Journal
NEUROTOXICOLOGY AND TERATOLOGY
Volume 36, Issue -, Pages 3-16Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.ntt.2012.12.001
Keywords
Autism Spectrum Disorders; Gene-environment interactions; Neuronal connectivity; Organophosphorus pesticides; Polyaromatic hydrocarbons; Polychlorinated biphenyls
Categories
Funding
- National Institutes of Health [R01 ES014901, R01 ES017425, P42 ES04699, P01 ES011269]
- United States Environmental Protection Agency [R833292, R829388]
- J.B. Johnson Foundation
- UC Davis Superfund Basic Research Program (NIH) [ES04699]
- P.E. Goines a Hartwell Foundation Biomedical Research Postdoctoral Fellowship
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Evidence implicates environmental factors in the pathogenesis of Autism Spectrum Disorders (ASD). However, the identity of specific environmental chemicals that influence ASD risk, severity or treatment outcome remains elusive. The impact of any given environmental exposure likely varies across a population according to individual genetic substrates, and this increases the difficulty of identifying clear associations between exposure and ASD diagnoses. Heritable genetic vulnerabilities may amplify adverse effects triggered by environmental exposures if genetic and environmental factors converge to dysregulate the same signaling systems at critical times of development. Thus, one strategy for identifying environmental risk factors for ASD is to screen for environmental factors that modulate the same signaling pathways as ASD susceptibility genes. Recent advances in defining the molecular and cellular pathology of ASD point to altered patterns of neuronal connectivity in the developing brain as the neurobiological basis of these disorders. Studies of syndromic ASD and rare highly penetrant mutations or CNVs in ASD suggest that ASD risk genes converge on several major signaling pathways linked to altered neuronal connectivity in the developing brain. This review briefly summarizes the evidence implicating dysfunctional signaling via Ca2+-dependent mechanisms, extracellular signal-regulated kinases (ERK)/phosphatidylinositol-3-kinases (PI3K) and neuroligin-neurexin-SHANK as convergent molecular mechanisms in ASD, and then discusses examples of environmental chemicals for which there is emerging evidence of their potential to interfere with normal neuronal connectivity via perturbation of these signaling pathways. (C) 2012 Elsevier Inc. All rights reserved.
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