The Redox/Methylation Hypothesis of Autism

Richard C Deth
US Psychiatry, 2010;3:48-52
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Abstract

The alarming increase in autism rates has brought attention to possible adverse effects of environmentally encountered toxic substances on neurodevelopment. Recent studies of autistic children reveal evidence of oxidative stress and neuroinflammation, consistent with the metabolic consequences of a toxic insult. Sulfur metabolism provides detoxification of heavy metals and xenobiotics, maintains cellular redox status, and supports a multitude of methylation reactions, including DNA methylation. When toxic exposures cause oxidative stress, it leads to impaired DNA methylation and can disrupt epigenetic regulation of gene expression, which is critical for normal development. Dopamine stimulates a unique form of methylation involving the D4 receptor subtype, known as phospholipid methylation, which appears to play a role in synchronization of neural networks during attention. The supply of methyl groups for this process depends on the folate- and vitamin B12-dependent enzyme methionine synthase, whose activity is inhibited during oxidative stress. Based on these metabolic relationships, a redox/methylation hypothesis of autism has been formulated, providing a molecular framework for understanding how environmental toxins can disrupt cognitive development. Preliminary studies suggest that metabolic interventions that normalize redox and methylation status may offer benefit in autism, and the underlying mechanisms may also have importance for other neurological and neuropsychiatric disorders.
Keywords
Autism, methylation, attention-deficit–hyperactivity disorder (ADHD), D4 dopamine receptor, epigenetic, glutathione, methionine synthase, methylcobalamin, neuroinflammation, neurodevelopmental disorder, oxidative stress, phospholipid methylation
Disclosure The author has no conflicts of interest to declare.
Received: January 29, 2009 Accepted September 07, 2009
Correspondence: Richard C Deth, PhD, Department of Pharmaceutical Sciences, Northeastern University, Boston, MA 02115. E: r.deth@neu.edu

The prevalence of autism has increased more than 10-fold in the US during the past two decades,1 raising public concern and increasing research efforts to identify factors that might be responsible. Earlier work established the importance of genetic factors,2 but it is highly unlikely that such a dramatic increase reflects purely genetic factors. Consequently, there has been increasing attention on the role of one or more ‘environmental factors’ whose exposure might lead to impaired development.3,4 Not surprisingly, many theories have been put forth, in part reflecting the vast number of xenobiotic substances encountered in contemporary society. Most controversial among these is the proposal that mercury, derived from the vaccine preservative thimerosal, might play an important role.5 However, removal of mercury from most childhood vaccines has not been associated with a decrease in autism.6 Nonetheless, the mercury debate continues as other potential toxins receive attention, including heavy metals (e.g. lead and aluminum),7,8 drugs (e.g. pre-natal terbutaline, antibiotics),9,10 and chemicals (e.g. bisphenol A, pesticides).11,12 Emerging awareness of the role of neuroinflammation and oxidative stress in autism not only illuminates the origins of this neurodevelopmental disorder,13–21 but also sheds light on other neurological, neuropsychiatric, and neurodegenerative disorders. This review focuses on those metabolic pathways regulating the redox status of cells (i.e. the balance between reduced and oxidized states), because these pathways also support the process of methylation, in which a carbon atom (methyl group) is added to a molecule. The importance of methylation reactions is increasingly appreciated, especially for its central role in the epigenetic regulation of gene expression.

Oxidative Stress and Methylation

Many xenobiotics adversely affect metabolic pathways concerned with maintaining cellular redox status, which may represent a shared mechanism for contributing to autism. This possibility is strongly supported by recent metabolic studies that have found a pattern of significant oxidative stress in autistic children, highlighted by a decrease in glutathione (GSH), the body’s principal antioxidant.13,14,19–21 GSH, a tripeptide containing the sulfur amino acid cysteine, binds heavy metals and xenobiotics, restricting their toxicity and promoting their excretion.

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