Curr Envir Health Rpt (2014) 1:333–340 DOI 10.1007/s40572-014-0026-8 MECHANISMS OF TOXICITY (CJ MATTINGLY, SECTION EDITOR) The Obesogen Hypothesis: Current Status and Implications for Human Health Jerrold J. Heindel & Thaddeus T. Schug Published online: 20 September 2014 # Springer International Publishing AG (outside the USA) 2014 Abstract Obesity and diabetes have overtaken smoking as agreed upon that this obesity epidemic is the product of poor the number 1 preventable health determinate in the United nutrition and lack of exercise. However, obesity is a complex States. In its basic form, obesity is due to disruptions of the endocrine disease caused by disruption of many control sys- endocrine systems that control food intake, satiety, and meta- tems involving interaction between genetic and environmental bolic rate. Recent studies have identified a subclass of endo- cues such as nutrition, exercise, drugs, behavior, alterations in crine disrupting chemicals that interfere with hormonally reg- the microbiome, and exposure to environmental chemicals. ulated metabolic processes, especially during early develop- Genome wide association studies using large populations ment. These chemicals, called “obesogens,” may predispose have uncovered some 40 novel single nucleotide polymor- individuals to gain weight despite efforts to limit caloric intake phisms that are associated with increased body mass index and increase physical activity. Evidence suggests that chemi- (BMI), but together these genetic identifiers account for less cal exposures early in life can predispose individuals to weight than 5 % of the incidence of obesity [2]. Indeed, there are no gain through programming changes, which may enhance dys- known genetic mechanisms that can explain the remarkable functional eating behaviors later in life. This review examines changes in body composition over the past 20 years. These the latest research on the obesogen hypothesis and its under- facts provide real biological plausibility to the notion that pinnings in the Developmental Origins of Heath and Disease environmental exposures interfere with endocrine signaling, model. We provide examples of known and suspected disrupt hormonally regulated metabolic processes, and are obesogens, and evidence of their general mechanisms of ac- contributing to increased rates of obesity. tion. The research reviewed here provides a solid foundation Recent studies have identified a subclass of endocrine of knowledge from which health scientists may draw from and disrupting chemicals (EDCs), which can disrupt hormonally build upon to inform their research and decision-making. regulated metabolic processes, especially during early devel- opment [3]. These chemicals, called “obesogens,” may pre- dispose individuals to gain weight despite efforts to limit Keywords Obesity . Endocrine . Endocrine disruptor . caloric intake and increase physical activity [4]. Plausible Obesogen . Developmental origins of health and disease evidence also suggests that chemical exposures early in life (DOHaD) can predispose individuals to weight gain through changes in metabolic ‘set-points’, and enhance dysfunctional eating be- haviors later in life. This chapter reviews the latest research on Introduction the obesogen concept, including discussions of susceptibility and the Developmental Origins of Heath and Disease Humans in both developed and developing countries are (DOHaD) model. gaining weight faster than they have in the past [1]. It is widely Conventional wisdom posits that obesity is strictly an : energy balance disorder caused by excess calorie intake J. J. Heindel (*) T. T. Schug coupled with a sedentary lifestyle. It is now clear that this Division of Extramural Research and Training, Population Health explanation is far too simplistic to explain all cases of obesity Branch, National Institute of Environmental Sciences, Research Triangle Park, NC, USA as there are data showing that in situations where there is equal e-mail: [email protected] access to food, only a subset of people become overweight [5]. 