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Intramural Papers of the Month

By Erin Hopper and Robin Arnette
December 2010

Succimer treatment shows limited efficacy at reducing organic mercury in children

Researchers at NIEHS recently examined the use of succimer to lower blood mercury levels in small children. Succimer is a chelating agent that the authors previously examined in the Treatment of Lead-exposed Children (TLC) trial. In the current study, the samples from the TLC trial were reanalyzed to determine whether succimer treatment was effective for treating low-level mercury exposure in children.

Organic mercury exposure comes mostly from diet, especially certain fish. Until 1999, vaccine preservatives contained organic mercury, but that source has been largely eliminated. Chelating drugs have been shown to help remove mercury from the body after an acute exposure, but these drugs have not been shown to be effective at reversing toxic effects. Research has determined that chelation does not reverse IQ deficits in lead-exposed children. 

A previous effort to study the efficacy of succimer for autism spectrum disorder, thought by some to be a form of mercury toxicity, was halted due to safety concerns, so the availability of the blood samples from the TLC trial provided a unique opportunity to study succimer treatment for mercury exposure.

Blood samples collected over a period of five months were tested for inorganic and organic mercury. Succimer treatment appeared to reduce organic mercury concentrations slightly but did not reverse mercury accumulation. The authors concluded that succimer is a less effective chelator for mercury than for lead and that the modest reduction in mercury concentration that they observed is unlikely to be of clinical benefit.

Citation: Cao Y, Chen A, Jones RL, Radcliffe J, Dietrich KN, Caldwell KL, et al. (http://www.ncbi.nlm.nih.gov/pubmed/20889164) Exit NIEHS 2010. Efficacy of succimer chelation of mercury at background exposures in toddlers: A randomized trial. J Pediatr Epub ahead of print doi:10.1016/j.jpeds.2010.08.036

Releasing the brake on synaptic plasticity

A recent collaboration between NIEHS and Emory University explored the role of the protein RGS14 in brain function. RGS14 acts as a signaling protein, but its role in the brain is poorly understood. One clue to its function is that RGS14 is localized predominantly in neurons of the CA2 subregion of the hippocampus, an area that normally has very little synaptic plasticity.

To explore the role of RGS14 in brain function, the authors used a line of knockout mice that was unable to express full-length RGS14. The knockout mice appeared healthy and displayed no apparent differences in phenotype than wild-type mice. However, they exhibited a marked increase in synaptic plasticity in the CA2 subregion of the hippocampus compared to their wild-type counterparts, suggesting that RGS14 plays a role as a brake on synaptic plasticity in the CA2.

The increased synaptic plasticity observed in the knockout mice suggested that these mice may have an increased capacity for learning and memory. Indeed, the authors found that the knockout mice exhibited superior object recognition memory and an improved initial learning rate in a spatial navigation task compared to wild-type mice. These results suggest that RGS14 also acts as a brake on hippocampal-based learning and memory. Further studies are required to determine exactly how RGS14 regulates synaptic plasticity on a molecular level and what role the CA2 plays in cognition.

Citation: Lee SE, Simons SB, Heldt SA, Zhao M, Schroeder JP, Vellano CP, et al. (http://www.ncbi.nlm.nih.gov/pubmed/20837545) Exit NIEHS 2010. RGS14 is a natural suppressor of both synaptic plasticity in CA2 neurons and hippocampal-based learning and memory. Proc Natl Acad Sci USA 107(39):16994-16998.

Related Story (http://www.niehs.nih.gov/news/newsletter/2010/september/science-unruly.cfm)

mtDNA helicase mutants differ biochemically

Investigators from NIEHS performed biochemical analyses on 20 mutant variants of the human mitochondrial DNA (mtDNA) helicase gene, C10orf2, and determined that all of the mutants functioned properly and retained the ability to unwind DNA similar to wild-type. However, the mutants differed in their response to three other biochemical tests such as DNA binding affinity, nucleotide hydrolysis kinetics, and thermal stability. These findings will help researchers better understand mitochondrial diseases such as progressive external ophthalmoplegia (PEO), hepatocerebral mtDNA depletion syndrome (MDS) and infantile-onset spinocerebellar ataxia (IOSCA), which are caused by C10orf2 missense mutations.

The enzyme product of C10orf2 is known as p72, and the team members generated single amino acid substitution mutants that were identified in patients with mitochondrial disease. The researchers used Escherichia coli to grow the variants, many of them with changes that occurred in a linker region involved in subunit interactions and hexamer formation.

The protein purification process presented several challenges, but, through trial and error, the scientists discovered that the use of certain reagents and conditions such as a lower temperature, non-ionic detergents, elevated ionic strength, and adenosine-5'-triphosphate (ATP) cofactor in the purification buffers dramatically increased the solubility and long term stability of p72.

Team members acknowledged that their analysis of C10orf2 proteins stressed the importance of experimental design and enzyme stability.

Citation: Longley MJ, Humble MM, Sharief FS, Copeland WC. (http://www.ncbi.nlm.nih.gov/pubmed/20659899) Exit NIEHS 2010. Disease variants of the human mitochondrial DNA helicase encoded by C10orf2 differentially alter protein stability, nucleotide hydrolysis, and helicase activity. J Biol Chem 285(39):29690-29702.

Story (http://www.niehs.nih.gov/news/newsletter/2010/october/science-jbc.cfm)

Gender differences in glucocorticoid-mediated inflammation

Research performed by scientists from NIEHS and Wake Forest University School of Medicine suggests that glucocorticoids, stress-induced steroids that regulate intermediary metabolism, may contribute to the development, progression, or susceptibility to inflammatory diseases in a gender-specific manner. This finding offers a possible explanation for why more females tend to have certain inflammatory diseases.

Using microarrays of male and female rat livers, the team discovered that glucocorticoids expanded the normal set of genes that exhibited sexually dimorphic expression. The investigators identified eight distinct patterns of glucocorticoid-regulated gene expression, which included sex-specific genes. Pathway analysis found that males had 84 additional glucocorticoid-responsive genes, which suggested the anti-inflammatory actions of glucocorticoids are more effective in males.

The authors wanted to rule out that growth hormone may be contributing to the sexually dimorphic response to glucocorticoids, so they treated isolated liver cells from male and female rats with glucocorticoids and found that the liver cells still elicited sex-specific differences in gene expression.

This work determined glucocorticoids regulate more liver genes in inflammatory pathways in males than females, suggesting that the failure by females to mount an adequate glucocorticoid inflammatory response may lead to more autoimmune diseases in women.

Citation: Duma D, Collins JB, Chou JW, Cidlowski A. (http://www.ncbi.nlm.nih.gov/pubmed/20940427) Exit NIEHS 2010. Sexually dimorphic actions of glucocorticoids provide a link to inflammatory diseases with gender differences in prevalence. Sci Signal 3(143):ra74.

(Erin Hopper, Ph.D., is a postdoctoral fellow in the NIEHS Laboratory of Structural Biology Mass Spectrometry Group.) 



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