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Neurodevelopmental Toxins Deplete Glutathione and Inhibit Folate and Vitamin B12‐Dependent Methionine Synthase Activity: A Link between Oxidative Stress and Autism

Ethanol, arsenic, lead, mercury, aluminum and the vaccine preservative thimerosal are suspected to be etiological factors for neurodegenerative and neurodevelopmental disorders. Autism is a neurodevelopmental disorder characterized by oxidative stress and impaired methylation status, including decreased activity of the folate and vitamin B12‐dependent enzyme methionine synthase (MS). MS‐mediated conversion of homocysteine to methionine is crucial for neurons and all mammalian cells to sustain normal methylation status, involving more than 100 different reactions. Glutathione (GSH) protects MS from oxidative inactivation by reactive oxygen species, while MS inactivation increases GSH synthesis by augmenting transsulfuration. Utilizing SH‐SY5Y cultured human neural cells, we found that a 1 hour pre‐incubation of cells with arsenic, lead, mercury, aluminum and thimerosal potently decreased both hydroxocobalamin (OHCbl) and methylcobalamin (MeCbl)‐based MS activity, although OHCbl exhibited greater sensitivity than MeCbl. At a concentration of 100 nmol, each of these neurodevelopmental toxins caused a 60–70% reduction of intracellular GSH levels. 22 mM (0.1%) ethanol caused a similar inhibition of OHCbl‐ and MeCbl‐based MS activity and a similar decrease in GSH levels. Our findings suggest that heavy metals and ethanol may contribute to the occurrence of neurodevelopmental disorders such as autism via a mechanism that involves oxidative stress and inhibition of MS activity.