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Laboratory of Environmental Epigenetics
Epidemiological and experimental studies clearly show that only a minority of neurological diseases are due strictly to genetic factors. More likely, neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases, and neurodevelopmental disorders including autism, are due to interactions between genes and the environment. Our laboratory studies the involvement of environmental pollutants on diseases that affect the brain.
A major problem, however, in uncovering the environmental factors has been the length of time between exposure and clinical diagnosis. In autism, exposure occurs during pregnancy and manifests two years or more after birth. Neurodegenerative diseases are due to exposures that have likely occurred decades before diagnosis.
Our approach has been to delineate mechanisms underlying the diseases that were initiated by exposure to environmental chemicals and then to develop new tools to measure the early biochemical changes resulting from the exposure. For example, we have shown that the benzene metabolite hydroquinone induces DNA demethylation by increasing oxidative stress. Benzene is ubiquitous in the environment and is found in secondhand cigarette smoke, water, and car exhaust. DNA methylation is the mechanism in which genes are silenced and is crucial for development. Dysfunctional regulation of DNA methylation has been found in several developmental and neurodevelopmental disorders and can be examined through biochemical assays.
To assess early changes occurring before autism is currently diagnosed, we have been examining responses displayed by peripheral blood mononuclear cells. Biomarkers measured in blood cells are potentially useful because blood specimens are accessible. Another advantage of studying responses by blood cells is the potential of delineating the molecular mechanisms that underlie the autistic phenotype. We have been focusing on responses regulated by the methyl DNA binding protein 2 (MeCP2). Mutations in MECP2 underlie Rett Syndrome and MECP2 polymorphisms have been identified in some children with autism. We have found that responses evoked by activating the NF-κB pathway, which regulates the expression of inflammatory cytokines, are enhanced in peripheral blood mononuclear cells made MeCP2 deficient. We are now determining the relevance of our findings in clinical populations.
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