Everyone's Health

Packing on the compounds

By Richard A. Lovett

Exposure to common chemicals may predispose some people to obesity

As obesity rates rise, some scientists say chemical “obesogens” may be partly to blame. UC Irvine biologist Bruce Blumberg said that tributyltin, used to keep barnacles from growing on the hulls of ships, acts as an obesogen at concentrations comparable to those found in the environment.

Obesity is generally thought of as an individual problem – an offshoot of the couch-potato syndrome, in which people eat too much while exercising too little.

As obesity rates rise, some scientists say chemical "obesogens" may be partly to blame.

It's also viewed as a societal problem. A team of researchers from Harvard and UCSD even suggested recently that obesity is “socially contagious.” If your friends gain weight, you're likely to do so, too – possibly because your standard of what's acceptable inflates with your companions.

Scientists have long known that genetics also plays a role. After all, some people eat like birds and yet gain weight, while others remain thin while gobbling everything in sight.

Still, obesity research has tended to focus on the “big two” – diet and exercise. But that approach is simplistic, like looking at a person in a wheelchair and concluding he's in the chair because he can't walk, said Ed Levin, a Duke University professor of biological psychiatry.

“That's true,” he said, “but it's not the whole story.”

Levin is one of a new generation of scientists examining another possible factor in the obesity epidemic. Their research suggests that minute exposures to common chemicals might pre-program children to be obesity-prone from birth.

Triggering obesity

This doesn't discount the importance of diet and exercise as a means of weight control for everyone. “But the fact is that it might be much more difficult for some people than for others, given certain environmental exposures,” Levin said.

Levin's particular interest is nicotine from tobacco smoke, to which, he said, about 1 in 4 babies is exposed before birth. Such infants are often born underweight, but later in life, studies have found they tend toward obesity, even when other factors, such as television watching, parental exercise habits, education level and computer-game playing are taken into account.

It's possible, of course, that other lifestyle factors might come into play, statistically linked to mothers' decisions not to quit smoking during pregnancy. But laboratory tests have found the same pattern in rats exposed to nicotine during fetal development. “So it seems like this is a real effect,” Levin said.

Tobacco smoke is a substance from which it is easy for pregnant women to protect themselves. More problematic is a chemical called bisphenol A. Currently under review by the U.S. National Toxicology Program as a possible developmental toxicant, bisphenol A is a critical ingredient of polycarbonate plastics, widely used in food and drink packaging. It is also used to make resins to coat metals in food cans, bottle tops and water pipes.

One of bisphenol A's leading critics is Frederick vom Saal, a biology professor at the University of Missouri. At a meeting of the American Association for the Advancement of Science earlier this year in San Francisco, he presented data from laboratory studies in which mice were exposed to this chemical during pregnancy. He found that exposures comparable to those encountered daily by many people can reprogram an embryonic mouse's genes to make the animal obesity-prone for the rest of its life.

Basically, he said, “You set up a metabolism that is entirely different from what it would have if it were not exposed.” The result: Exposed mice are normal-weight at birth, but grow fat with age.

Bruce Blumberg, an associate professor of developmental and cell biology at UC Irvine, refers to such chemicals as “obesogens.”

He believes that tributyltin, a substance used to keep barnacles from growing on the hulls of ships, is another one. The compound, part of a larger class called organotins, has gotten into seawater, contaminating seafood. It's also found in certain types of plastic used for food packaging and water pipes, Blumberg said. A treaty to ban maritime use of tributyltin is in the process of being ratified.

Obesogens don't cause mutations or birth defects. Rather, they interfere with gene expression at critical times in development, programming the body to have ever-hungry fat cells.

“They don't change the genes,” Blumberg said. “The compounds we're talking about act through hormone receptors.” And because the alteration occurs during fetal development, the change in exposed lab animals appears to be lifelong.

“With normal diet and exercise, they get significantly fatter than animals that were not exposed,” he said.

Furthermore, vom Saal and Blumberg cautioned, this isn't simply a matter of feeding high doses to rats and watching for effects that might not occur under real-world exposure levels. With tributyltin, Blumberg said, the concentrations involved are in the low parts per billion, comparable with those found in the diet and the environment.

Similarly, vom Saal said, bisphenol A programs laboratory animals to be fat even at exposure levels below those often found in humans tissues.

