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New Mechanisms and Chemicals Copyedited by: OUP MINI REVIEW Environmental Obesogens and Their Impact on Susceptibility to Obesity: New Mechanisms and Chemicals Riann Jenay Egusquiza1,2 and Bruce Blumberg1,2,3 Downloaded from https://academic.oup.com/endo/article-abstract/161/3/bqaa024/5739626 by guest on 01 May 2020 1Department of Developmental and Cell Biology, University of California Irvine, Irvine, California 92697- 2300; 2Department of Pharmaceutical Sciences, University of California Irvine, Irvine, California 92697; and 3Department of Biomedical Engineering, University of California Irvine, Irvine, California 92697 ORCiD numbers: 0000-0002-6731-1087 (R. J. Egusquiza); 0000-0002-8016-8414 (B. Blumberg). The incidence of obesity has reached an all-time high, and this increase is observed worldwide. There is a growing need to understand all the factors that contribute to obesity to effectively treat and prevent it and associated comorbidities. The obesogen hypothesis proposes that there are chemicals in our environment termed obesogens that can affect individual susceptibility to obesity and thus help explain the recent large increases in obesity. This review discusses current advances in our understanding of how obesogens act to affect health and obesity susceptibility. Newly discovered obesogens and potential obesogens are discussed, together with future directions for research that may help to reduce the impact of these pervasive chemicals. (Endocrinology 161: 1–14, 2020) Key Words: obesity, obesogen, endocrine disrupting chemicals, EDCs, transgenerational, adipogenesis besity is a pandemic that has reached worldwide diseases, and cancers, and have contributed to approxi- O proportions, affecting essentially every country mately 4 million deaths worldwide between 1980 and (1). The most dramatic increase in obesity incidence has 2015 (3). There is an urgent need to understand all the occurred over the past 5 decades. Approximately 39.6% factors contributing to obesity to best implement ef- of US adults were characterized as obese in 2016, com- fective prevention and treatment approaches that have pared to 13.4% in 1980 (2). Even more alarming, the so far proved elusive. incidence of obesity in children has also been increasing, with 18.5% of US children being characterized as obese in 2016, compared to just 4% before 1980 (2). In some The Obesogen Hypothesis countries, the prevalence of childhood obesity exceeds that of adults (3). Obesity and high body mass index The predominant medical explanation continues to be (BMI) are not just cosmetic concerns, but are also as- that obesity is the result of a simple imbalance between sociated with comorbidities such as increased risk excessive calorie intake and insufficient energy expend- for heart disease, type 2 diabetes and other metabolic iture—the energy balance or “calories in, calories out” ISSN Online 1945-7170 Abbreviations: AhR, aryl hydrocarbon receptor; BMI, body mass index; BPA, © Endocrine Society 2020. bisphenol A; BPF, bisphenol F; BPS, bisphenol S; CAR, constitutive androstane This is an Open Access article distributed under the terms of the Creative Commons receptor; DBT, dibutyltin; DDT, dichlorodiphenyltrichloroethane; DEHP, di-2- Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits ethylhexyl phthalate; DOSS, dioctyl sulfosuccinate; EDCs, endocrine-disrupting unrestricted reuse, distribution, and reproduction in any medium, provided the chemicals; HbAA, hemoglobin adducts of acrylamide; HbGA, hemoglobin ad- original work is properly cited. ducts of glycidamide; isoDMBs, isodirectionally differentially methylated blocks; Received 10 January 2020. MEHP, mono-2-ethylhexyl phthalate; MSCs, mesenchymal stem cells; NHANES, Accepted 13 February 2020. National Health and Nutrition Examination Survey; PPARγ, peroxisome prolifer- First Published Online 18 February 2020. ator–activated receptor γ; PVC, polyvinyl chloride; RXR, retinoid X receptor; TBT, Corrected and Typeset 7 March 2020. tributyltin; WAT, white adipose tissue. doi: 10.1210/endocr/bqaa024 Endocrinology, March 2020, 161(3):1–14 https://academic.oup.com/endo 1 Copyedited by: OUP 2 Egusquiza and Blumberg Environmental Obesogens Endocrinology, March 2020, 161(3):1–14 model. However, recent studies have demonstrated that and its heterodimeric partner, the 9-cis retinoid X re- this simple paradigm cannot explain the increase in ceptor (RXR), in vitro (21, 22), and lead to increased BMI seen in recent years. A study analyzing National adiposity in vivo (22). The identification of chemicals Health and Nutrition Examination Survey (NHANES) that activated PPARγ to promote adipocyte differenti- data compared BMI between US adults in 1988 and ation and white adipose tissue (WAT) accumulation led 2006 and found a 2.3-kg/m2 increase in adult BMI in to the coining of the term obesogen (23). 