ReviewEnvironmental estrogens and obesity
Introduction
Obesity and overweight are quickly becoming a significant human health problem worldwide (Ogden et al., 2007, Oken and Gillman, 2003). The prevalence of obesity has risen dramatically in wealthy industrialized countries over the last 2–3 decades, but it is also on the rise in poorer underdeveloped nations. In the United States, the Center for Disease Control (CDC) reported in 2008 that obesity has reached epidemic proportions with more than 60% of adults being either obese or overweight (CDC, 2008). Not only is obesity a problem for adults, but it is of particular concern in children since most obese and overweight children grow up to be obese adults. The number of children and adolescents who are considered overweight or at risk for being overweight has increased similarly to adults (Ogden et al., 2002). Obesity has proven to be a challenge to treat effectively once it is established. Further, obesity and overweight are known to have adverse health effects, and to impact the risk and prognosis for a number of serious medical conditions such as Type 2 diabetes, hyperinsulinemia, insulin resistance, coronary heart disease, high blood pressure, stroke, gout, liver disease, asthma and pulmonary problems, gall bladder disease, kidney disease, reproductive problems, osteoarthritis, and some forms of cancer (Collins, 2005, Mokdad et al., 2003, Mokdad et al., 1999). Unfortunately, these illnesses are starting to be more frequently reported in obese and overweight children whereas in the past, these were diseases of older adults. Health professionals warn that the current generation of children may be the first in history to experience a shorter life expectancy than their parents due to the impact of obesity-related diseases.
Obesity is caused by a complex interaction between genetic, behavioral, and environmental factors. The most common causes are thought to be overeating high caloric fatty diets combined with a sedentary lifestyle which is imposed on a background of genetic predisposition for the disease. Although much interest has focused on these factors including the need to incorporate healthy foods in our diets and more exercise into our lifestyle, these factors cannot solely explain the alarming rise in obesity. Further, it remains puzzling why some people are more successful in dieting and loosing weight than others. Obesity is most definitely a multi-factorial disease. Although many of the causative factors remain unknown, health experts agree that since obesity is so difficult to treat, prevention becomes of the upmost importance.
Until the 1990s, fat cells or “adipocytes” were considered to be just storage depots for excess metabolic fuel. However, following the discovery of an adipocyte-derived hormone termed “leptin” that communicates energy reserve information from adipocytes to other organs of the body including the central nervous system, a new appreciation emerged that these “fat storage cells” actually function as an endocrine organ (Collins, 2005). Today it is well accepted that adipocytes have an endocrine function in addition to fat storage. Since the discovery of leptin, evidence has shown that adipocytes secrete many other cytokines and growth factors that play important roles in growth and differentiation of the organism, as well as, in the feedback of information to other endocrine organs. Considering the newly identified endocrine function of adipocytes and recognizing that their endocrine signaling pathways are established during perinatal development, it is of interest to us to investigate whether exposure to endocrine disrupting chemicals (EDCs), in particular those with estrogenic activity, during critical period of development, is related to obesity or any of its associated diseases including diabetes.
It is well established that many environmental chemicals can interfere with complex endocrine signaling pathways and cause adverse consequences in the developing organism (Bern, 1992, Colborn et al., 1996). Although concern initially focused on reproductive and carcinogenic effects, we now know that multiple organ systems are affected by EDCs including the cardiovascular and neuro-endocrine systems. Most recently, an association of environmental chemicals with the development of obesity has been proposed (Baillie-Hamilton, 2002, Heindel, 2003, Heindel and Levin, 2005, Newbold et al., 2008, Newbold et al., 2005, Newbold et al., 2007a, Newbold et al., 2007b, Newbold et al., 2007c) Mechanistic studies have further described the disruptive effects of environmental chemicals on normal adipocyte development, and homeostatic control over adipogenesis and early energy balance (Grun and Blumberg, 2006, Grun et al., 2006). Although uncertainties remain about the full extent of health consequences that follow exposure to environmental chemicals, especially low dose exposures that are relevant to the general population, we are just beginning to understand that the complexities and interactions of endocrine signaling mechanisms include adipocytes and weight controlling mechanisms.
