CHILDHOOD OBESITY Month 2017 j Volume X, Number X ª Mary Ann Liebert, Inc. DOI: 10.1089/chi.2017.0180

REVIEW

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Prenatal Exposure to Endocrine Disruptors and Reprogramming of Adipogenesis: An Early-Life Risk Factor for Childhood Obesity Ayman El-Sayed Shafei, MD,1 Enas Samir Nabih, MBBCh, MSc, PhD,2 Kirolos Atalla Shehata,3 Emad Sherif Mohamed Abd Elfatah,3 Abou bakr Ahmed Sanad,3 Mohamed Yehia Marey,3 Abd Alla Mohamed Ahmed Hammouda,3 Mounir Mostafa Moussa Mohammed,3 Randa Mostafa, MD,1 and Mahmoud A. Ali, MD1

Abstract Obesity is a global health problem. It is characterized by excess adipose tissue that results from either increase in the number of adipocytes or increase in adipocytes size. Adipocyte differentiation is a highly regulated process that involves the activation of several transcription factors culminating in the removal of adipocytes from the cell cycle and induction of highly specific proteins. Several other factors, including hormones, genes, and epigenetics, are among the most important triggers of the differentiation process. Although the main contributing factors to obesity are high caloric intake, a sedentary lifestyle, and genetic predisposition, strong evidence supports a role for life exposure to environmental pollutants. Endocrine-disrupting chemicals are exogenous, both natural and man-made, chemicals that disrupt the body signaling processes, thus interfering with the endocrine system. Several studies have shown that prenatal exposure to endocrine disruptors modulates the mechanisms, by which multipotent mesenchymal stem cells differentiate into adipocytes. This review discusses adipocytes differentiation and highlights the possible mechanisms of prenatal exposure to endocrine disruptors in reprogramming of adipogenesis and induction of obesity later in life. Therefore, this review provides knowledge that reduction of early life exposure to these chemicals could open the door for new strategies in the prevention of obesity, especially during childhood. Keywords: adipogenesis; childhood; endocrine disruptors; obesity; prenatal; reprogramming

also children and adolescents. The prevalence of obesity has been increasing since 1980. The World Health Organization (WHO) statistics stated that about 1.9 billion adults were suffering from overweight (BMI ‡25). Of these, over 600 million were having obesity (BMI ‡30). Also, an estimated 41 million children younger than the age of 5 years were overweight (a BMI in the 85th to 94th percentiles for age and gender) or obese (a BMI in the 95th percentile or higher for age and gender).3 Although the main contributing factors to obesity are high caloric intake, a sedentary lifestyle, and genetic predisposition, strong evidence supports a role for life exposure to environmental pollutants.4 Obesity is the most common metabolic disorder in the industrialized world. It is associated with

Introduction

he word ‘‘obesity’’ generally means having too much body fat. It is characterized by excess adipose tissue that results from positive energy balance. The expansion of adipose tissue can be either due to increase in the number of adipocytes (hyperplasia) and this represents hyperplastic type of obesity or increase in adipocytes size (hypertrophy) and this represents hypertrophic type of obesity. The definition of obesity differs among adults, children, and adolescents. In adults, it is determined by calculating BMI (in kg/m2), while in children and adolescents, it is based on standard growth charts.1,2 Obesity is increasingly a global problem affecting not only adults but

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Department of Biomedical Research, Armed Forces College of Medicine, Cairo, Egypt. Department of Medical Biochemistry, Faculty of Medicine, Ain Shams University, Cairo, Egypt. 3 Undergraduate Armed Forces College of Medicine, Cairo, Egypt. 2

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increased risk of heart disease, strokes, and diabetes and has been estimated to account for 3.4 million deaths in 2010.3

