Lab Accident Reveals Potential Health Risks of Common Compound
Jon Cohen

In August 1998, geneticist Patricia Hunt noticed a bizarre change in the eggs of the female mice she was studying. For some inexplicable reason, the chromosomes in 40% of the eggs looked abnormal--a wild jump from the 1% to 2% abnormality her lab typically observes. Something seemed to have gone terribly wrong with meiosis, the process that separates chromosomes during reproduction so that when egg and sperm come together, they each contribute half the genetic material to an embryo. Hunt, whose lab at Case Western Reserve University in Cleveland, Ohio, specializes in problems with meiosis--which in humans causes more birth defects, mental retardation, and miscarriage than any other factor--had her lab workers redo the study twice, yielding the same baffling results each time.

Figure 1 Meiotic mess. Chromosomes (red) should neatly line up on spindle (green), but BPA wreaks havoc (bottom) in mouse eggs.     CREDIT: P. A. HUNT ET AL., CURRENT BIOLOGY 13, 546 (2003)

The first clue came that fall, when Hunt noticed that her mouse cages, made of a plastic called polycarbonate, appeared to be melting. She found that a lab worker had mistakenly washed the cages with a highly alkaline detergent. "He was a temporary worker who made a lasting impression," Hunt says. Hunt, Terry Hassold, and their colleagues eventually pinned the meiotic abnormalities on a chemical called bisphenol A (BPA) leaching from the damaged plastic. Although several labs have shown that BPA, a compound widely used in plastics manufacturing, can disrupt the reproductive system of rodents, none had previously shown an effect on meiosis.

The detective work, described in a paper in the 1 April issue of Current Biology, has thrust Hunt's lab into the middle of the controversial field of endocrine disrupters. Some researchers and environmentalists have argued that low levels of certain synthetic chemicals in the environment are causing reproductive problems in wildlife and perhaps humans. BPA, which weakly mimics the effects of estrogen has been among the suspects.

Researchers from diverse disciplines say the work deserves serious attention. "It's fascinating," says Charles Epstein, a developmental biologist at the University of California, San Francisco, who studies chromosomal imbalances in mice. Even Stephen Safe of Texas A&M University in College Station, a leading skeptic of evidence linking endocrine disruptors to health problems, says, "I think their data are very interesting." Leading proponents of BPA's harmful effects predictably have stronger words: "I look at this as a watershed paper," says reproductive biologist Frederick vom Saal of the University of Missouri, Columbia, whose lab has published several studies of BPA's impact on mouse reproductive development.

Hunt and co-workers first noticed problems when they took a routine "snapshot" of the meiotic process in their mice. They found that 40% of the mouse eggs failed to assemble their chromosomes neatly on the spindle apparatus, a step that must occur for separation to take place properly. They also found abnormal numbers of chromosomes, an aberration called aneuploidy, in about 12% of the eggs. "When I read that I said, 'Zowee, that's really out of sight,' " says John Eppig, a reproduction biologist at the Jackson Laboratory in Bar Harbor, Maine.

Once they suspected BPA, Hunt and co-workers recreated the accident. They intentionally damaged polycarbonate cages and water bottles with detergent and compared the mice in those cages with animals kept in undamaged cages with glass bottles. They found the same levels of meiotic error in the mice kept in the damaged cages. They then showed that BPA was the culprit by adding the chemical to mouse water; it caused chromosomal problems, though not as severe. "It's probably the only convincing demonstration of an environmental effect on the frequency of aneuploidy," says Dorothy Warburton, a cytogeneticist at Columbia University in New York City who has studied aneuploidy extensively. "It's a little scary."

Although Hunt stresses that no data clearly link BPA to human aneuploidy, she thinks the question deserves study because the compound is so widely used: Plastics that contain it are made into baby bottles, the liners of food cans, dental sealants, and many other common products. More immediately, she says her finding should cause researchers to consider retiring their polycarbonate cages, which naturally degrade over time. And for her own research, this serendipitous finding provides a powerful new tool to create and study aneuploidy in mice.