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DERT Papers of the Month

By Jerry Phelps
March 2007

Asthma Exacerbated by Exposure to Florida Red-Tide Toxins

Some of the most deadly and potent natural toxins known are derived from harmful algal blooms known as red tides. The microalgae Karenia brevis causes red tides each year throughout the Gulf of Mexico. The organism produces a highly potent toxin called brevetoxin. NIEHS grantee Dan Baden from the University of North Carolina at Wilmington and colleagues report in the journal Chest that exposure to brevetoxins exacerbates asthma symptoms in people with physician-diagnosed asthma.

Brevetoxins are sodium channel blockers and may activate histamine leading to immune responses. Previous research in laboratory animals demonstrated that brevetoxins caused airway constriction, a classic symptom of asthma. The new research was conducted in 97 asthmatics who visited a beach for one hour during periods with and without active algal blooms. They carried personal air monitors that were later used to determine the concentration of toxin they were exposed to. All 97 subjects had more difficulty breathing after exposure to brevetoxin, as determined by a questionnaire and by a series of airflow tests.

These findings could have major implications for asthmatics living near beaches in the Gulf of Mexico region since red tides occur frequently there. Future research will focus on more in-depth analysis of susceptible populations and the potential for long-term effects of brevetoxin exposure.

Citation: Fleming LE, Kirkpatrick B, Backer LC, Bean JA, Wanner A, Reich A, Zaias J, Cheng YS, Pierce R, Naar J, Abraham WM, Baden DG. 2007. Aerosolized red-tide toxins (brevetoxins) and asthma. Chest 131(1):187-194.

Bisphenol-A Alters Fetal Mammary Gland Development in Mice

New work from the laboratory of NIEHS grantee Ana M. Soto at Tufts University School of Medicine illustrates that female mice exposed to bisphenol-A (BPA) in utero from days 8 to 18 of fetal development experience alterations in mammary gland development.

Pregnant female mice were given an environmentally relevant dose of BPA daily from gestational days 8 to 18. The mammary glands of the female pups were evaluated on gestational day 18. Results showed that this dose of BPA, which fell within the range of estimated human exposure, sped development of the fat pad and altered collagen localization in the stromal region of the glands. In the mammary epithelium, BPA exposure delayed lumen formation and led to decreases in cell size.

BPA's current uses are as a component in polycarbonate plastic and resins. BPA has been known to leach from plastics that are cleaned with harsh detergents or used to contain acidic or high temperature liquids. The chemical is found in most people who live in developed countries.

BPA activates estrogen receptors, resulting in similar physiological effects to those caused by the body's own naturally occurring estrogens. Other studies have demonstrated that fetal exposure to bisphenol A increased the chances of breast cancer in laboratory rats. Soto's work expands the knowledge of the effects of BPA and suggests that alterations in mammary glands observed at puberty and in adulthood in perinatally exposed mice originate during fetal development.

Citation: Vandenberg LN, Maffini MV, Wadia PR, Sonnenschein C, Rubin BS, Soto AM. 2007. Exposure to environmentally relevant doses of the xenoestrogen bisphenol-A alters development of the fetal mouse mammary gland. Endocrinology 148(1):116-127.

Urinary Arsenic Levels Correlate with Intelligence Scores

Research findings from the laboratory of NIEHS grantee Allan Smith at the University of California-Berkeley demonstrate adverse effects on children's intellectual function and intelligence associated with urinary arsenic levels.

The study was carried out in West Bengal, India, a region known for high levels of arsenic in ground water. The 351 children in the study were divided into three groups according to high, medium, and low urinary arsenic. The intelligence test results showed a decline of 12 percent for a vocabulary test, 21 percent for an object assembly test, and 13 percent in a picture completion test for the children in the high urinary arsenic group. These findings were similar to another NIEHS-supported arsenic study in neighboring Bangladesh.

Acute neurotoxic effects of arsenic have been well documented and include short-term memory loss and problems in learning and concentration. Children are known to be particularly susceptible to the neurotoxic effects of other metals, especially lead and mercury. Limited evidence from animal studies and earlier studies in children gave some indication that arsenic is associated with neurodevelopmental delays. The current findings need to be confirmed; however, they add to the body of knowledge of the adverse health effects of arsenic in children.

Citation: von Ehrenstein OS, Poddar S, Yuan Y, Mazumder DG, Eskenazi B, Basu A, Hira-Smith M, Ghosh N, Lahiri S, Haque R, Ghosh A, Kalman D, Das S, Smith AH. 2007. Children's intellectual function in relation to arsenic exposure. Epidemiology 18(1):44-51.

Lead and Mercury Disrupt Neuronal Stem Cells

Groundbreaking research from Mark Noble at the University of Rochester concludes that low levels of diverse environmental agents, namely lead, methylmercury and paraquat, disrupt the normal functioning of progenitor cells within the central nervous system.

Noble and his colleagues found a previously unknown mechanism by which these agents cause the effects. The agents make the cells more oxidized, which causes the activation of an enzyme known as Fyn kinase, which in turn activates another enzyme called c-Cbl. C-Cbl modifies and degrades protein receptors necessary for cell division and survival. When the receptors are degraded, their downstream signaling pathways are repressed and the cells fail to divide and develop properly.

The work was conducted in cell cultures of glial progenitors, advanced-stage stem cells important for the growth and development and normal functioning of the central nervous system. The cells proved to be exquisitely sensitive to minute levels of the toxicants. The pathway they activate is a normal cellular regulatory pathway; however, according to the authors, "they are just activating it inappropriately."

The discovery of a molecular target that is shared by a variety of compounds may represent a new tool for rapidly screening compounds to determine their potential neurotoxicity. It may also provide insights into how to protect cells from the signaling disruption once exposure has occurred.

Citation: Li Z, Dong T, Proschel C, Noble M. 2007. Chemically diverse toxicants converge on Fyn and c-Cbl to disrupt precursor cell function. PLoS Biol 5(2):e35.



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