Environmental Factor, February 2011, National Institute of Environmental Health Sciences
Extramural papers of the month
By Jerry Phelps
- Mitochondrial dysfunction in children with autism
- DNA damage mapped out
- Less toxic and more effective carbon nanotubes for drug delivery
- Sperm may be harmed by BPA exposure
Mitochondrial dysfunction in children with autism
Children with autism are far more likely to have deficits in mitochondrial function, specifically in their ability to produce cellular energy, than are typically developing children. These findings are from a new study by NIEHS-supported researchers at the University of California, Davis. The results suggest that cumulative damage and oxidative stress in mitochondria could influence both the onset and severity of autism.
The brain is the second largest consumer of energy in the body, after the heart. The investigators propose that deficiencies in the ability to fuel brain cells might lead to some of the cognitive impairments associated with autism. Mitochondrial dysfunction has already been associated with other neurological diseases and conditions including Parkinson's and Alzheimer's disease, schizophrenia, and bipolar disorder.
Although the study was small, including only 10 children with autism and 10 age-matched controls, the findings may eventually help physicians provide early diagnosis. Larger studies are necessary to confirm these findings. The study does not identify the cause of autism, which affects as many as one in every 110 children, but it does offer new insights into prevention and intervention efforts.
Citation: Giulivi C, Zhang YF, Omanska-Klusek A, Ross-Inta C, Wong S, Hertz-Picciotto I,Tassone F, Pessah IN.(https://www.ncbi.nlm.nih.gov/pubmed/21119085) 2010. Mitochondrial dysfunction in autism. JAMA 304(21):2389-2396. Story(https://factor.niehs.nih.gov/2011/january/science-mitochondrial.cfm)
DNA damage mapped out
Using a new technique called differential epistasis maps, an international team lead by NIEHS grantee Trey Ideker, Ph.D., has documented, for the first time, how a cellular genetic network is completely reorganized in response to DNA damaging agents.
Epistasis refers to the interaction of genes and how they suppress, activate, or alter other gene's functions. To create an epistasis map, the research team focused on 400 genes that govern signal transduction pathways in yeast. They then created approximately 80,000 mutant cell lines in which each mutant line carries mutations in a different pair of the 400 genes. When the cells grow much more slowly or quickly than expected, these mutant genes are said to interact.
The map was created by identifying interactions before and after exposure to a DNA-damaging agent similar to compounds used in chemotherapy. To their surprise, the team found that most of the interactions identified after exposure to the drug were not present without the exposure, leading them to believe that the genetic network was completely reprogrammed by DNA damage.
This discovery suggests that similar systems in more advanced organisms will be even more complex and more complicated to study. It represents a new frontier in probing dynamic interactions that enable cells to survive and thrive in varying environmental and genetic contexts. Experiments at this higher level will give scientists deeper insights into the changing environment of a living cell.
Citation: Bandyopadhyay S, Mehta M, Kuo D, Sung MK, Chuang R, Jaehnig EJ, Bodenmiller B,Licon K, Copeland W, Shales M, Fiedler D, Dutkowski J, Guénolé A, van Attikum H, Shokat KM, Kolodner RD, Huh WK, Aebersold R, Keogh MC, Krogan NJ, Ideker T.(https://www.ncbi.nlm.nih.gov/pubmed/21127252) 2010. Rewiring of genetic networks in response to DNA damage. Science 330(6009):1385-1389.
Less toxic and more effective carbon nanotubes for drug delivery
NIEHS-supported researchers at the University of Connecticut have found that single-walled carbon nanotubes treated with polyethylene glycol (PEG) make more effective and less toxic drug delivery vehicles than untreated nanotubes. These results give further credence to the use of drug delivery systems utilizing single-walled carbon nanotubes.
Carbon nanotubes have been touted for their potential uses in products ranging from cosmetics and drug delivery devices to the construction of a space elevator. However, concerns over their toxicity and potential to cause inflammatory reactions have hindered their uses.
The researchers layered carbon nanotubes with PEG, which has been shown to improve their dispersion in aqueous solutions. Both PEG-treated and -untreated nanotubes were then incubated with the chemotherapeutic drug cisplatin. The nanotubes were then injected into laboratory mice, and a number of cytotoxicity assays were performed. Untreated nanotubes were found to clump together in lung tissue, while PEG-treated nanotubes showed little or no accumulation. Other assays revealed biliary or renal excretion routes of PEG-treated nanotubes. PEG-cisplatin nanotubes successfully inhibited growth of head and neck tumor grafts in the laboratory mice.
Citation: Bhirde AA, Patel S, Sousa AA, Patel V, Molinolo AA, Ji Y, Leapman RD, Gutkind JS, Rusling JF.(https://www.ncbi.nlm.nih.gov/pubmed/21143032) 2010. Distribution and clearance of PEG-single-walled carbon nanotube cancer drug delivery vehicles in mice. Nanomedicine (Lond) 5(10):1535-1546.
Sperm may be harmed by BPA exposure
In one of the first human studies of its kind, researchers have found that urinary concentrations of the controversial chemical bisphenol A (BPA) may be related to decreased sperm quality and concentration. This work was carried out by NIEHS-supported scientists at the Harvard University School of Public Health.
The study included 190 men recruited through a fertility clinic. Sperm concentration, motility, shape, and DNA damage were measured in semen samples from the participants. BPA was detected in 89 percent of the men's urine samples. Sperm concentration was about 23 percent lower in men in the top quartile of exposure, as compared with the lowest quartile. The highest exposed men also had about 10 percent more damaged sperm than the lowest exposed group.
These findings are consistent with a previous study suggesting that follicle-stimulating hormone and Inhibin B concentrations are altered in response to BPA, which mimics the pattern in men with low sperm production. The researchers are continuing this line of research with a larger cohort of men, to confirm their findings.
Citation: Meeker JD, Ehrlich S, Toth TL, Wright DL, Calafat AM, Trisini AT, Ye X, Hauser R.(https://www.ncbi.nlm.nih.gov/pubmed/20656017) 2010. Semen quality and sperm DNA damage in relation to urinary bisphenol A among men from an infertility clinic. Reprod Toxicol 30(4):532-539.
(Jerry Phelps is a program analyst in the NIEHS Division of Extramural Research and Training.)