"This is the first time that thimerosal has been shown to selectively alter the normal functions of dendritic cells," said Isaac Pessah, a toxicologist with the UC Davis School of Veterinary Medicine, director of the Children's Center for Environmental Health and Disease Prevention and senior author of the study. "Dendritic cells play pivotal roles in overcoming viral and bacterial invaders by coordinating the immune system's overall combat response." One dendritic cell can activate as many as 300 T-cells – white blood cells that help find and kill external agents that attack the immune system – making them the most effective immune system activators.
The study shows how intricate connections between calcium channels in dendritic cells change when exposed to thimerosal.
"The slightest fluctuation in how calcium channels 'communicate' can alter the growth, maturation and activation of dendritic cells," explained Pessah. "Thimerosal dramatically alters how two key calcium channels, code-named RyR1 and IP3R1, found in dendritic cells function as a team by 'garbling' the normal signaling system between them."
When thimerosal, at a concentration as low as 20 parts per billion, alters the fidelity of normal calcium signals, dendritic cells show abnormal secretion of IL-6 cytokine – a potent chemical signal that initiates inflammatory responses. Higher concentrations – 200 parts per billion – causes programmed death of dendritic cells, preventing them from maturing and doing their primary job of activating T-cells. Without proper feedback to guide its response, a normal dendritic cell can quickly become "a rogue, producing misinformation that could activate aberrant and harmful immune responses," Pessah explained. "Even one rogue dendritic cell can activate many inappropriate immune responses."
The research team conducted the study on cells cultured from a strain of mouse not particularly susceptible to immune dysregulation. Using fluorescent stains and powerful microscopes to study both immature and mature dendritic cells from bone marrow cultured under normal physiological conditions, the researchers discovered that extremely small levels of thimerosal interfere significantly with calcium channel function after just a few minutes of exposure. They also observed that immature dendritic cells are particularly sensitive to thimerosal.
Thimerosal is a cheap and effective mercury-based preservative. Its potential effects on embryonic neuron development led to its removal from many pediatric vaccines. However, it is still used in influenza, diphtheria and tetanus vaccines, blood products and many over-the-counter pharmaceuticals. The concentrations of thimerosal used by the UC Davis researchers were comparable to those attained in childhood vaccinations containing the preservative.
Researchers and parents have previously proposed links between childhood vaccines and autism, a neurodevelopmental disorder that affects language skills and social interactions. The UC Davis study indicates that in addition to being a direct neurotoxicant, thimerosal may also be an immunotoxicant, leaving the immune system vulnerable to microbes and other external influences.
"Our findings do not directly implicate thimerosal as a single causative agent for triggering neurodevelopmental disorders such as autism," Pessah said. "There is growing evidence that autism is several disorders that we now refer to as just one. There is also growing evidence that some children with autism have unique immune cell composition and responses to antigens. The results of our work provide a framework to test the hypothesis that the genetic background of some individuals may render them especially susceptible to thimerosal."
Other experts also advise drawing no final conclusions regarding thimerosal and autism based on these outcomes.
"These findings should be interpreted cautiously. Although they suggest that thimerosal may affect dendritic cell function, the pathophysiological consequences of thimerosal remain unclear," said David A. Schwartz, a physician and director of the National Institute of Environmental Health Sciences.
Since cell functions can differ across organisms, Pessah will next study dendritic cells isolated from the blood of children with and without autism to confirm if the intercellular changes are the same in humans. The initial mouse study was funded by the National Institute of Environmental Health Sciences and the UC Davis M.I.N.D. Institute. Joining Pessah on the scientific team were molecular bioscientists Samuel R. Goth, Ruth A. Chu and Gennady Cherednichenko and pathologist Jeffrey P. Gregg.
A copy of "Uncoupling of ATP-mediated Calcium Signaling and Dysregulated IL-6 Secretion in Dendritic Cells by Nanomolar Thimerosal" can be downloaded at http://www.ehponline.org/docs/2006/8881/abstract.html.
The NIEHS-funded Center for Children's Environmental Health and Disease Prevention is a multi-disciplinary research organization established to examine how toxic chemicals may influence the development of autism in children. The center's goal is to contribute knowledge about autism that will lead to new prevention and treatment strategies. For more information, visit www.vetmed.ucdavis.edu/cceh. The UC Davis M.I.N.D. (Medical Investigation of Neurodevelopmental Disorders) Institute is a unique collaborative center bringing together parents, scientists, clinicians and educators for research on autism and other neurodevelopmental disorders. For more information, visit www.mindinstitute.org.
Environmental Health Perspectives