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DIR Papers of the Month

By Jerry Phelps
August 2006

Proteomics Responses to Anthrax Lethal Toxin Exposure

NIEHS researchers report in the June issue of Electrophoresis progress in understanding how toxins released during anthrax infection adversely affect a variety of cellular processes. According to the paper, this knowledge "should be of great value in understanding and combating this disease."

Jeffrey Kuhn and Ken Tomer along with colleagues from Agilent Technologies used a proteomics approach to investigate how anthrax disrupts the cell signaling process. The team identified 67 proteins produced after exposure to anthrax lethal toxin in a macrophage cell culture system. Many of the proteins are involved in the oxidative stress response along with apoptotic pathways. The researchers conclude that the tumor necrosis factor pathway is a target in lethal toxin exposed cells. This study also highlights improvements in the laboratory techniques used to isolate and identify the proteins produced in response to toxin exposure.

The most severe form of Anthrax results from inhalation of Bacillus anthracis spores which are engulfed or phagocytised by macrophages in the lung. Phagocytosis of bacteria by macrophages is a normal and effective method of the innate immune system to fight the spread of infection. However, in the case of anthrax, the bacteria survive phagocytosis, reproduce within the cells, and use the macrophages as a transport mechanism to invade lymph nodes and eventually the blood stream leading to widespread infection, disease, and death.

Citation: Kuhn JF, Hoerth P, Hoehn ST, Preckel T, Tomer KB. Proteomics study of anthrax lethal toxin-treated murine macrophages. Electrophoresis. 2006 Apr;27(8):1584-97.

Czech Uranium Miners Exposed to Radon are at Higher Risk for Leukemia and Lymphoma

In an epidemiologic study of uranium miners, Dale Sandler and colleagues in the Czech Republic report a statistically significant positive association between radon exposure and leukemia of all causes.

They also found that radon exposure is associated with risk for chronic lymphocytic leukemia (CLL), which was previously thought to be unrelated to radiation. Sandler said, "because we studied incidence and not mortality and had relatively long follow-up of miners with good access to medical screening we found this association that has not been seen, but it is plausible that radiation does increase risk for CLL."

Miners exposed to radon were about twice as likely to develop leukemia. The team also found increased risks for myeloid leukemia and Hodgkin's lymphoma, but the relative risks were not statistically significant. In this study, there was no association between radon exposure and non-Hodgkin's lymphoma or multiple myeloma.

The authors conclude that that if their findings are confirmed in other studies, CLL "should be considered an occupational disease in workers with prolonged low-level exposure to radon and perhaps to other kinds of radiation."

Citation: Rericha V, Kulich M, Rericha R, Shore DL, Sandler DP. Incidence of leukemia, lymphoma, and multiple myeloma in Czech uranium miners: a case-cohort study. Environ Health Perspect. 2006 Jun;114(6):818-22.

Estrogen Receptor Alpha Involved in Estrogen Induced Liver Toxicity

New NIEHS research provides insight into how estrogen exposure during pregnancy, from oral contraceptive use, or from postmenopausal estrogen replacement therapy may cause a liver condition known as intrahepatic cholestasis. Using genetically altered mice lacking the estrogen receptor, researchers determined that the estrogen receptor alpha is involved in the development of the condition. Mice lacking the receptor showed no signs of liver toxicity after being dosed with estradiol. However, wild-type mice treated with estrogen had decreased expression of bile acid and cholesterol transporters. They also found the receptor is involved in shifting the bile acid synthesis toward a more acidic pathway. These findings suggest that estrogen receptor antagonists such as tamoxifen may be used to treat some cases of this condition.

Intrahepatic cholestasis is the most common liver disease during pregnancy and is caused by an impairment of bile secretion in the liver. As the bile backs up in the liver, the level of bile acids increases in the bloodstream. These bile acids are deposited in the skin causing intense itching. Cholesterol, triglyceride, and bilirubin levels are also increased. Elevated bile acids in the blood stream can cause premature delivery and death of the fetus.

Members of the NIEHS Laboratories of Reproductive and Developmental Toxicology and Experimental Pathology performed this research along with colleagues from the National Cancer Institute.

Citation: Yamamoto Y, Moore R, Hess HA, Guo GL, Gonzalez FJ, Korach KS, Maronpot RR, Negishi M. Estrogen receptor alpha mediates 17alpha-ethynylestradiol causing hepatotoxicity. J Biol Chem. 2006 Jun 16;281(24):16625-31. Epub 2006 Apr 10.

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