肥胖新解釋(環境因素):Obesogens:An Environmental Link to Obesity

全文: published online in the journal Environmental Health Perspectives(Environ Health Perspect 120:a62-a68. http://dx.doi.org/10.1289/ehp.120-a62)

http://ehp03.niehs.nih.gov/article/fetchArticle.action?articleURI=info%3Adoi%2F10.1289%2Fehp.120-a62

Obesity has risen steadily in the United States over the past 150 years,¹ with a marked uptick in recent decades.² In the United States today more than 35% of adults³ and nearly 17% of children aged 2–19 years are obese.⁴ Obesity plagues people not just in the United States but worldwide, including, increasingly, developing countries.⁵ Even animals—pets, laboratory animals, and urban rats—have experienced increases in average body weight over the past several decades,⁶ trends not necessarily explained by diet and exercise. In the words of Robert H. Lustig, a professor of clinical pediatrics at the University of California, San Francisco, “[E]ven those at the lower end of the BMI [body mass index] curve are gaining weight. Whatever is happening is happening to everyone, suggesting an environmental trigger.”⁷

Many in the medical and exercise physiology communities remain wedded to poor diet and lack of exercise as the sole causes of obesity. However, researchers are gathering convincing evidence of chemical “obesogens”—dietary, pharmaceutical, and industrial compounds that may alter metabolic processes and predispose some people to gain weight.^8,9

Obesity is rising steadily around the world. Convincing evidence suggests that diet and activity level are not the only factors in this trend—chemical “obesogens” may alter human metabolism and predispose some people to gain weight. Fetal and early-life exposures to certain obesogens may alter some individuals’ metabolism and fat-cell makeup for life. Other obesogenic effects are linked to adulthood exposures.

Joseph Tart/EHP; woman: gokhanilgaz/iStockphoto; fat cells: David M. Phillips/Photo Researchers, Inc.; fetal development cycle: Dragana Gerasimoski/Shutterstock.com; french fries: Richard Peterson/Shutterstock.com

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A Growing List of Potential Obesogens

Obesity is strongly linked with exposure to risk factors during fetal and infant development.¹⁵ “There are between fifteen and twenty chemicals that have been shown to cause weight gain, mostly from developmental exposure,” says Jerry Heindel, who leads the extramural research program in obesity at the National Institute of Environmental Health Sciences (NIEHS). However, some obesogens have been hypothesized to affect adults, with epidemiologic studies linking levels of chemicals in human blood with obesity²⁴ and studies showing that certain pharmaceuticals activate PPARγ receptors.^15,25

Chemical pesticides in food and water, particularly atrazine and DDE (dichlorodiphenyldichloroethylene—a DDT breakdown product), have been linked to increased BMI in children and insulin resistance in rodents.^26,27 Certain pharmaceuticals, such as the diabetes drug Avandia® (rosiglitazone), have been linked to weight gain in humans and animals,^9,17 as have a handful of dietary obesogens, including the soy phytoestrogen genistein²⁸ and monosodium glutamate.¹⁵

Most known or suspected obesogens are endocrine disruptors. Many are widespread,²⁹ and exposures are suspected or confirmed to be quite common. In one 2010 study, Kurunthachalam Kannan, a professor of environmental sciences at the University at Albany, State University of New York, documented organotins in a designer handbag, wallpaper, vinyl blinds, tile, and vacuum cleaner dust collected from 24 houses.³⁰ Phthalates, plasticizers that also have been related to obesity in humans,³¹ occur in many PVC items as well as in scented items such as air fresheners, laundry products, and personal care products.

One of the earliest links between human fetal development and obesity arose from studies of exposure to cigarette smoke in utero.^32,33 Although secondhand-smoke exposure has decreased by more than half over the past 20 years, an estimated 40% of nonsmoking Americans still have nicotine by-products in their blood, suggesting exposure remains widespread.³⁴ Babies born to smoking mothers are frequently underweight, but these same infants tend to make up for it by putting on more weight during infancy and childhood.³⁵ “If a baby is born relatively small for its gestational age, it tries to ‘play catch-up’ as it develops and grows,” explains Retha Newbold, a developmental biologist now retired from the NTP.

This pattern of catch-up growth is often observed with developmental exposure to chemicals now thought to be obesogens, including diethylstilbestrol (DES), which Newbold spent the last 30 years studying, using mice as an experimental model. Doctors prescribed DES, a synthetic estrogen, to millions of pregnant women from the late 1930s through the 1970s to prevent miscarriage. The drug caused adverse effects in these women’s children, who often experienced reproductive tract abnormalities; “DES daughters” also had a higher risk of reproductive problems, vaginal cancer in adolescence, and breast cancer in adulthood.³⁶ Newbold discovered that low doses of DES administered to mice pre- or neonatally also were associated with weight gain,³⁷ altered expression of obesity-related genes,^38,39 and modified hormone levels.^38,39

“What we’re seeing is there’s not a difference in the number of fat cells, but the cell itself is larger after exposure to DES,” Newbold says. “There was also a difference in how [fat cells] were distributed—where they went, how they lined up, and their orientation with each other. The mechanism for fat distribution and making fat cells are set up during fetal and neonatal life.”

