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Thimerosal linked to immune system ills "This is not a smoking gun," said Isaac Pessah, the University of California, Davis, toxicologist who led the study for the university's MIND Institute and the National Institute of Environmental Health Sciences. "This provides a framework, but not the answer." Pessah's study is part of a large, federally funded research effort exploring the role of environmental toxicants in autism and other disorders. It will be published this morning in the online edition of Environmental Health Perspectives, a peer-reviewed publication of the NIEHS. "This is important because it does add to our knowledge of the potential effects of thimerosal," said Cindy Lawler, a program administrator for the NIEHS in charge of the UC Davis research grant. "It provides a good clue for other studies that can be conducted in other animals or in biological samples from humans." The results come seven years after the Centers for Disease Control and Prevention and the American Academy of Pediatrics asked drug makers to remove thimerosal from childhood vaccines. Except for trace amounts used in vaccine production, thimerosal is no longer used in childhood vaccines. The exception is the flu vaccine; although manufacturers are now producing a thimerosal-free version of the flu shot, the lion's share of vaccine supplies still contains the preservative. Concerns about the safety of the preservative grew after the Food and Drug Administration concluded that babies up to 6 months old were getting more mercury than considered acceptable by the Environmental Protection Agency. Several large-scale studies failed to established a link between mercury-containing vaccines and autism. That has not deterred parents who believe their child was developing normally until receiving the recommended childhood immunizations. Researchers now believe that autism is a disorder - or group of disorders - with many possible causes. A prevailing theory is that autism is caused by several genetic abnormalities, which may be the basis for a heightened susceptibility to certain chemical exposures. The UC Davis study is not likely to settle the matter, but it does indicate that the preservative may leave the immune system vulnerable in susceptible groups. Based on earlier and yet-to-be published studies establishing differences in the immune systems of autistic children from children without the disorder, Pessah looked for clues to those discrepancies. He focused on a type of cell called a dendritic cell, which is responsible for marshalling the body's response to invaders such as bacteria, viruses or other antigens such as vaccine ingredients. "They take up those foreign substances and process them," he said. "Once they do that, they migrate to the lymph nodes to present their information to the other immune cells, which can activate a global immune response." For his research, Pessah used a mouse strain not particularly sensitive to mercury or other heavy metals, and introduced concentrations of thimerosal comparable to those attained in childhood vaccinations that contain the preservative. "What we found was rather unexpected," he said. "In fact, the dendritic cells seemed to be extremely sensitive to the effects of thimerosal." Specifically, the thimerosal disrupted the normal biological signals that take place in cells, Pessah said. At lower concentrations, the signal disruption caused an inflammatory response; at higher concentrations it caused cell death. "One could imagine that as concentrations of thimerosal vary in the organisms, you could get a plethora of unwanted or uncontrolled effects," Pessah said. And those effects could vary depending on the organism's genetic background, he said. Many children diagnosed with autism experience immunological problems including gut disorders, allergies and frequent infections. "We now understand one of the ways in which thimerosal could adversely impact the immune system," Pessah said. "We have a target that provides a framework for now studying this in autistic children." Pessah, who directs the Children's Center for Environmental Health and Disease Prevention at UC Davis, hopes now to determine whether dendritic cells from children with autism are particularly sensitive to the effects of thimerosal, various forms of mercury and other environmental toxicants. Rick Rollens, the father of an autistic boy who has been active in advocating for autism research, said he is pleased that UC Davis has taken on the issue of the potential role of thimerosal. Rollens, recently appointed by the state Legislature to a blue ribbon commission on autism, noted that after years of surges in new autism cases, the numbers of new cases reported to the state have dropped since 1999, when vaccine makers were asked to remove the chemical from their products. Still, Rollens is cautious about the implications of this and other ongoing research. "Until the good science is done, we need to withhold our judgment on what exactly is the cause," he said. "I am very encouraged by this study." US DAVIS PRESS RELEASE FOR IMMEDIATE RELEASE: March 21, 2006, 12:01 a.m. EST CONTACT: Karen Finney (916) 734-9064 karen.finney@ucdmc.ucdavis.edu UC DAVIS STUDY WITH MICE LINKS
THIMEROSALWITH IMMUNE SYSTEM DYSFUNCTION (Sacramento, Calif.) – A team of cell biologists, toxicologists and molecular bioscientists at the University of California, Davis, has published a study connecting thimerosal with disruptions in antigen-presenting cells known as dendritic cells obtained from mice. The study provides the first evidence that dendritic cells show unprecedented sensitivity to thimerosal, resulting in fundamental changes in the immune system’s ability to respond to external factors. The study was published online today and will be available in the July print edition of Environmental Health Perspectives, the peer-reviewed scientific publication of the National Institute of Environmental Health Sciences. “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. In addition to being a direct neurotoxicant, the UC Davis study indicates that 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.
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