Columbia University Medical Center

Cellular Target For Mutagenic Radiation Larger Than Previously Thought

New York, NY, April 27, 1999 — Ionizing radiation can cause potentially carcinogenic mutations of DNA no matter what part of the cell it strikes, according to a report by researchers at Columbia University College of Physicians & Surgeons. The findings, published in the April 27 issue of the Proceedings of the National Academy of Sciences, contradict the prevailing belief that radiation causes genetic mutations only when it strikes the cell nucleus. DNA mutation rates rose as much as threefold above normal after Dr. Tom K. Hei and his colleagues irradiated the cell cytoplasm, the portion of the cell outside the cell nucleus, with alpha particles, the radiation emitted by radon. The results suggest that scientists may have to alter cancer-risk estimates for people exposed to low levels of ionizing radiation, such as radon and X-rays.

“The nucleus has always been considered as the quintessential target for any carcinogenic mutations,” says Dr. Hei, associate professor of radiation oncology and public health. “We have learned that if you hit the cytoplasm with alpha particles there is a chance that you will mediate a mutational event in the nucleus.”

A state-of-the-art microbeam at Columbia University’s Radiological Research Accelerator Facility in Irvington, N.Y., allowed Dr. Hei’s team to fire a precise number of alpha particles at specific regions within a cell. After irradiating the cytoplasm of thousands of cells, the researchers found that cells hit by eight alpha particles showed a mutation rate threefold above normal mutation rates.

Analysis of the mutations showed that they differed significantly from mutations caused by nuclear irradiation and may pose a greater risk of cancer. When alpha particles strike the nucleus, they generally damage large sections of DNA, more often than not killing the cell. The mutations caused by cytoplasmic irradiation, on the other hand, were generally much smaller, similar to spontaneous mutations, and killed far fewer cells. Since cancer arises from non-lethal mutations to a cell’s DNA, cytoplasmic irradiation may play a significant role in carcinogenesis.

Cytoplasmic irradiation should be considered a major concern to human health in terms of risk of exposure for cancer and birth defects, as well as having a profound impact on our understanding of the relationship between radiation exposure and disease, wrote the authors in their paper. Current estimates of the risk posed by low-level radiation are based in part on the theory that ionizing irradiation can cause genetic mutations only when it strikes the cell nucleus.

Irradiation of the cytoplasm appears to cause genetic mutations by creating highly reactive free radicals, which migrate to the nucleus where they mutate the DNA. When the cells were pretreated with the antioxidant DMSO before irradiation, the mutation rate remained near normal.

The other authors of the paper were Li-Jun Wu, Gerhard Randers-Pehrson, An Xu, and Charles R. Geard, all of the Center for Radiological Research at the College of Physicians & Surgeons, Charles A. Waldren of the Colorado State University, and ZengLiang Yu of the Chinese Academy of Sciences in Hefei, China.

The research was supported by the National Institutes of Health and the National Aeronautics and Space Administration.

Copies of the paper are available to reporters from the PNAS news office, tel. (202) 334-2138, or email pnasnews@nas.edu.

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