic studies so far in AD are limited by the sample size and the genome coverage. "
ABSTRACT: Preclinical studies are essential for translation to disease treatments and effective use in clinical practice. An undue emphasis on single approaches to Alzheimer's disease (AD) appears to have retarded the pace of translation in the field, and there is much frustration in the public about the lack of an effective treatment. We critically reviewed past literature (1990-2014), analyzed numerous data, and discussed key issues at a consensus conference on Brain Ageing and Dementia to identify and overcome roadblocks in studies intended for translation. We highlight various factors that influence the translation of preclinical research and highlight specific preclinical strategies that have failed to demonstrate efficacy in clinical trials. The field has been hindered by the domination of the amyloid hypothesis in AD pathogenesis while the causative pathways in disease pathology are widely considered to be multifactorial. Understanding the causative events and mechanisms in the pathogenesis are equally important for translation. Greater efforts are necessary to fill in the gaps and overcome a variety of confounds in the generation, study design, testing, and evaluation of animal models and the application to future novel anti-dementia drug trials. A greater variety of potential disease mechanisms must be entertained to enhance progress.
- "of transposable element and repeat sequences (Hou et al. 2014). To circle back to early life for a moment, environmental lead exposure in early life has been suggested as a contributing factor to rates of epigenetic drift in later life, and to risk of Alzheimer's disease caused by ensuing destabilization of cellular regulation (Bakulski et al. 2012). This work is correlational: it takes a measure of exposure in the past or in the present through whatever proxy is available, and it measures some aspect of methylation in the genome, and it looks for a relation between the two. "
Article: How The Genome Got a Life Span[Show abstract] [Hide abstract]
ABSTRACT: In the space of little more than a decade, ideas of the human genome have shifted significantly, with the emergence of the notion that the genome of an individual changes with development, age, disease, environmental inputs, and time. This paper examines the emergence of the genome with a life span, one that experiences drift, instability, and mutability, and a host of other temporal changes. We argue that developments in chromatin biology have provided the basis for this genomic embodiment of experience and exposure. We analyze how time has come to matter for the genome through chromatin, providing analysis of examples in which the human life course is being explored as a set of material changes to chromatin. A genome with a life span aligns the molecular and the experiential in new ways, shifting ideas of life stages, their interrelation, and the temporality of health and disease.
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