High-Profile Exposures 

Animal studies have also implicated another suspected obesogen: bisphenol A (BPA), which is found in medical devices, in the lining of some canned foods, and in cash register receipts.⁴⁰ “BPA reduces the number of fat cells but programs them to incorporate more fat, so there are fewer but very large fat cells,” explains University of Missouri biology professor Frederick vom Saal, who has studied BPA for the past 15 years. “In animals, BPA exposure is producing in animals the kind of outcomes that we see in humans born light at birth: an increase in abdominal fat and glucose intolerance.”

Many endocrine disruptors exhibit an inverted U-shaped dose–response curve, where the most toxic response occurs at intermediate doses.⁴¹ However, in a recent unpublished study, vom Saal found that BPA affected rodent fat cells at very low doses, 1,000 times below the dose that regulatory agencies presume causes no effect in humans, whereas at higher doses he saw no effect. Receptors typically respond to very low levels of hormone, so it makes sense that they may be activated by low levels of an endocrine mimic, whereas high levels of a chemical may actually cause receptors to shut down altogether, preventing any further response.⁴¹ This is known as “receptor downregulation.” As a result, some endocrine disruptors have greater effects at low than at high doses; different mechanisms may be operating.¹⁵

Still another widespread obesogen is perfluorooctanoic acid (PFOA), a potential endocrine disruptor and known PPARγ agonist.⁴² “Pretty much everyone in the U.S. has it in their blood, kids having higher levels than adults, probably because of their habits. They crawl on carpets, on furniture, and put things in their mouth more often,” explains NIEHS biologist Suzanne Fenton. PFOA is a surfactant used for reduction of friction, and it is also used in nonstick cookware, Gore-Tex™ waterproof clothing, Scotchgard™ stain repellent on carpeting, mattresses, and microwavable food items. In 2005 DuPont settled a class-action lawsuit for $107.6 million after its factory outside Parker*****urg, West Virginia, tainted nearby drinking water supplies with PFOA.⁴³ In December 2011 an independent science panel found the first “probable link” between PFOA and a human health outcome, pregnancy-induced hypertension⁴⁴ (for more information, see “Pregnancy-Induced Hypertension ‘Probably Linked’ to PFOA Contamination,” p. A59 this issue⁴⁵).

Fenton studied how PFOA levels similar to those in the tainted drinking water affected the hormone levels and weight of rodent offspring exposed in utero.⁴⁶ “We gave pregnant mice PFOA only during pregnancy. It has a long half-life, so it hangs around during lactation and gets delivered in milk to babies,” Fenton says. “Once the offspring reached adulthood, they became obese, reaching significantly higher weight levels than controls.”

Exposed offspring also had elevated levels of leptin, a hormone secreted by adipose tissue that affects appetite and metabolism. Leptin normally suppresses appetite, but obese people and animals have elevated leptin levels, leading researchers to suspect the brain can become resistant to its effects.⁴⁷ Fenton did not observe weight gain when mice were exposed to PFOA as adults, although her team did find abnormalities in the uterus and mammary gland in exposed adults.

Eye on Prevention 

If exposure during pregnancy predisposes people to gain weight, can diet and exercise ultimately make any difference? Blumberg does not consider the situation hopeless. “I would not want to say that obesogen exposure takes away free will or dooms you to be fat,” he says. “However, it will change your metabolic set points for gaining weight. If you have more fat cells and propensity to make more fat cells, and if you eat the typical high-carbohydrate, high-fat diet we eat [in the United States], you probably will get fat.”

Blumberg postulates that the effects of early-life exposure are irreversible, and those people will fight a life-long battle of the bulge. However, if such people reduce their exposure to obesogens, they will also reduce health effects that may arise from ongoing adulthood exposures. Blumberg believes it’s good to reduce exposure to all kinds of endocrine-disrupting chemicals. “Eat organic, filter water, minimize plastic in your life,” he says. “If there’s no benefit and some degree of risk, why expose yourself and your family?”

Heindel hopes the NIH’s new grant-making effort will yield important discoveries. “It’s a very new field, and people are always skeptical of new fields,” he says. “It’s up to us to get more data to show that chemicals are actually interfering with the endocrine system that controls weight gain and metabolism. And there’s still the question of how important is this to humans. We’re never going to know until we get more data.”

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