In a series of manuscripts currently being published, Isaac Pessah, Ph.D. from UC Davis and recipient of the Autism Speaks Environmental Innovator award in 2006, reports the potential effects of low dose polychlorinated biphenyls (PCBs) on brain development. Using an animal model, Dr. Pessah focused his research on the impact of PCBs on a protein known as the ryanodine receptor. This receptor regulates calcium signaling in the brain and plays a role in "turning on or off" the activity of nerve cells, thereby influencing their growth, plasticity and metabolism. Other research has suggested that autism may involve abnormalities in the activity of brain cells, specifically, how they communicate with one another.
There are over 209 different PCBs originally released into the environment, and since these chemicals were banned from use in the 1970's, levels of PCB's in blood have decreased by as much as 80%. However, PCBs do not break down in the environment equally, and some are converted to others that are much more persistent and considered by the EPA to still be a public health hazard. Prenatal exposures to high levels of PCBs have been reported to cause developmental deficits. The PCBs that Dr. Pessah is studying are the so-called non-dioxin PCBs, those which are currently the most abundant in human tissue and environmental samples.
One of Dr. Pessah's papers, published in the March issue of Toxicology and Applied Pharmacology, investigates two commonly detected PCB subtypes. At very low concentrations these PCBs were found to differentially influence nerve cell communication by changing the balance of excitatory/inhibitory neural transmission in the hippocampus, a region of the brain important for memory formation.
In a second collaborative study with Pam Lein, Ph.D. of UC Davis, published in the March issue of Environmental Health Perspectives, the researchers studied the impact of PCBs on brain development in mice, focusing on the number of ryanodine receptors and the anatomical structure of nerve cells, as well as on the learning and memory ability of mice that are exposed during development to these compounds. Their research suggests that the brain is actually more sensitive to PCBs than other organs, including the thyroid, which is a previously known target of PCBs. The lowest dose produced changes in the length of dendrites, the parts of the nerve cells that connect them to one another. These low doses also resulted in impairments in spatial learning when the mice were tested. Taken together, the results indicate that the specific PCBs studied act by interrupting the normal cellular changes that are associated with learning and memory in the mouse brain.
Finally, in a paper just published in the journal PLoS Biology, Dr. Pessah and his collaborators used the specific congener PCB 95, which has been identified in human tissues and found in air samples and sediment, to move one step further and study the actual molecular interaction between PCBs and the ryanodine receptors in the nerve cells. In collaboration with Montserrat Samso, Ph.D. at Harvard, they used electron microscopy to show how PCB 95 interferes with the function of individual ryanodine receptor molecules, identifying the structural changes at unprecedented resolution. In the long-term, structural information such as this may allow the design of chemicals to block the disruptive interaction that Dr. Pessah and his colleagues have demonstrated.
While these papers do not directly link autism to PCBs, it demonstrates a mechanism by which PCBs can affect brain development by interacting with the ryanodine receptor to interrupt calcium signaling and the normal function of nerve cells. This is important because some of the genes associated with autism risk either regulate calcium signaling or are themselves regulated by calcium (read science highlights from a 2008 Autism Speaks' sponsored symposium on calcium signaling in autism and other disorders here). Moreover, these reports provide evidence of a new way that molecular, cellular and behavioral assays can be combined to study the biological impact of environmental toxicants, which according to Autism Speaks Chief Science Officer Geri Dawson, Ph.D., was the original vision for the award to Dr. Pessah. "Although we know that genes play a major role in autism, we continue to be interested in how environmental factors may interact with specific genetic vulnerabilities in autism," said Dr. Dawson. "The Environmental Innovator Award was designed to recognize researchers who can increase our understanding of the role of environmental exposure in brain development." Dr. Pessah is currently continuing his studies in this area, focusing both on additional toxicants and on other biological interactions.