Adipose Tissue

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Adipose tissue is the most abundant tissue in the human body. It is primarily composed of adipocytes, also known as fat cells or lipocytes.5 Besides adipocytes, adipose tissue contains other cells such as fibroblasts, smooth muscle cells, pericytes, endothelial cells, and adipogenic progenitor cells.6 Based on the color of the adipose tissue, adipocytes are classified into three main types: white, brown, and beige. White adipocytes are used to store energy, since they are composed mainly of triglycerides and cholesteryl ester.7 Brown adipocytes are used to generate energy in a heatproducing process called thermogenesis. Beige cells arise from unique precursor cells,8 but there is also evidence that they may arise from white adipocytes in a process referred to as transdifferentiation, and they are similar to brown fat cells in their ability to dissipate energy, thus, they can serve as an antiobesity therapeutic.9 Adipocytes play important roles in several processes. They regulate body weight through secretion of many proteins such as leptin, resistin, adiponectin, and apelin.7,10,11 They are an important site for the synthesis of estrogen and storage of steroid hormone.12–14 They also play a role in immunological responses through the secretion of peptides, cytokines, complement factors, and bioactive mediators called adipokines.11,15

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Therefore, adipogenesis is a multistep process, involving a cascade of transcription factors and cell cycle proteins, regulating gene expression and leading to adipocyte development. Several positive and negative regulators of this network have been elucidated in the last years.29–37

Regulators of Adipocyte Differentiation Studies have revealed several factors affecting the adipocyte differentiation process. As indicated in Figure 1, there are many positive and negative regulators that, respectively, promote or inhibit adipocyte differentiation. It is well known that insulin, glucocorticoids, estrogen, and progesterone promote adipogenesis. In addition, growth hormone, retinoic acid, vitamin D, and various prostaglandins are among the hormones that affect adipogenesis.38,39 Concerning the effect of insulin on the differentiation of preadipocytes into mature adipocytes,25,40–42 studies demonstrated a requirement for the insulin receptor and activation of Phosphoinositol 3-kinase and Akt in the process of adipogenesis.43–45 Insulin also affects the differentiation of adipocytes through cross-activation of the insulin growth factor 1 (IGF-1) receptor, thus activating several distinct downstream signal transduction pathways mediating adipogenesis.15,46 In addition, insulin-stimulated prenylation of the Ras family GTPases assures normal phosphorylation and activation of CREB that, in turn, triggers the intrinsic cascade of adipogenesis.47 Peroxisome proliferator-activated receptor gamma (PPARc) regulates fatty acid storage and glucose metabolism. The genes activated by PPAR-c stimulate lipid uptake and

The Adipogenic Lineage and Adipocyte Differentiation

The growth of white adipose tissue is a result of increased adipocyte size and number. Fat cells are produced from fat cell precursors and this process continues throughout life.16–18 Multipotent clonal cell lines are commonly used as in vitro experimental models in determining the mechanisms involved in adipocyte proliferation, differentiation, and adipokine secretion. Studies done on multipotent clonal cell lines suggested that the adipogenic lineage is derived from embryonic stem cell-derived mesenchymal stem cells, which has the capacity to differentiate into adipocytes and osteoblasts.15,19 Many different events contribute to the commitment of a mesenchymal stem cell into the adipocyte lineage, including the coordination of a complex network of transcription factors, cofactors, and signaling intermediates from numerous pathways. New fat cells constantly arise from a preexisting population of undifferentiated progenitor cells or through the dedifferentiation of adipocytes to preadipocytes, which then proliferate and redifferentiate into mature adipocytes. Analysis of adipocyte turnover showed that adipocytes are a dynamic and highly regulated population of cells.20–28

Figure 1. Regulators of adipocyte differentiation. IGF-1, insulin growth factor 1; IL-1, interleukin 1; miRNAs, micro-RNAs; PPAR-c, peroxisome proliferator-activated receptor gamma; TNF-a, tumor necrosis factor a; TGFb, transforming growth factor b.