Although some of these chemicals may also affect adults, obesity researchers are more concerned about prenatal exposures. That's because, while adult exposures may also produce weight gain, the effect is likely to be reversed when the exposure ceases, said Retha Newbold, a researcher at the National Institute of Environmental Health Sciences. With prenatal exposures, the effect appears to be permanent.

Newbold compared the action of obesogens with that of DES, a drug once given to pregnant women to reduce the risk of miscarriage. Unfortunately, daughters of many of these women wound up with health problems, including a rare cancer of the reproductive tract. Although with obesogens, the end point is weight gain, not cancer, both effects follow a comparable delay pattern. “I think we're seeing very similar effects,” Newbold said.

After years of studying the effects of DES on the reproductive tracts of mice, Newbold realized that DES was also an obesogen. When she tabulated the food consumption of mice that had become obese after exposure to DES, she found they did not eat significantly more than unexposed animals. Nor were the obese mice unusually sedentary. When cages were crisscrossed with light beams that the animals would break whenever they moved, she found them to be just as active as normal-weight control mice.

Obviously, the changes occur at a deeper metabolic level than appetite and exercise.

The science is so new that health officials are just beginning to come to grips with it. Conventional regulatory toxicology tests may be “completely blind” to such effects, said John Peterson Myers of Environmental Health Sciences, a nonprofit environmental group in Charlottesville, Va.

For example, tests in mice have found DES is an obesogen at doses of 1 part per billion. But at 100 parts per billion, it retards growth. The drug itself, now banned, is only of laboratory interest. But if other chemicals behave similarly, traditional high-dose tests might be producing completely erroneous results.

Double whammy

Vom Saal is particularly concerned about a double whammy such chemicals might administer to certain types of low-birth-weight babies. Such babies, he said, are common among those born to older mothers or women undergoing infertility treatments.

The difficulties these women have becoming pregnant may mean their babies experience reduced placental blood flow, which programs them to have a lifelong thrifty metabolism. Just like nicotine-exposed babies, they tend to be underweight at birth, then surge in weight to catch up . . . and keep surging.

“A prenatal world of under-nutrition programs (them) to expect a postnatal world of under-nutrition,” vom Saal said. When instead they hit a world of fast-food super-meals, these children aren't going to fare well. “They are likely to become obese even eating a diet the average person would be able to get away with,” vom Saal said.

Add an obesogen to the mix and the effect might be overwhelming, he said. “Obesity is not just a matter of eating too much and exercising too little. You come into this world with a legacy set into your genes by environmental and chemical events in early life.”

Many scientists believe that the chemicals of greatest concern fall into an increasingly scrutinized class known as endocrine disruptors. Like DES, they interfere with (or mimic) the body's natural hormones, particularly estrogens. The effects can be potent at doses comparable to the body's natural hormone levels.

“I would advise my kids and grandkids to avoid any compound that they had any idea had endocrinic or estrogenic action,” said Newbold. These would include bisphenol A, many cosmetics and lotions, and some pesticides. “There's no way you can avoid everything, but at least you can avoid the things you know about.”

That, she added, includes soy formula for infants. “Breast-feed,” she said.

As for bisphenol A, vom Saal advises pregnant women to avoid canned foods. They should also avoid heating food in plastics, he said, even in “microwave-safe” containers, because bisphenol A appears to be a chemical that can be emitted under heat.

The Society of the Plastics Industry, a trade association representing many of the largest producers, disagrees. On its Web site, it categorizes fears of microwave-safe plastics as an urban myth, noting that the U.S. Food and Drug Administration extensively evaluated the safety of these products before allowing them onto the market.

“The FDA does acknowledge that substances in plastics can leach into food when the plastic containers are used incorrectly,” the association states. “However, the FDA does not consider this to be a significant risk to humans.”

Steven Hentges, executive director of a bisphenol A subsection of the American Chemistry Council, another trade association, concurred. “Bisphenol A has been evaluated by governmental bodies worldwide, and every one supports the assertion that bisphenol A is not a risk to human health, especially at these very low levels,” he said. Nor, he added, have the vast majority of prior studies found any effect on body weight.

Whatever may eventually be decided by the next set of experiments, the scientists don't want obesogen-exposed people to feel they have no hope of controlling their weight.

“It's not that you're doomed for life,” Blumberg said. “The point is that we're making it more difficult to not become obese by exposing ourselves to chemicals that reprogram our metabolism.”

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