Section snippets
The developmental origins of adult disease
The developing fetus and neonate are uniquely sensitive and can be easily disturbed by exposure to chemicals with hormone-like activity (Bern, 1992). The protective mechanisms that are available to the adult such as DNA repair mechanisms, a fully competent immune system, detoxifying enzymes, liver metabolism, and the blood/ brain barrier are not fully functional in the fetus or neonate. Further, the developing fetus and neonate have an increased metabolic rate as compared to an adult which in
The developmental exposed DES animal model to study obesity
DES, a potent synthetic estrogen, was widely prescribed to pregnant women from the 1940s through the 1970s with the mistaken belief that it could prevent threatened miscarriages. It was estimated that a range of 2–8 million pregnancies worldwide were exposed to DES. Today, it is well-known that prenatal DES treatment resulted in a low but significant increase in neoplastic lesions, and a high incidence of benign lesions in both the male and female offspring exposed during fetal life. To study
Other environmental estrogens and EDCs role in obesity
In 2002, Baillie-Hamilton postulated a role for chemical toxins in the etiology of obesity by showing that the obesity epidemic coincided with the marked increase of industrial chemicals in the environment over the past 40 years (Baillie-Hamilton, 2002). She further speculated that the current obesity epidemic could not be explained solely by alterations in food intake and/or decrease in physical activity. She cited numerous studies where chemicals including pesticides, organophosphates,
Summary and conclusions
The data included in this review supports the idea that brief exposure, early in development to environmental chemicals with estrogenic activity, increases body weight gain with age and alters markers predictive of obesity in experimental animals. Epidemiology studies support the findings in experimental animals and show a link between exposure to environmental chemicals (such as PCBs, DDE, and persistent organic pollutants) and the development of obesity (Smink et al., 2008). Furthermore, the
Acknowledgments
This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. The authors gratefully acknowledge Dr. Terry Phillips, Division of Bioengineering and Physical Sciences, Office of Research Services, Office of the Director, NIH, DHHS, Bethesda, MD for the serum measurements. The authors would also like to thank Ms. Sherry Grissom for the microarray analysis of gene expression changes in the uterus following neonatal DES treatment and
References (43)
- et al.
Peroxisome proliferator-activated receptor gamma (PPARgamma) as a molecular target for the soy phytoestrogen genistein
J. Biol. Chem.
(2003) The association of the ratio of waist to hip girth with blood pressure, serum cholesterol and serum uric acid in children and youths aged 6–17 years
J. Chronic. Dis.
(1987)- et al.
The developmental origins of the metabolic syndrome
Trends Endocrinol. Metab.
(2004) - et al.
Environmental chemical tributyltin augments adipocyte differentiation
Toxicol. Lett.
(2005) - et al.
Bisphenol A in combination with insulin can accelerate the conversion of 3T3-L1 fibroblasts to adipocytes
J. Lipid Res.
(2002) Lessons learned from perinatal exposure to diethylstilbestrol (DES)
Toxicol. Appl. Pharmacol.
(2004)- et al.
Developmental exposure to endocrine disruptors and the obesity epidemic
Reprod. Toxicol.
(2007) - et al.
The epidemiology of obesity
Gastroenterology
(2007) - et al.
Low doses of bisphenol A and diethylstilbestrol impair Ca2 + signals in pancreatic alpha-cells through a nonclassical membrane estrogen receptor within intact islets of Langerhans
Environ. Health Perspect.
(2005) - et al.
The estrogenic effect of bisphenol A disrupts pancreatic beta-cell function in vivo and induces insulin resistance
Environ. Health Perspect.
(2006)
Chemical toxins: a hypothesis to explain the global obesity epidemic
J. Altern. Complement Med.
Fetal origins of adult disease: strength of effects and biological basis
Int. J. Epidemiol.
The Fragil Fetus
Our Stolen Future
Overview of clinical perspectives and mechanisms of obesity
Birth Defects Res. A Clin. Mol. Teratol.
Evidence for a role of developmental genes in the origin of obesity and body fat distribution
Proc. Natl. Acad. Sci. U.S.A.
Environmental obesogens: organotins and endocrine disruption via nuclear receptor signaling
Endocrinology
Endocrine-disrupting organotin compounds are potent inducers of adipogenesis in vertebrates
Mol. Endocrinol.
Endocrine disruptors and the obesity epidemic
Toxicol. Sci.
Developmental origins and environmental influences—Introduction NIEHS symposium
Birth Defects Res. A Clin. Mol. Teratol.
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