Expert Reviews ajog.org Obesogens: an emerging threat to public health Amanda S. Janesick, PhD; Bruce Blumberg, PhD Endocrine disrupting chemicals fi The eld of endocrine disruption Endocrine disrupting chemicals (EDCs) are defined as exogenous chemicals, or mixtures is historically rooted in reproductive of chemicals, that can interfere with any aspect of hormone action. The field of endocrine endocrinology and wildlife biology. disruption is historically rooted in wildlife biology and reproductive endocrinology where Endocrine disrupting chemicals (EDCs) EDCs are demonstrated contributors to infertility, premature puberty, endometriosis, and fi are de ned as exogenous chemicals other disorders. Recently, EDCs have been implicated in metabolic syndrome and (including pharmaceuticals), or mixtures obesity. Adipose tissue is a true endocrine organ and, therefore, an organ that is highly of chemicals, that can interfere with any 1 susceptible to disturbance by EDCs. A subset of EDCs, called “obesogens,” promote aspect of hormone action. One poster adiposity by altering programming of fat cell development, increasing energy storage in child EDC, diethylstilbestrol (DES), was fat tissue, and interfering with neuroendocrine control of appetite and satiety. Obesity prescribed by obstetricians throughout adds more than $200 billion to US healthcare costs and the number of obese individuals the mid-20th century with the aim of continues to increase. Hence, there is an urgent, unmet need to understand the helping women avoid pregnancy 2 mechanisms underlying how exposures to certain EDCs may predispose our population complications. Regrettably, children to be obese. In this review, we discuss the history of obesogen discovery from its origins born from DES-treated mothers were at in reproductive biology to its latest role in the transgenerational inheritance of obesity in higher risk for clear cell adenocarcinoma, mice. We discuss the development of adipose tissue in an embryo, maintenance of infertility, miscarriage, ectopic preg- 3-6 adipocyte number in adults, how EDC disruption programs stem cells to preferentially nancy, and breast cancer. The words make more adipocytes, the mechanisms by which chemicals can permanently alter the “ ” endocrine disruptor did not enter our germline epigenome, and whether there are barriers to EDCs in the gametes. scientific literature until 1993.7 This was long after the first DES baby was diag- Key words: adipogenesis, endocrine disruptors, metabolic disruptors, obesogens, nosed8 and even longer since an transgenerational obesity accidental polychlorinated biphenyl exposure in cooking oil had contributed to cognitive decline in offspring in 9 declining male sperm counts were organ and, therefore, susceptible to Japan. Some of the most widely studied attributed to environmental chem- chemical disturbance. The endocrine EDCs are chemicals, such as DDT, that icals.11,12 Today, EDCs are well known property of adipose tissue further alter estrogen and androgen homeostasis to be associated with early puberty, implied that disruption could contribute in wildlife and contribute to reproductive infertility, and reproductive dysfunctions to systemic diseases beyond obesity, such endpoints such as sex reversal and/ 13-16 10 later in life in humans and animals. as diabetes, infertility, and cancer. EDCs or sterility in marine animals. In have now found a place distinct from the United States, media coverage Adipose tissue as an endocrine organ reproductive biology and entered the fi surrounding EDCs intensi ed when At about the same time that reproductive field of metabolic syndrome and obesity. biologists and toxicologists became This subset of EDCs, called “obesogens,” aware of EDCs, adipose tissue was only or metabolic disruptors,21 promote From the Departments of Developmental and beginning to become accepted as an adiposity by altering programming of fat Cell Biology (Drs Janesick and Blumberg) and endocrine/paracrine organ (reviewed cell development (adipogenesis), Pharmaceutical Sciences (Dr Blumberg), 17,18 University of California, Irvine, Irvine, California. in ), let alone an organ that could be increasing energy storage in fat tissue, fi Received Sept. 11, 2015; revised Dec. 11, subject to disruption. The identi cation and interfering with neuroendocrine 2015; accepted Jan. 22, 2016. of fat as an endocrine organ was largely control of appetite and satiety in exper- 19 Bruce Blumberg is a named inventor on U.S. instigated by the discovery of leptin and imental animals and, presumably, patents 5,861,274, 6,200,802, 6,815,168 and the master regulator of fat cell develop- humans. The obesogen field is still in its 7,250,273 related to PPARg. ment, the nuclear hormone receptor infancy, but