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Posted on Sun, Oct. 09, 2005
More research urged into effects of inorganic mercury
By JUDY L. THOMAS
The Kansas City Star
Researchers and lawmakers worry that not enough is known about ethylmercury, the kind of mercury in flu vaccines. For years, health officials assumed that ethylmercury was less toxic to infants than methylmercury, which poses a risk to pregnant women and is found in some seafood.
A recent study funded by the National Institutes of Health found that while there was less total mercury in monkeys' brains after injections containing thimerosal than after exposure to methylmercury in food, there was twice as much inorganic mercury in the monkeys'™ brains after the thimerosal injections. Thimerosal is a compound that is 49.6 percent ethylmercury by weight.
"Having less total mercury in your brain is good news, but having this inorganic mercury twice as high in your brain is concerning,"said Thomas Burbacher, a mercury toxicology expert at the University of Washington and the key researcher on the project. Previous studies had shown that inorganic mercury can inflame certain kinds of brain cells.
Some scientists and lawmakers say the NIH study shows that more research is needed. "Clearly, prior assumptions about the way thimerosal is handled by the human body must be revisited, and follow-up studies must be undertaken," U.S. Rep. Dave Weldon wrote in April to Michael Leavitt, secretary of health and human services.
Critics say that some of the studies that were used to show no connection between thimerosal and autism were done by researchers who were too cozy with government agencies and drug companies. They also note that some decisions on vaccine policy were made by advisory boards and that some members of those boards had ties to drug companies that would be affected by their decisions.
For example, in a recent congressional hearing, it was revealed that members of committees that advise the Food and Drug Administration and the Centers for Disease Control and Prevention owned stock in drug companies that made vaccines. Committee members also held patents on vaccines affected by the decisions of their committees.
Some researchers and scientists also complain that when their findings suggested possible links between thimerosal and autism, government agencies cut off their funding.
Boyd Haley, a University of Kentucky biochemist, received hundreds of thousands of dollars in grants from the National Institutes of Health to make compounds called "photoaffinity probes" that are used to study neurological diseases. "It was a major scientific accomplishment, and they'™re used all over the world today," Haley said. "Our biggest customer is the National Institutes of Health."
But Haley noted that it was "only when I started using these probes to show that mercury was toxic that I lost my NIH grant, which I had for 27 years."
Weldon said he had heard similar complaints.
"What I've had said to me repeatedly by researchers is that they would start working on it and they will have their department chairman or their colleagues "saying, You really shouldn't do this; you're going to ruin your career," Weldon said. Glen Nowak, the CDC'™s director of media relations, said he was not aware of any researchers losing funding as a result of their findings. "At CDC, almost all the research that we fund is peer reviewed and it's usually blind peer reviewed," Nowak said. "We don't know who wrote the proposal. And NIH does this, too. We have objective reviews of the proposals that come in.To reach Judy L. Thomas, call (816) 234-4334 or send e-mail to
jthomas@kcstar.com .
Thimerosal Induces Apoptosis in a Neuroblastoma Model via the cJun N-Terminal Kinase Pathway http://toxsci.oxfordjournals.org/cgi/content/abstract/92/1/246
Michelle L. Herdman*, Aileen Marcelo*, Ying Huang, Richard M. Niles, Sanjit Dhar and Kinsley Kelley Kiningham*,1 Departments of * Pharmacology, Physiology, and Toxicology and Biochemistry and Microbiology, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia 25704; and Graduate Center for Toxicology, University of Kentucky, Lexington, Kentucky 40536
Received January 9, 2006; accepted April 17, 2006
The cJun N-terminal kinase (JNK)-signaling pathway is activated in response to a variety of stimuli, including environmental insults, and has been implicated in neuronal apoptosis. In this study, we investigated the role that the JNK pathway plays in neurotoxicity caused by thimerosal, an ethylmercury-containing preservative. SK-N-SH cells treated with thimerosal (0–10µM) showed an increase in the phosphorylated (active) form of JNK and cJun with 5 and 10µM thimerosal treatment at 2 and 4 h. To examine activator protein-1 (AP-1) transcription, cells were transfected with a pGL2 vector containing four AP-1 consensus sequences and then treated with thimerosal (0–2.5µM) for 24 h. Luciferase studies showed an increase in AP-1 transcriptional activity upon thimerosal administration. To determine the components of the AP-1 complex, cells were transfected with a dominant negative to either cFos (A-Fos) or cJun (TAM67). Reporter analysis showed that TAM67, but not A-Fos, decreased AP-1 transcriptional activity, indicating a role for cJun in this pathway. To assess which components are essential to apoptosis, cells were treated with a cell-permeable JNK inhibitor II (SP600125) or transfected with TAM67, and the downstream effectors of apoptosis were analyzed. Cells pretreated with SP600125 showed decreases in activation of caspases 9 and 3, decreases in degradation of poly(ADP-ribose) polymerase (PARP), and decreased levels of proapoptotic Bim, in comparison to cells treated with thimerosal alone. However, cells transfected with TAM67 showed no changes in those same components. Taken together, these results indicate that thimerosal-induced neurotoxicity occurs through the JNK-signaling pathway, independent of cJun activation, leading ultimately to apoptotic cell death.
Key Words: thimerosal; mercury; neurotoxicity; JNK; cJun; Bim.
