24th Annual International Neurotoxicology Meeting Focuses on Oxidative Stress

December 27, 2007

The 24th Annual International Neurotoxicology Conference was held in San Antonio on November 10-14, with Autism Speaks helping to sponsor the event. This year's theme was entitled "Environmental Etiologies of Neurological Disorders." Many of the world's experts in epidemiology, neuropharmacology, cell and molecular biology, toxicology, animal behavior and immunology gathered to discuss the role of environmental toxicants in the causes of disorders such as Parkinson's Disease, Alzheimer's Disease, and Autism Spectrum Disorders. On the final day of the conference, a symposium entitled "Oxidative Stress in Autism - Cause or Consequence?" drew over 60 participants. The session chair, Isaac Pessah, Ph.D. from the University of California at Davis, lead the plenary session and presented data from his CAN/Autism Speaks Environmental Innovator Award.

One major topic of discussion for this special session was "oxidative stress." Under normal circumstances, cells in the body regulate the levels of reactive oxygen species, molecules that have lost electrons as a result of normal cellular processes. An imbalance can lead to toxicity and cell death, through a process called lipid peroxidation. This is where the outer membrane of the cells are damaged or destroyed. The process of oxidative stress has been linked to many diseases including, but not limited to: Parkinson's Disease, Alzheimer's Disease, cancer, aging, heart disease, and can also regulate communication between cells. It can be disregulated by changes in gene expression or environmental exposures.

Jill James, Ph.D., from the University of Arkansas College of Medicine introduced the session by reviewing the metabolic pathways involved in homeostasis and cellular methylation. These include the folate cycle, the methionine pathway and the transsulferation pathway. She described her recent studies published in 2004 and 2006 which reported an abnormal metabolic profile in children with autism, as a result of either environmental toxicants and/or an abnormal genetic phenotype. Measured by cellular methylation capacity and detoxification capacity, her data suggest that a subgroup of children with autism demonstrate metabolic profiles which reflect systemic oxidative stress with reduced capacity to buffer pro-oxidant environmental exposures. This altered metabolic state has been linked to changes in gene expression which regulate these pathways. Other preliminary data presented from the labs of George Perry, Ph.D. and Elizabeth Sajdel-Sulkowska, Ph.D. using tissue from the Autism Tissue Program, showed an elevation in some markers for oxidative stress in brain tissue. Taken together, this suggests that oxidative stress may be present in some individuals with autism. However, as oxidative stress is common to almost all disease states, it is not known whether the oxidative stress these labs have found is a cause of autism or rather a reaction to the underlying pathological processes.

In order to better understand the mechanisms by which this may be occurring, Mark Noble, Ph.D. from the University of Rochester presented CAN/Autism Speaks–funded research using neural progenitor cells to study the effects of environmental agents on cellular functioning. His research focuses on the effects of thimerosal and methyl mercury upon whether these progenitor cells either proliferate (grow and divide in an immature state) or differentiate (develop into a mature cell type, like neurons or glial cells). For instance, using this model, he has shown differences in the ability to proliferate rather than differentiate based on where in the brain the cells were derived. In this talk he presented data that the imbalance of oxidant vs. reducing capacity of the cell also affects the ability of that cell to differentiate or proliferate, and those that are more oxidized are more likely to be sensitive to toxic agents. Putting all of these concepts together, exposure of cells to thimerosal and/or methylmercury can lead to a reduction in cell proliferation (or conversely, a premature differentiation). Other mechanisms of oxidative stress were also presented as possible mediators of the effect, such as changes in cerebral blood flow and immune dysfunction. As discussed by CAN/Autism Speaks grantee Paul Ashwood, Ph.D., one potential cause of changes in oxidative stress markers in people with autism is an inappropriate or ineffective immune response to pathogen challenge. He presented new evidence of genes that regulate the immune system that do not function correctly in some individuals with autism, and further studies will need to be conducted to link these specific changes to oxidative stress.

Dr. Isaac Pessah finished the session by pointing out the interactions between genes and environmental agents on oxidative stress, using the example of Timothy Syndrome. Timothy Syndrome is a disease marked by an irregular heartbeat; however, 80% of these children also show symptoms of autism spectrum disorder. It is caused by a genetic mutation in a specific calcium channel gene. Calcium channels regulate cell signaling, and fortunately, the cardiovascular effects of this mutation can be treated with pharmacological agents. Many of the candidate genes under study for autism, including neuroligin, PTEN and MET, have effects on calcium signaling. Dr. Pessah's lab is characterizing the calcium receptor, and its link to another protein known as the ryanodine receptor. Interestingly, this receptor is sensitive to changes in the “redox” potential of a cell, which tells the cell whether it is oxidized or reduced. As pointed out by Dr. Noble, cells which are in an oxidized state can be more susceptible to environmental toxicity. Dr. Pessah's lab will now specifically be studying animal models of mutations of the ryanodine receptor to determine the role that this receptor plays in mediating toxicity to environmental agents, including mercury and PBDE's. In addition, he will be studying the prevalence of genetic polymorphisms of this receptor in individuals affected with autism. This type of research illustrates the important interaction of genes and the environment.

Even if there is no consensus on whether oxidative stress is a cause or a consequence of autism spectrum disorders, it is clear that this process plays an important role in the etiology and neuropathology of several neurological disorders. Many treatment regimens, including glutathione and vitamin B12, utilize agents that alter the “redox” potential of cells and may change the metabolic profile of cells that cannot process reactive oxygen species normally. The goal of such treatments in autism will be to alter the biochemistry of neurons in affected individuals, and further studies are needed to determine their effectiveness in making the individuals feel better and potentially treating the behavioral symptoms.

For more information about this meeting, visit www.neurotoxicology.com/conf2007/conference.htm