Genetics Meets Environment: Evaluating Gene-Environment Interactions in Neurologic Diseases

Toronto Western Hospital, University of Toronto, Ontario, Canada.
Seminars in Neurology (Impact Factor: 1.79). 11/2011; 31(5):553-61. DOI: 10.1055/s-0031-1299793
Source: PubMed


The vast majority of disease is due to complex relationships between genetic and environmental factors. Single genetic or environmental causes are rare. Unfortunately, this presents major challenges for assessing disease risk in individuals. Further complicating the situation is the fact that there are many ways in which genetic and environmental determinants can combine to cause disease. This review explores the concepts of gene-environment interaction to provide a basic understanding of the principles of interactions and approaches to studying them. Collaborations between genetics and environmental experts will be crucial to understand the complex relationships.

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    • "Among the aforementioned essential and non-essential metals, Fe, Mn and Hg have received considerable attention due to their ability to induce oxidative damage and neurodegeneration. Notably , the etiologies of neurodegenerative disease such as Parkinson's disease (PD) and Alzheimer's disease (AD) seem to be greatly dependent on environmental factors or on environmental/genetic interactions (Marras and Goldman, 2011). Of particular importance , specific metals have pro-oxidative properties and can perturb neurodegenerative genes by epigenetic events, leading to altered gene expression and late-onset neurodegenerative diseases (Kwok, 2010). "
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    ABSTRACT: Essential metals are crucial for the maintenance of cell homeostasis. Among the 23 elements that have known physiological functions in humans, 12 are metals, including iron (Fe) and manganese (Mn). Nevertheless, excessive exposure to these metals may lead to pathological conditions, including neurodegeneration. Similarly, exposure to metals that do not have known biological functions, such as mercury (Hg), also present great health concerns. This reviews focuses on the neurodegenerative mechanisms and effects of Fe, Mn and Hg. Oxidative stress (OS), particularly in mitochondria, is a common feature of Fe, Mn and Hg toxicity. However, the primary molecular targets triggering OS are distinct. Free cationic iron is a potent pro-oxidant and can initiate a set of reactions that form extremely reactive products, such as OH•. Mn can oxidize dopamine (DA), generating reactive species and also affect mitochondrial function, leading to accumulation of metabolites and culminating with OS. Cationic Hg forms have strong affinity for nucleophiles, such as -SH and -SeH. Therefore, they target critical thiol- and selenol-molecules with antioxidant properties. Finally, we address the main sources of exposure to these metals, their transport mechanisms into the brain, and therapeutic modalities to mitigate their neurotoxic effects. Keywords: Manganese; iron; mercury; oxidative stress; glutathione.
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