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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 and (including pharmaceuticals), or mixtures . 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, (DES), was fat tissue, and interfering with neuroendocrine control of 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 number in adults, how EDC disruption programs stem cells to preferentially nancy, and breast cancer. The words make more , the mechanisms by which chemicals can permanently alter the “ ” 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 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 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 , 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 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 metabolic syndrome. [email protected] hormones (estrogens, , 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 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, , and puberty led to weight gain, (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 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 higher capacity to expand by hyperplasia lines.27,28 Hardly a decade after organo- are associated with increased body (increasing fat cell number).54-56 We and tins were introduced, the first reports mass index and/or type II diabetes in others57 concluded from these studies of imposex in snails surfaced,29,30 and humans in cross-sectional epidemio- that increased adipogenesis during early subsequent studies identified TBT as logic studies.46 Other chemicals induce development permanently establishes an the causative agent.31-33 Given that snails adipogenesis in cells or activate PPARg, elevated fat cell number in adulthood. lack most vertebrate orthologs of sex but have not been tested in vivo.47,48 Exposure of adult animals to TBT in- steroid receptors (eg, androgen and Some EDCs have only been studied in creases fat mass, but it is not known progesterone receptors),34 this result did adults, while others predispose a devel- whether this effect is reversible or heri- not interest vertebrate developmental oping fetus to subsequent obesity.49 We table. Subsequent increases in body fat biologists until 2003, when TBT was reserve the designation as a bona fide are primarily derived from a hypertro- shown to masculinize female fish.35,36 obesogen for chemicals that can induce phic mechanism in the absence of The mechanism proposed was that increased fat mass in vivo. obesogen exposure. TBT inhibited action, thereby The mechanistic detail underlying Mesenchymal stem cells harvested preventing the biosynthesis of estradiol obesogen action can also range from from adipose tissue or bone marrow can from testosterone.37,38 limited to thorough. For example, the be induced to differentiate into fat, bone, Hypothesizing that TBT might func- crystal structure of TBT binding PPARg cartilage, and other lineages in culture,58 tion at a transcriptional level via sex and RXR has been solved, whereas although it is uncertain whether they steroid receptors, we tested whether TBT other obesogens such as bisphenol A have the same plasticity in vivo.59 could activate steroidal estrogen and may affect multiple numerous endo- Commitment to each of these lineages androgen receptors in cell culture. The crine pathways.49 Whether a chemical is largely mutually exclusive and

560 American Journal of Obstetrics & Gynecology MAY 2016 ajog.org Expert Reviews irreversible.60 Transformation of a histone modifications in the mesen- rat, reduced fertility in subsequent mesenchymal stem cell into an adipocyte chymal stem cell population.41,50,74 Such generations, including F3 (great-grand- requires initial commitment to the alterations will ultimately poise adipo- children) and F4 (great-great-grand- adipose lineage, followed by terminal genic genes to become more transcrip- children), that were not exposed to the differentiation into a mature adipocyte tionally active and osteogenic genes to be chemical.78 In a landmark study of (reviewed in61,62). The initial commit- transcriptionally silent during cellular humans from Sweden, it was demon- ment is mediated by various transcrip- differentiation. strated that food availability during the tion factors that function to sensitize prepubescent period (8e12 years old) cells to BMP signaling, repress osteo- Potential consequences of affected longevity and mortality from genic Wnt signaling, and promote obesogens on metabolic setpoint cardiovascular disease of that in- PPARg expression.63-67 Terminal differ- in humans dividual’s grandchildren.79 A single entiation is marked by an induction of Obese humans have more fat cells53 and winter of overeating could lead to a metabolic genes and adipokines associ- likely developed them early in life, by 6-year decrease in longevity of a prepu- ated with mature adipocytes. This step is mechanisms outlined above. We theo- bescent boy’s grandsons, but not grand- primarily controlled by PPARg and rize that adipogenic stimuli (such as daughters.79 Other examples of heritable CCAAT-enhancer-binding proteins obesogen exposure) received perinatally, effects of environmental chemicals on (C/EBP) -a,-b, and ed.68,69 Treatment or during adolescence, permanently in- obesity in rats have been demonstrated, of committed pre-adipocytes with an crease fat cell number, thereby creating albeit at relatively high doses. These “adipogenic cocktail” (glucocorticoids, an altered metabolic set point. If true, the compounds include components cAMP agonists, and insulin) increases implications are profound: The higher such as BPA, diethylhexyl and