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The BCERF program on the Cancer Risks of Environmental Chemicals in the Home and Workplace closed on March 31, 2010. No further updates will be made to this web site. Please go Cornell University’s eCommons web site to access BCERF’s archived research and educational materials (http://ecommons.library.cornell.edu/handle/1813/14300).

Vol. 14 Issue 1, Winter 2009

Chemicals With Obesogenic Action: An Emerging Area of Concern
The Ribbon 

By Barbour S. Warren, Ph.D., Research Associate, BCERF

Body weight results from the difference between energy intake from food and energy use in physical activity, and basic metabolism (energy used for daily body operations). However, while true, this statement is a simplification. Body weight regulation is quite complex, involving numerous signaling pathways and communication between many body systems/organs. This complexity is shown in animal studies that have defined nine types of causes of overweight and obesity. One new area of concern is that exposure to some chemical toxins both during and after early life development may affect body weight and contribute to obesity. An understanding of these chemicals and the different ways in which they might be acting is not yet well developed. One hypothesis is that exposure to these chemicals may have played a role in the recent and dramatic rise in obesity. This hypothesis is biologically possible but much more study is required before it can be assessed.

Obesity

Obesity (having too much body fat) has been called a “bad player” for a number of reasons. It is a significant risk factor for a number of cancers (including breast cancer), diabetes, cardiovascular disease and arthritis (1). Obesity sneaks up on people gradually, arising from gains of two to four pounds of weight each year (2). Studies in animals have shown nine types of obesity including neural (related to the nervous system), hormonal, drug/toxin, nutritional, environmental, seasonal, genetic, viral, and undetermined (3). Excess body fat is also hard to lose. Our bodies actively protect their fat stores and fat or weight lost is usually largely regained (4). About 72 million adults in the US (one third of the adult population) are currently considered obese.

The control of body weight is complex

How our bodies control their energy stores is very complex and not completely understood (5). The processes involved include the control of appetite, physical activity, basic metabolic rate, and the amount of fat tissue. The coordination of these processes requires organ-to-organ communication between the brain, muscle tissue, liver, stomach, intestines, pancreas, and fat tissues. This coordination uses many signaling agents. These chemical communicators include factors from fat itself, hormones from the liver, stomach, and intestines, and hormones acting in the brain, as well as responses resulting from memory, time of day, and what we see, smell, and taste. This level of complexity provides many targets for disruptive effects.

Chemicals with obesogenic actions

Scientists have recognized the existence of chemical exposures that promote obesity for a long time. Examples include the considerable weight gain seen with long-term use of some antipsychotic (6) and antiepileptic drugs (7), and after nicotine withdrawal following stopping smoking (8). Beyond these examples, this obesogenic effect of some chemicals has to some extent been ignored. Drug and chemical safety evaluations have focused on the more common end point of toxicity, weight loss rather than weight gain. This important oversight was pointed out in a recent review of the scientific literature that discussed many examples of weight gain reported in animal toxicity studies (9). Compounds leading to weight gain included organochlorine pesticides, organophosphate pesticides, carbamate pesticides, polychlorinated biphenyls (PCBs), polybrominated biphenyls (PBBs), phthalates, bisphenol A (BPA), heavy metals, and solvents. Although the necessary chemical dose and the extent of weight gain were not examined, these effects are potentially important. Recent studies have begun to evaluate the effect of some of these chemicals on weight gain.

Laboratory studies of obesogenic chemicals

Only a few chemicals with obesogenic action have been studied so far. Chemicals studied in some detail include: BPA, a building block for the synthesis of plastics; tributyltin, a pesticide added to marine paints; diethylstilbestrol (DES), a synthetic estrogen; and nonylphenol, a wastewater pollutant. Exposure to all of these compounds is common.

The ability of chemicals to promote obesity can be studied several ways. One direct but not definitive method is to examine the ability of chemicals to cause the formation of adipocytes (fat cells). Body fat tissue can be formed in two ways: by the creation of new fat cells and by the storage of more fat in existing and new fat cells. A number of cell lines have been developed for these evaluations (10). These cells are considered preadipocytes, or fat cells at an early stage of development. Differentiation or conversion of these early fat cells to mature fat cells is dramatic. It involves a single round of cell division, a change in cellular shape, and the accumulation of fat in the cells. This is not a definitive examination as it only examines one stage in the pathway to obesity (the formation and filling of fat cells). Tributyltin (11), BPA (12), nonylphenols (13), and phthalates (14) have all shown the ability to cause the formation of mature fat cells in this assay.

