24th Annual Intl Neurotox. Conf item

[Guest guest]

Take a gander at Dr Ashwood's presentation .. hmmmm ..

The 24th Annual International Neurotoxicology Conference was held in San

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 , 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 , 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

, Ph.D. and 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 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 Syndrome. 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

<http://www.neurotoxicology.com/conf2007/conference.htm>