NEWS OF THE WEEK and Alan N. Wolf, an associate profes sor of physics at Cooper Union, New York City, and a lawyer. The three others on the committee are Judith L. Craven, president, United Way of Texas Gulf Coast, Houston; Richard T. Jones, assistant dean of aca demic affairs and professor, School of Medicine, Oregon Health Sciences Uni versity, Portland; and Keith Marton, vice president, Medical Academic Af fairs Department, St. Mary's Medical Center, San Francisco. Pointer wants the committee to rec ommend "one to three neutral persons with appropriate expertise" in each of four disciplines: epidemiology, immu nology, rheumatology, and toxicology. The experts' eventual written report and depositions would be used as evi dence by either plaintiffs or defendants to make their case in court. Marc Reisch
Estrogenic chemicals act synergistically Mixtures of estrogenic chemicals have a more potent effect on the endocrine sys tem than the chemicals do individually, new research suggests. The finding lends support to the controversial theory that low levels of chemicals in the environ ment could be disrupting human endo crine function, causing cancer, and pro ducing reproductive defects in developing offspring.
Pesticide mixtures show higher estrogenic activity β-Gal EC 50 a (μΜ)
Chemical b
17p-Estradiol Endosulfan Dieldrin Toxaphene Chlordane Endosulfan + dieldrin Endosulfan + toxaphene Endosulfan + chlordane Dieldrin + toxaphene Dieldrin + chlordane Toxaphene + chlordane
0.0001 >33 >33 >33 ndc 0.092 0.121 0.189 0.210 0.286 0.306
a Concentration required to increase activity of β-galactosidase 50% in yeast cells containing human estrogen receptor. β-Galactosidase activity is a measure of estro genic activity of tested compounds, b A natural human estrogen, c EC50 for chlordane was not detected (nd) because chlordane did not increase β-galactosidase activity at any concentration tested.
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JUNE 10,1996 C&EN
Molecular endocrinologist Steven F. Arnold of Tulane University and co workers engineered the gene for the human estrogen receptor into yeast cells and linked its activity to a gene that encodes the enzyme β-galactosi dase. The researchers tested four pesti cides alone and in combinations for their ability to bind to and turn on the estrogen receptor in this system [Sci ence, 272,1489 (1996)]. When tested individually, endosul fan, dieldrin, and toxaphene were weakly estrogenic, and chlordane showed no activity at all, Arnold and his colleagues report. But several com binations of two of the chemicals were far more potent—much lower concen trations yielded equivalent estrogenic activity. For example, the mixture of endosulfan and dieldrin was 160 to 1,600 times more potent than either chemical alone. The other mixtures were at least 100 times more estrogenic than the single chemicals. (In the U.S., endosulfan is still a wide ly used pesticide; dieldrin, chlordane, and toxaphene are now banned but still found widely in the environment.) In addition, Arnold tested two hydroxylated polychlorinated biphenyls in the yeast system and found the com bination five times more estrogenic than the individual PCBs. Because yeast cells differ from mammalian cells, he also tested the PCBs on human en dometrial cells and found the same fivefold synergistic increase. John A. McLachlan, environmental endocrinologist at Tulane and a coau thor of the study, says the research pro vides a molecular explanation for in vivo studies that show synergistic ef fects of environmental estrogens. For example, when individual PCB com pounds are painted on turtle eggs, they reverse the sex of the eggs. Much lower concentrations of a mixture of two PCB compounds are required to achieve the same effect. Arnold's work "poses more ques tions than it answers," S. Stoney Si mons Jr., a researcher in the steroid hormones section at the National Insti tute of Diabetes & Digestive & Kidney Diseases, tells C&EN. It is still not known whether estrogen-receptorregulated genes that are important for development are synergistically acti vated by environmental estrogens, he notes. And pesticides have not yet been tested in mammalian cells, he adds.
In contrast to X-ray crystallography data that indicate a single binding site on the human estrogen receptor, Ar nold's work suggests there may be two or more binding sites, Simons points out. In any event, estrogen receptor ac tivation seems to be more complicated than one molecule interacting with a single binding site and initiating an es trogenic response, he says. McLachlan expects the Tulane re search will spur a great deal of followup work. Epidemiologists will be test ing the theory that combinations of chemicals are having effects on hu mans. Other researchers will test the ef fects of chemical mixtures on develop ing rodents. McLachlan's lab will be looking at synergism and inhibition be tween natural and synthetic estrogens. The researchers will also be dissecting the estrogen receptor to see what parts are involved in the synergy. Bette Hileman
Transition state of complex system probed A team of scientists has obtained unique spectroscopic data on what they describe as "by far the most com plex [transition-state] system for which detailed structural information . . . has been experimentally accessible." The study is also the first to demonstrate experimentally a strict violation of Hund's rule, a standard precept of physical chemistry. The research on cyclooctatetraene (COT) was carried out by chemistry professor W. Carl Lineberger and post doctoral associate Paul G. Wenthold of the University of Colorado, Boulder, and chemistry professor Weston Thatcher Borden and research scientist David A. Hrovat of the University of Washington, Seattle [Science, 272, 1456 (1996)]. Their research "represents a qualita tive jump in the complexity of reactions accessible to transition-state spectrosco py," comments chemistry professor Daniel M. Neumark of the University of California, Berkeley. He adds that it is "an important expansion ... from the type of model chemical reactions usual ly studied by chemical physicists to much more complex species of interest to the wider chemistry community." Borden, Lineberger, and coworkers