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adipogenesis by fat cells. On the contrary, Pref-1 is a transmembrane protein that belongs to a family of epidermalgrowth factor-like repeats containing proteins and is activated by proteolytic cleavage.48 Pref-1 is implicated in the regulation of adipogenesis through FOXA2,49 KLF2,50 and KLF6.51 Also, cleavage of Pref-1 releases an extracellular moiety that inhibits adipogenesis, possibly through interaction with Notch. Expression of Pref-1 is high in preadipocytes and normally declines during differentiation, and forced Pref-1 expression in 3T3-L1 cells blocks adipogenesis. A soluble form of Pref-1 is sufficient to decrease adipose tissue mass and insulin sensitivity.52 Regarding glucocorticoid receptor, it is a nuclear hormone receptor in the same superfamily as PPAR-c.44 Activation of glucocorticoid receptor by dexamethasone reduces the expression of pref-1 and induces C/EBP-d, which may account for some of its adipogenic activity.53,54 The expression of PPAR-c and subsequent adipocyte differentiation requires C/EBP-b.55 Isobutylmethylxantine has been shown to increase the expression of C/EBP-b and may also function through increasing the accumulation of cAMP, which acts through cAMP response elementbinding protein and promotes the differentiation of adipocytes by inducing C/EBP-b.56,57 Inhibitors of PPAR-c were also studied. Cytokines have the potential to decrease adipocyte numbers through multiple points in the adipogenic program and by activation of several distinct intracellular signaling pathways.58–60 For example, tumor necrosis factor a (TNF-a) and interleukin 1 (IL-1) suppress adipose conversion by activating the TAK1/TAB1/NIK cascade, which in turn inhibits PPAR-c activity.61 Another blocker of the induction of the key adipogenic transcription factors PPAR-c and C/EBP-a is Wnt family. Glycoproteins of the Wnt family have been demonstrated to influence the development of many cell types, including adipocytes. Several studies have demonstrated that Wnt is a potent inhibitor of differentiation. Inhibition of Wnt signaling in preadipocytes results in spontaneous differentiation suggesting that preadipose cells produce endogenous Wnt. Furthermore, ectopic expression of the Wnt gene has been shown to potently repress adipogenesis.62 Studies done specifically on WNT10b, a gene which is highly expressed in preadipocytes and downregulated during the course of differentiation, showed interesting results. The constitutive expression of WNT10b inhibited adipogenesis.63 Ectopic expression of WNT10b stabilizes free cytosolic b-catenin, which functions as a Wnt effector. b-catenin binds to the androgen receptor and translocates to the nucleus in response to testosterone, where it interacts with the TCF/LEF transcription factors to inhibit adipogenesis. Loss of b-catenin in myometrial tissue causes its conversion to adipose tissue indicating that the Wnt-b-catenin pathway is an important regulator of adipogenesis and mesenchymal-cell fate in vivo. In vivo, transgenic expression of WNT10b in adipocytes results in a 50% reduction in white adipose tissue mass and absence of development of brown adipose tissue.64–66

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Another regulator of the adipogenic transcription factors C/EBPs is the cytokine transforming growth factor b (TGFb). Its signaling components are expressed in cultured adipocytes and adipose tissue. Studies demonstrated that TGFb inhibits adipogenesis in vitro. Transgenic overexpression of TGFb impairs the development of adipose tissue.67 Blockade of endogenous TGFb signaling by inhibition of SMAD3 increases adipogenesis through binding of SMAD3 to C/EBPs and inhibiting their transcriptional activity.68 Epigenetics is the study of heritable changes in gene expression that occur without a change in the DNA sequence. Epigenetic mechanisms, including histone modifications, DNA methylation and specific micro-RNAs (miRNAs) expression, have been proposed to mediate transgenerational transmission and can be triggered by environmental factors. The growing evidence that DNA methylation might contribute to obesity has been demonstrated by several studies which found that methylation of CpG islands of certain genes’ promoters are not only associated with childhood obesity but also predicts adiposity in adolescence.69–71 Regarding miRNAs, they are short noncoding RNA molecules that posttranscriptionally repress the expression of genes by binding to 30 -untranslated regions of the target mRNAs. Given that there is strong evidence that miRNAs are regulated by hormones, researchers investigated the potential role for environmental endocrine-disrupting chemicals (EDCs) in the deregulation of miRNAs expression and actions.72 Several miRNAs have been identified as enhancers of adipogenesis. miRNA-143 and miRNA-103 have been shown to increase during human and murine preadipocyte differentiation, whereas their ectopic overexpression enhanced triglyceride accumulation in differentiating 3T3-L1 preadipocytes.73–80 Furthermore, the miRNA-30 family has been found to be important for adipogenesis. miRNAs-30a-e were strongly upregulated during adipogenesis of human cells, and inhibition of the miRNA-30 family inhibited adipogenesis. RUNX2 is an osteogenesis regulator that promotes adipogenesis when downregulated.79 Overexpression of miRNA-30a and d targets RUNX2.80 miRNA-204 has also been shown to directly target RUNX2.81 Among miRNAs that serve as regulators of the clonal expansion during adipogenesis is the miRNA17-92 cluster, which comprises miRNA-17-3p, miRNA-175p, miRNA-18, miRNA-19a, miRNA-19b, miRNA-20, and miRNA-92–1.82