dibutyl expression of PPARg and C/EBP number of fat cells from the beginning of phthalates,80 a mixed hydrocarbon proteins, which establish a sustained life cannot be reduced by diet, exercise, mixture (jet fuel JP-8),81 and the once positive feedback loop.68,70,71 or even surgery.53 Visceral fat depot sizes widely used , DDT.82 Together with adipogenic cocktail, can be expanded in adults via prolifera- Pregnant F0 mice treated with low activation of PPARg via exogenous tion,54-56 but permanently decreasing doses of TBT in their drinking water ligands such as or TBT cell number by has not been produced offspring that had larger fat strongly promotes adipocyte differenti- documented. Rigorous and faithful depots, increased expression of adipo- ation and maintenance, together with adherence to a restrictive diet and a genic markers, and fatty livers, despite a the expression of genes involved in vigorous exercise regimen can success- normal chow diet providing only 13.2% lipid droplet formation, glucose uptake, fully shrink, or even empty, existing fat of calories from fat.50 Mesenchymal fatty acid synthesis, and adipokine cells. However, 83e87% of those who stem cells from these animals showed secretion.50,72 Obesogens such as TBT, achieve significant weight loss regain the decreased expression of bone markers or the fungicide triflumizole, can weight within a few years,75,76 support- and a gene expression pattern indicating commit mesenchymal stem cells to the ing the existence of altered metabolic a bias toward the adipogenic lineage.50 adipocyte fate while diverting them away set points. There is no evidence that Strikingly, these impacts of TBT treat- from the osteogenic lineage. A single empty fat cells automatically undergo ment in pregnant F0 animals persisted dose of TBT given to mice prenatally apoptosis; such a scenario is evolution- through at least the F3 generation.50 caused the mesenchymal stem cell pop- arily unlikely because healthy fat cells Therefore, prenatal TBT exposure ulation in offspring to veer toward the would be required in order for the or- caused heritable alterations in the adipose lineage at the expense of bone.41 ganism to survive periods of fasting. directly exposed F1 fetuses (and/or F2 When mice were exposed to triflumizole Moreover, it is likely that shrunken fat germ cells), predisposing the MSC in the water throughout pregnancy, cells would “crave to be filled” because compartment toward the adipocyte mesenchymal stem cells preferentially expression of the satiety hormone, lineage even in the F3 generation that differentiated into adipocytes in a leptin, closely parallels fat mass and was not directly exposed to the chemical. PPARg-dependent process.73 Prenatally small fat cells secrete the least leptin.77 Transgenerational effects, such as TBT-treated animals had more and those elicited by TBT, are likely to be larger fat cells and substantial fat accu- Transgenerational inheritance epigenetic in origin. That is, they mulation in the liver.50 Based on the of obesity involve changes in gene expression experimental design in this study, A startling recent finding in the EDC without accompanying changes in the skewing the mesenchymal stem cell field is the identification of trans- DNA sequence. The major factors un- lineage toward adipocytes was judged generational effects that do not follow derlying epigenetic inheritance include likely to be an epigenetic phenomenon Mendelian inheritance. This research expression of noncoding RNAs and rather than a genetic mutation. The ac- took root in the reproductive endocri- alterations in chromatin structure and tion of obesogens early in development nology field when Michael Skinner transcriptional activity resulting from can be written into the epigenetic code and colleagues found that the fungicide changes in DNA and histone methyl- consisting of DNA methylation or vinclozolin, given only to the pregnant ation (which are heritable).83 Other

MAY 2016 American Journal of Obstetrics & Gynecology 561 Expert Reviews ajog.org histone modifications (acetylation, at play. There are 2 barriers that protect cases of accidental exposure (eg, Mina- phosphorylation, ubiquitination) affect the germline from environmental mata mercury poisoning,99 Yusho disease gene expression, but these are not chemicals and obesogens: the blood- from PCB poisoning100) or unanticipated thought to be heritable.83 Perhaps follicular barrier (females) and Sertoli side effects of prescription drug treat- the most commonly cited changes in cell barrier (males). Numerous chem- ment101 because one simply does not the epigenome resulting from EDC icals of various sizes and charges can perform double-blind, placebo- exposure is DNA methylation.78,80 pass the blood follicular barrier.91 controlled chemical exposures on DNA methylation also happens to be Lipid-soluble compounds penetrate humans. The medical community readily the modification easiest to measure the Sertoli cell barrier quite effectively, accepts evidence of a drug’s effectiveness genome-wide, and is associated with the while larger hydrophilic compounds do in preclinical animal studies as adequate most evidence for heritability. The usual not readily diffuse and are not actively justification to move drug candidates into function of DNA methylation is to transported.92 The extent to which human clinical trials. Therefore, we regulate the transcriptional repression of environmental chemicals cross these believe that evidence of harm from certain genes in order to promote and barriers is largely unknown. The chemical exposure in animal studies stabilize