2006 compared with 1988, even at the same amount Obesogens were defined functionally as chemicals of caloric intake and energy expenditure (4). Moreover, that lead to increased WAT accumulation, in vivo, after the quality of carbohydrate calories consumed (high vs exposure. The environmental obesogen hypothesis holds low glycemic load) appears to be more important than that obesogen exposure is an under-recognized and Downloaded from https://academic.oup.com/endo/article-abstract/161/3/bqaa024/5739626 by guest on 01 May 2020 the total quantity of calories consumed (5, 6). Genetics understudied factor in the obesity pandemic (reviewed in is widely believed to be associated with obesity; how- 23, 24). Although the obesogen hypothesis was initially ever, known gene variants can explain only 2.7% of the controversial, many chemicals known to be obesogenic individual variation in BMI (7). Therefore, the 2 most in animal models are also associated with increased commonly given explanations—genetics and energy obesity prevalence, BMI, and body weight in humans balance—cannot fully explain the substantial increases (9). Research in this area has burgeoned and numerous in obesity incidence observed worldwide. recent reviews have summarized aspects of obesogen Multiple environmental factors can affect obesity research (eg, 8, 18, 25, 26). It was subsequently recog- susceptibility (reviewed in 8, 9). These include the nized that obesogens may have more diverse effects on gut microbiome composition (10, 11), stress (12), metabolism than just contributing to obesity; although, and disrupted circadian rhythms (13), to name a few. obesity may be a key contributor to such effects. These Environmental stressors experienced during fetal devel- include type 2 diabetes, nonalcoholic fatty liver disease, opment have significant impacts on obesity susceptibility and the central control of metabolism. Thus, it can be later in life. For example, mothers who were in their first argued that most obesogens are a subset of a larger class and second trimester of pregnancy during the Dutch of chemicals termed metabolism-disrupting chemicals, Hunger Winter of 1944 to 1945 gave birth to children not all of which are obesogens (reviewed in 9, 27). Here who were predisposed to obesity later in life compared we summarize what is known about the mechanisms to mothers not exposed to famine during pregnancy (14). underlying obesogen action, discuss newly identified Maternal smoking during pregnancy was also shown to obesogens and potentially obesogenic chemicals and lead to a predisposition toward obesity later in life for propose important areas for future research. prenatally exposed children (reviewed in 15). In 2003, Jerry Heindel put endocrine-disrupting Classic Effects and Mechanisms of chemicals (EDCs) and obesity on the same map for the Obesogens first time (16). His idea followed from a proposal ori- ginally made by Paula Baillie-Hamilton that increased Obesogens affect the differentiation of white adipo- chemical usage since World War II was responsible for cytes, in vitro, and the storage of fat, in vivo, in mul- the rapid increase in obesity over the same time period tiple model organisms (reviewed in 8, 9)(Fig. 1). We (17). Although it was not justifiable to link increased distinguish bona fide obesogens that induce increased chemical use, per se, to obesity, Heindel’s proposal that WAT weight, in vivo, from potential obesogens that EDCs might be influencing obesity was reasonable be- can induce adipogenesis, in vitro, but have not yet been cause nearly every aspect of the control of appetite, sa- demonstrated to induce WAT accumulation in vivo. tiety, metabolism, and fat storage is regulated by the Numerous potentially obesogenic compounds have been endocrine system. Heindel’s proposal eventually ignited identified using in vitro assays that assess the ability of research in the area of obesity among researchers al- candidate chemicals to promote differentiation of es- ready working on EDCs (reviewed in 18). tablished cell lines such as 3T3-L1 preadipocytes (28, The idea of EDCs as factors in obesity did not crys- 29) or primary mouse and human multipotent mesen- tallize until it was recognized that certain EDCs could chymal stromal stem cells (also known as mesenchymal activate nuclear hormone receptors important for the stem cells or MSCs) into mature adipocytes (29, 30). development of white adipocytes, such as peroxisome Many chemicals that promote differentiation of white proliferator–activated receptor γ (PPARγ) (19). Further adipocytes in these assays activate PPARγ and/or RXR support came from the findings that EDCs such as (29, 30). This
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