TRICLOSAN THE DIRTY SIDE OF SOAP

Triclosan is an antimicrobial commonly found in soaps, shampoos, toothpastes and many other household items. Despite its widespread use, researchers at University of California, San Diego School of Medicine report potentially serious consequences of long-term exposure to the chemical. The study, published Nov. 17 by Proceedings of the National Academy of Sciences, shows that triclosan causes liver fibrosis and cancer in laboratory mice through molecular mechanisms that are also relevant in humans.

Triclosan's increasing detection in environmental samples and its increasingly broad use in consumer products may overcome its moderate benefit and present a very real risk of liver toxicity for people, as it does in mice, particularly when combined with other compounds with similar action," said Robert H. Tukey, PhD, professor in the departments of Chemistry and Biochemistry and Pharmacology. Tukey led the study, together with Bruce D. Hammock, PhD, professor at University of California, Davis. Both Tukey and Hammock are directors of National Institute of Environmental Health Sciences (NIEHS) Superfund Programs at their respective campuses.

Tukey, Hammock and their teams, including Mei-Fei Yueh, PhD, found that triclosan disrupted liver integrity and compromised liver function in mouse models. Mice exposed to triclosan for six months (roughly equivalent to 18 human years) were more susceptible to chemical-induced liver tumors. Their tumors were also larger and more frequent than in mice not exposed to triclosan.

The study suggests triclosan may do its damage by interfering with the constitutive androstane receptor, a protein responsible for detoxifying (clearing away) foreign chemicals in the body. To compensate for this stress, liver cells proliferate and turn fibrotic over time. Repeated triclosan exposure and continued liver fibrosis eventually promote tumor formation.

Triclosan is perhaps the most ubiquitous consumer antibacterial. Studies have found traces in 97 percent of breast milk samples from lactating women and in the urine of nearly 75 percent of people tested. Triclosan is also common in the environment: It is one of the seven most frequently detected compounds in streams across the United States.

"We could reduce most human and environmental exposures by eliminating uses of triclosan that are high volume, but of low benefit, such as inclusion in liquid hand soaps," Hammock said. "Yet we could also for now retain uses shown to have health value -- as in toothpaste, where the amount used is small."

Triclosan is already under scrutiny by the FDA, thanks to its widespread use and recent reports that it can disrupt hormones and impair muscle contraction.

Co-authors include Koji Taniguchi, Shujuan Chen and Michael Karin, UC San Diego; and Ronald M. Evans, Salk Institute for Biological Studies.

This research was funded, in part, by U.S. Public Health Service grants ES010337, GM086713, GM100481, A1043477, ES002710 and ES004699.

HOW THE ENDS OF CHROMOSOMES ARE MAINTAINED FOR CANCER CELL IMMORTALITY

Maintaining the ends of chromosomes, called telomeres, is a requisite feature of cells that are able to continuously divide and also a hallmark of human cancer. "Telomeres are much like the plastic cap on the ends of shoelaces -- they keep the ends of DNA from fraying," says Roger Greenberg, MD, PhD, associate professor of Cancer Biology in the Perelman School of Medicine at the University of Pennsylvania. In a new study published this week in Cell, he and his colleagues describe a mechanism for how cancer cells take over one of the processes for telomere maintenance to gain an infinite lifespan

Telomeres stay intact in most cancer cell types by means of a specialized enzyme called telomerase that adds the repetitive telomere DNA sequences to the ends of chromosomes. Cancer cells can also use a second method involving a DNA-repair-based mechanism, called alternative lengthening of telomeres, or ALT for short. In general, cancer cells take over either type of telomere maintenance machinery to become immortal. Overall, approximately fifteen percent of cancers use the ALT process for telomere lengthening, but some cancer types use ALT up to 40 to 50 percent of the time.

Greenberg's co-authors of the new findings are Nam Woo Cho and Robert L. Dilley, both MD/PhD students in his lab, and Michael A. Lampson, an associate professor of Biology at Penn. Greenberg is also an associate investigator at the Abramson Family Cancer Research Institute and director of Basic Science for the Basser Research Center for BRCA.

Going Fishing The team showed that when DNA breaks, it triggers DNA repair proteins like the breast cancer suppressor protein BRCA2 into action, along with other helper proteins, that attach to the damaged stretch of DNA. These proteins stretch out the DNA, allowing it to search for complementary sequences of telomere DNA. Breast cancer is linked to mutations in the BRCA1 and BRCA2 genes and mutations in several genes involved in BRCA-related pathways have also been associated with breast cancer susceptibility. Breast and ovarian cancers are associated with a breakdown in the DNA repair systems involving these BRCA and other related proteins.

"This process of repair triggers the movement and clustering of telomeres like fish being reeled toward an angler," explains Greenberg. "The broken telomeres use a telomere on a different chromosome -- the homologous telomere -- as a template for repair." In fact, in cancer cells that use ALT to maintain their telomeres, the team could visualize this process by imaging these clusters of telomeres coming together.

"We are very excited about the data as it has provided new insights into this mechanism of telomere maintenance and ways to think about BRCA dependent and independent DNA recombination," he says. "But, as with most scientific studies, many more questions are raised than answers provided."

The team would like to find other proteins involved in ALT and look for small molecule drugs that target this telomere maintenance mechanism in cancer cells to selectively kill cancer types that use ALT.