Endocrine Disruptors EDCs are exogenous, both natural and man-made, chemicals that disrupt the body signaling processes, thus interfering with the endocrine system. They are capable of mimicking or blocking the action of hormones by binding to or interfering with their receptors. They can also function indirectly by disrupting hormone levels or by altering hormonal transport mechanisms.83,84

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Obesogens, a subclass of EDCs, predispose to weight gain, despite increasing physical activity and decreasing caloric intake.83,85,86 They can alter hormonal pathways that regulate lipid metabolism, and thereby stimulate adipocyte differentiation and predispose to obesity and related metabolic disorders.87 EDCs can increase the number of adipocytes by directing the differentiation of mesenchymal stem cells into adipocytes and can also increase the size of adipocytes by promoting the accumulation of triglycerides in mature adipocytes, thus causing weight gain.88

Prenatal Exposure to Endocrine Disruptors and Obesity Predisposition

Human and animal studies that encompass the prenatal period indicated that prenatal exposure to various components of air pollution might have a role in susceptibility to obesity later in life. Strong evidence has emerged about prenatal exposure to cigarette smoke and obesity in later life. Reports from human epidemiological studies suggest that cigarette smoking of pregnant females induces fetal intrauterine growth restriction, which is considered a significant environmental contributor to obesity in later life.89,90 Also, prenatal exposure of rats to nicotine resulted in reduced birth weight and more obese rats compared with control rats.91 Among the most common air contaminants are polycyclic aromatic hydrocarbons (PAHs). The main metabolic products of PAHs are hydroxy-PAHs, which have been known to be structurally similar to estrogen and have been shown to have estrogenic activity,92 benzo[a]pyrene that inhibits lipolysis,93 phenanthrene that has antiandrogenic effects,94,95 and 1-naphthol and 2-naphthol that may act as thyroid hormone receptor antagonists.96 Also, PAHs are transported into the human body tissues containing fat and have strong lipophilic properties.97,98 Prenatal exposure to PAHs in humans during the second trimester was associated with increased body size at age 5 and 7 years.99,100 Animals exposed to PAHs in utero had higher susceptibility to obesity, insulin resistance, and inflammation later in life.101,102 Another obesogenic chemical is the fungicide tributyltin. Prenatal exposure to tributyltin in mice increased lipid accumulation in adipose tissue and liver in neonatal mice, which persists into adulthood and even into future generations.4,103 Tributyltin also stimulates adipogenesis in 3T3 L-1 preadipocytes.104–106 Mesenchymal stem cells from tributyltin-treated animals have an increased susceptibility to develop into adipose tissue rather than bone.107–110 Bisphenol A is an organic synthetic compound used to make plastic water bottles, metal food cans, and thermal receipt paper.111 Recent evidence indicated that prenatal exposure to bisphenol A is positively associated with BMI.112 The master regulators of adipogenesis are the peroxisome proliferator-activated receptors. Both tributyltin and tetrabromobisphenol A are pollutants that have been