334 Curr Envir Health Rpt (2014) 1:333–340 Obese people tend to eat more high fat and high sugar foods that the epigenetic system is responsive to environmental and continue to eat even when they are not hungry, suggesting stimuli, such as drugs of abuse, diet or chemical exposures differences in brain chemistry, which may predispose some [16]. Animal studies indicate that many changes to our epige- individuals to gain weight [6]. Recent studies show that the netic landscape are likely to be permanent and can be mani- number of overweight infants under 6 months old increased fested in multiple generations, even if the original chemical more than 70 % from 1980 to 2001 [7]. The puzzling rise in insult is no longer present (Fig. 1)[17]. infant weight and body mass appears to begin at birth and There are now a variety of environmental chemicals, in- cannot be explained by changes in diet and exercise habits cluding those that activate peroxisome proliferator-activated among the infants. In the US 12.4 % of kindergarten children receptor gamma (PPARγ), such as tributyltin (TBT), estro- are obese and another 14.9 % are overweight. Indeed, data genic chemicals such as bisphenol A (BPA), and chemicals show that 87 % of obese 8th graders had a BMI above the 50th acting through other mechanisms such as lead, percentile in kindergarten and 75 % had been above the 70th perfluoroctanoic acid, phthalates and tobacco smoke (a highly percentile, whereas only 13 % of children that were normal complex mixture of chemicals), that have been shown to lead weight were overweight in kindergarten [8]. These data point to weight gain later in life [18–21]. New advances relative to to infancy or early childhood as an important time in estab- the obesogen hypotheses include the delineation of emerging lishing body weight regulation and increased susceptibility for chemical obesogens, the development of nuclear receptor- individuals to gain weight later in life. activating screens to detect new obesogens, and mechanisms Early development is a time period in which an organism is of action of obesogens including epigenetic and critically sensitive to perturbations such as alterations in hor- transgenerational effects, plus new data linking exposures to mone levels that can lead to changes in gene expression and obesity in human populations. Recent general reviews related protein levels, which persist as tissues and organs develop [9]. to the obesogen hypothesis have reviewed potential mecha- This increased sensitivity is also a consequence of incomplete nisms by which environmental chemicals can cause obesity development or partial function of protective mechanisms (Fig. 2)[13, 21–24]. such as DNA repair, immunity, xenobiotic metabolism, and the blood brain barrier in the fetus or newborn compared with older individuals. Adverse perturbations in the metabolic sys- Chemical Obesogens tem of the developing organism translate to a higher risk of metabolic and hormonal disorders later in life [10]. Thus, the Bisphenol A DOHaD hypothesis provides a framework to assess the effects of exposure to diverse factors, such as nutrition and There has been a great deal of interest in BPA because of its obesogenic chemicals, on long-term health. Many disease high production volume and widespread commercial use. patterns linked to poor nutrition, such as elevated risks for Numerous animal studies have shown a link between BPA cardiovascular disease, diabetes, and obesity, have also been exposure during development and increased body weight and linked to maternal chemical exposure [11••], suggesting a adiposity across the lifespan and it is presumed, although not common mechanism for chemical and nutritional stress that yet demonstrated, that these effects of BPA are mediated ultimately leads to long-term obesity in the offspring. through estrogen receptors [25, 26]. However, several other Altogether a confluence of factors including altered develop- studies have failed to find direct associations between BPA mental programming (in utero and the first few years of life), andweightgain[27–29], suggesting a need for more research followed by overnutrition, decreased activity, and additional to delineate the effects of BPA on metabolic systems including environmental exposures over the lifespan creates an impor- the importance of diet, animal species and strain, doses, and tant combination that is likely driving the obesity epidemic timing of exposures in the BPA effect on weight gain. [12••, 13]. Childhood and adolescence are also marked by Epidemiologic studies linking BPA exposure to weight gain continued maturation of key endocrine systems, including the are inconsistent overall, with the most significant associations major metabolic organs, and are, therefore, also likely suscep- observed in cross sectional analyses of NHANES data in the tible to chemical exposures that may alter developmental US [30]. Large prospective birth cohort studies are needed to programming. confirm and validate findings from cross sectional human At least part of the developmental programming of disease studies as well as findings in laboratory animals. and metabolic dysfunction is the result of alterations in the Several laboratory animal studies have demonstrated that epigenetic control of gene expression during development. BPA exposure can not only lead to increased body weight but Epigenetic modifications, such as DNA methylation and his- also can alter