it has numerous ramifica- This work was supported by a grant from NIH peroxisome proliferatoreactivated re- tions for prenatal and postnatal care and (ES023316-01). ceptor gamma (PPARg).20 Adipose tis- the control/prevention of obesity and Corresponding author: Bruce Blumberg, PhD. sue is highly connected to steroid metabolic syndrome. [email protected] hormones (estrogens, androgens, and 0002-9378/$36.00 glucocorticoids) and maintains a close Economic impact of obesogens ª 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2016.01.182 relationship with the immune system via Seventeen percent of American children adipokines (reviewed in17,18). aged 2e19 are now obese (95th Related editorial, page 555 As a result, the EDC field expanded to percentile on Centers for Disease include adipose as a bona fide endocrine Control and Prevention growth charts) MAY 2016 American Journal of Obstetrics & Gynecology 559 Expert Reviews ajog.org and 32% are overweight (85th results were negative. Instead, TBT can elicit permanent epigenetic changes percentile).22 More alarming is the rise bound to and activated the nuclear in an organism and whether exposure in obesity rates among children under hormone receptors PPARg and the occurs during a critical window of 2 years of age.23 Since it is improbable retinoid X receptor (RXR) from human, development (when germ cells are being that children in this age group are mouse, and frog with nanomolar affin- programmed) can determine if the consuming more food or exercising less ity, and frogs treated with TBT devel- effects of an obesogen will be transient than previous generations, it seems likely oped testes containing fat that replaced or permanent and transmitted that an altered in utero or postnatal testicular tissue.39 This was significant throughout multiple generations (dis- environment affects fat deposition dur- because PPARg and RXR function as a cussed below).50,51 Therefore, EDCs can ing development. Obesity adds more heterodimer to promote adipose differ- have a direct effect on a particular target than $200 billion to US healthcare costs, entiation and lipid storage.40 In mice, tissue via a known mechanism of action and the number of obese individuals prenatal exposure to TBT led to and can also cause widespread, some- continues to increase.22 In the European offspring with an increased propensity to times subtle effects on multiple organ Union (EU), EDCs contribute V157 make fat cells at the expense of bone41 systems that ultimately promote obesity billion per year (a conservative mea- and showed increased adiposity at 10 in the exposed individual and in subse- surement) to the cost of human weeks of age.39 TBT exposure during quent generations. disease,24 with DDE, phthalates, and puberty led to weight gain, insulin bisphenol A (BPA) exposures specifically resistance, increased leptin, and fatty Developmental origin of adipose contributing over V18 billion per year to liver in male mice.42 Structural studies tissue and susceptibility to EDC adult and childhood obesity and dia- confirmed that TBT possesses nano- disruption betes.25 Given weaker regulations of molar binding affinity for RXR, whereas Adipogenesis begins in the 14th week of EDCs in the United States vs the EU,26 a related organotin, triphenyltin, bound human gestation52 and continues during the economic cost is likely to be pro- both PPARg and RXRa avidly.43,44 the early postnatal period.53 Adipose portionally greater in the United States. Organotins still remain the only obes- tissue turnover in humans persists Hence, there is an urgent, unmet need to ogens for which a molecular mechanism through childhood and adolescence, understand the mechanisms underlying has been delineated. then levels off at about 10% renewal per how EDC exposures can predispose our year in adulthood.53 This phenomenon population to be obese. Evidence supporting the existence is mostly independent of body mass in- of obesogens dex, as weight gain/loss in adults is pre- A brief history of obesogens Numerous other chemicals that may dominantly due to changes in adipocyte In the 1960s, organotins like tributyltin be obesogens have been identified (see size.53,54 Adult mice that are challenged (TBT) were found to be effective in Table 43.1 in Janesick et al45). The type with a high-fat diet accumulate fat by preventing biofouling on ship hulls of evidence supporting the obesogenicity hypertrophy (increasing fat cell size) in by marine invertebrates and rapidly of individual chemicals varies. Some most adipose depots, with the exception replaced copper as a biocide on ships, studies are correlative; for example, of gonadal (visceral) fat, which possesses underwater instruments, and oil pipe- chlorinated persistent organic pollutants