Studies in whole animals have also been used to evaluate a chemical’s obesogenic potential. In these studies, animals are fed a chemical over a long period of time while their weight is monitored and compared to control animals that have not received the chemical. This is a reliable test since it involves an entire animal, but sometimes effects on animal and humans do not agree. In contrast to what would have been predicted from the fat cell studies, animals fed tributyltin (15), BPA (16), nonylphenols (17), and phthalates (17) all lost weight. These results best support the idea that although these compounds can cause the generation of fat cells, they do not have this activity in whole adult animals.

Effects of these chemicals on the growth and development of animals have also been studied. This is especially important during the time of development of fat tissue. Two critical periods of fat tissue development are before birth and shortly after birth (10, 18). For studies of this type, pregnant animals are exposed to the chemical or their offspring are given the chemical just after birth. These studies have identified several chemicals that can lead to adult obesity following exposure during these critical developmental periods. Compounds with this effect include tributyltin (11, 19), BPA (20), and DES (21, 22). The effects of tributyltin and DES are best understood, and these compounds have been shown to interact directly with some of the cell pathways involved in fat development.

Human epidemiological studies

Epidemiological studies in humans have largely looked for associations between the levels of environmental chemicals within the body and obesity.

Two studies have used results from the National Health and Nutrition Examination Survey, which examined the levels of phthalates in 5149 participants (23, 24). Phthalates are chemicals mainly used as additives to plastics to increase their flexibility but are also found as additives to cosmetics, soaps, pesticides, paints and lubricants. They are known to be antiandrogenic (counteracting the effects of male hormones). Both of these studies examined associations between the levels of six phthalate breakdown products in urine and waist circumference (a measure of obesity) in men. They found an association between the phthalate levels and waist circumference. These studies were in agreement for all but one of the metabolites examined. One of these studies also examined another measure of the men’s body fat: body mass index (BMI). Similar effects of the metabolites were seen with BMI and waist circumference. Only one of the metabolites was active in women and girls. In addition, one of the metabolites that was inactive in men was linked to a decrease in BMI in girls. The phthalates are broken down in the body more quickly than some other chemicals; this raises the question of whether these studies were examining changing exposure levels. However, exposure to these compounds has been found by other researchers to be fairly regular, so that levels of phthalates in the body remain fairly constant (25). Much more study is needed to determine if these results show a cause and effect association between phthalates and obesity.

One study has examined dichlorodiphenyl-dichloroethylene, DDE, a highly stable metabolite of the once commonly used organochlorine pesticide DDT, to see whether there was an effect of prenatal exposures to DDE on later obesity (26). Earlier studies had measured the DDE levels in fish-eating women living in the area around Lake Michigan; 213 adult daughters of these women were assembled and their DDE exposure while they themselves were developing in the womb was estimated from an earlier study of their mothers. The daughters’ weights and levels of body fat (BMI) were measured to see if there was an association between body fatness and estimated DDE levels during the daughters’ development. The authors concluded that there was a link between the mothers’ DDE levels and the daughters’ body fat and that this link provided compelling evidence that other similar chemicals should also be studied.

Two studies examining PCBs and BMI found opposite results. One small study (53 participants from Quebec, Canada) reported no association between PCB levels in the blood plasma and BMI (27). In contrast, a larger study of a different population (335 Akwesasne Mohawks from New York State) reported an association between PCBs and BMI (28). Interpretation of these results is difficult, as PCBs tend to accumulate in fat tissue. Plasma PCB levels could merely result from the size of the participants’ fat reservoirs for the PCBs and have nothing to do with fat generation itself.

Conclusions

Results to date have shown that some chemicals have actions that can promote obesity. However, the research in this area is very limited. Needed research in this area should first ask: which compounds have obesogenic activity, what are the critical periods of exposure for different compounds, and what levels of exposure are required to produce this effect? While some have suggested that exposure to chemicals with obesogenic activity has contributed to the increase in obesity seen in the US, understanding of this effect is in its very infancy, and it is far too early to conclusively evaluate this hypothesis.

References

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