a particular cell lineage.84 For PPARg agonist rosiglitazone likely should be sufficiently persuasive to example, if the promoters of osteogenic crosses both the Sertoli cell93 and counsel patients to show caution toward genes are methylated in the mesen- blood-follicular94 barriers. Rosiglita- EDC exposure, including obesogens. In chymal stem cell population but those of zone decreases fatty acid oxidation in our opinion, EDCs should be routinely adipogenic genes are demethylated, the mouse cumulus oocyte complexes that discussed by obstetricians with their pa- adipogenic lineage would be favored are matured in vitro. While the resul- tients. One way to minimize EDC expo- owing to increased expression of adipo- tant eggs fertilized efficiently, fewer sure is to consume organic fruits, genic genes. embryos developed to the morula stage, vegetables, and grain products insofar as EDC alteration of DNA methylation and even fewer into hatching blasto- possible. Increasing numbers of fungi- in somatic cells is well documented; cysts.94 This suggests that xenobiotic cides routinely applied to fruits and veg- however, it is more challenging to chemicals not only can exert effects at etables are being identified as obesogens prove that EDCs are eliciting permanent the level of the adipocyte in the parental and metabolic disruptors73,102 and the changes in germ cell methylation, as generation, but also can dysregulate levels of agrochemical residues such as would be required for transgenerational lipid homeostasis at the level of the glyphosate on corn, wheat, and rice con- inheritance. The currently favored ovary. tinues to rise.103 It may also be reasonable mechanism underlying transgenera- to recommend that women minimize tional inheritance of altered DNA How to cope with obesogen exposure the use of cosmetics and personal care methylation is that EDCs improperly Obesity adversely affects many repro- products containing EDCs (such as par- cause regions of DNA to evade erasure of ductive health outcomes, including abens and phthalates). methylation marks during the 2 main infertility and menstrual disorders, early While we have focused on xenobiotic demethylation events that occur during puberty, and pregnancy complica- EDCs and obesogens that are encountered development.85-88 Various enzymes tions.95,96 While the aftermath and via exposures to , , her- (eg, Uhrf1, Dnmt1) are responsible for consequences of obesity are familiar, bicides, industrial products, personal care global demethylation,89 and EDCs could how to prevent its development is less products, etc, it should be noted that there disrupt, or locally prevent, the expres- certain. An article published by AJOG are numerous chemicals shown to be sion of these genes. Skinner and brought attention to EDCs and discussed obesogens in animals (and humans104) associates have identified germline the worthwhile endeavor of taking his- that are intentionally added to foods.105 epimutations caused by the EDC, vin- tories regarding environmental expo- Theseinclude(butarenotlimitedto) clozolin, that persist through multiple sures from mothers before conception artificial sweeteners,106,107 phytoes- generations.85 By comparing DNA and during pregnancy.97 Although many trogens,108 preservatives,109 and added methylation in male primordial germ obstetricians believe that counseling pa- sugars, in particular high-fructose corn cells (when DNA methylation is erased) tients would help avoid environmental syrup (extensively reviewed in110). Women to that in prospermatogonia (when DNA contaminants, only 45% routinely hoping to minimize even potential expo- methylation is reestablished), they discuss mercury, 20% discuss pesticides/ sures to obesogens may consider limiting clearly demonstrated that some methyl- insecticides, and 5e10% discuss PCBs, these chemicals during pregnancy. ation marks are not erased in the BPA, and phthalates during prenatal Such behavior modifications have EDC-treated cells.90 care.98 Presumably, obesogens are dis- already been tested on a limited basis. cussed with even fewer patients. One study showed that simply replacing EDC exposure in the gametes It should be obvious that it is impos- foods with organic, nonpackaged, fresh Another important question is whether sible to conclusively establish a causal link foods had a significant effect on lower- EDC exposure is acting directly on the between chemical exposure in humans ing BPA and di-(2-ethylhexyl) gametes, or if more systemic effects are and any adverse health outcome except in levels in the urine.111 Counterintuitively,

562 American Journal of Obstetrics & Gynecology MAY 2016 ajog.org Expert Reviews in another study where households were 4. Palmer JR, Hatch EE, Rao RS, et al. Infer- 21. Heindel JJ, vom Saal FS, Blumberg B, et al. provided catered, local, organic foods tility among women exposed prenatally to Parma consensus statement on metabolic diethylstilbestrol. Am J Epidemiol 2001;154: disruptors. Environ Health 2015;14:54. delivered in wood crates and glass con- 316-21. 22. Ogden CL, Carroll MD, Kit BK, Flegal KM. tainers, prepared without use of plastic 5. Kaufman RH, Adam E, Hatch EE, et al. Prevalence of childhood and adult obesity in the containers/utensils, and eaten in ceramic Continued follow-up of pregnancy outcomes United States, 2011-2012. JAMA 2014;311: dishes with metal utensils, the levels of in diethylstilbestrol-exposed offspring. Obstet 806-14. urinary DEHP metabolites increased Gynecol 2000;96:483-9. 23. Koebnick C, Smith N, Coleman KJ, et al. 112 6. Stillman RJ. 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