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shown to interfere with hypothalamic gene regulations through retinoic acid receptors (RXR)/PPAR-c activation.88 Prenatal exposure to polybrominated diphenylethers, one of the widely used flame retardants, is associated with low fetal birth weight and altered thyroid function in offspring.113–115 Experimental studies done on pregnant rats demonstrated the obesogenic effects of Firemaster 550 flame retardant. They found increased weight gain (which became evident before puberty and continued into adulthood), glucose intolerance, and increased serum levels of thyroxine.116 Subsequent studies reported that these effects might be mediated by binding to and activation of PPAR-c.117,118 Data from NHANES 1999–2002 survey and other human studies support an association between, the major component of the highly persistent organic pollutants, polychlorinated biphenyls and metabolic disease and childhood obesity.119,120 In vivo and in vitro studies demonstrated a link between prenatal exposure of phthalates and increasing adipose tissue mass during development and later in adulthood. They suggested that phthalates could induce the expression of PPAR-c and its target genes, thus increasing the differentiation of preadipocytes into adipocytes.121–127

Endocrine Disruptors and Reprogramming of Adipogenesis Several endocrine disruptors modulate the mechanisms, by which multipotent mesenchymal stem cells differentiate into adipocytes mainly through activation of peroxisome proliferator-activated receptor c signaling pathway. In utero exposure of C57BL/6 mouse pups to tributyltin increased adipose tissues in mammary and inguinal glands and epididymal fat pads. Also, when Xenopus laevis tadpoles were exposed to tributyltin at environmentally low doses (1–10 nM), ectopic adipocyte formation was detected posterior to the fat bodies in and around the gonads of both males and females. Interestingly, testicular tissue was interspersed or replaced by adipocytes in case of exposure to 10 nM tributyltin, suggesting that tributyltin could induce adipogenesis at the expense of other cells. Similarly, exposure to the retinoid X receptor and peroxisome proliferator-activated receptor c ligands also increased ectopic adipocyte formation, suggesting that tributyltin modulated mesenchymal stem cells programming through RXR:PPAR-c activation. They also found that tributyltin directed differentiation of 3T3-L1 embryonic murine preadipocyte fibroblast cells into adipocytes through RXR: PPAR-c signaling. Therefore, they suggested that developmental exposure to tributyltin and its congeners that activate RXR/PPAR-c can increase the incidence of obesity in exposed individuals through directing mesenchymal stem cells differentiation and that chronic exposure to these endocrine disruptors during lifetime could act as a potential chemical stressor for obesity and its related disorders.104

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Several other studies studied the effect of endocrine disruptors in modulating PPAR-c signaling during adipocyte differentiation. Multipotent adipose-derived stromal stem cells isolated from white adipose tissue of mice exposed to tributyltin in utero showed enhanced lipid accumulation and increased expression of PPAR-c target genes. In vitro exposure of human and mouse adipose-derived stromal stem cells to tributyltin or an PPAR-c activator called rosiglitazone increased adipogenesis, cellular lipid content, and expression of adipogenic genes. These effects were inhibited by the addition of PPAR-c antagonists suggesting that PPAR-c promoted the tributyltin and rosiglitazone-mediated effects on adipocyte differentiation.110 Biemann et al.127 investigated the effects of Bisphenol A, bis(2-ethyl-hexyl)phthalate, and tributyltin during early adipogenic commitment and differentiation using the pluripotent CGR8 ESC and murine mesenchymal stem cells C3H/10T1/2 cell lines. They found that they did not affect adipogenesis in ESCs. However, during the undifferentiated mesenchymal stem cells growth phase, exposure to 10 mM of Bisphenol A, adipocyte differentiation, and the expression of the adipogenic markers, FABP4, PPAR-c2, LPL, and adiponectin, were reduced. In contrast, tributyltin increased the number of adipocytes, triglycerides content, and expression of adipocyte-specific gene. Exposure to bis(2-ethyl-hexyl)phthalate showed no effect. Chamorro-Garcia et al.128 reported that while bisphenol (BPA) failed to promote adipogenesis in MSCs, BPA could induce adipogenesis in 3T3-L1 cells. Furthermore, the BPA derivate, BPA diglyceraldyl ether (BADGE), was capable of inducing adipogenesis in human and mouse MSCs as well as in mouse 3T3-L1 preadipocytes. Interestingly, neither BPA nor BADGE activity could be blocked by PPAR-c antagonists, nor did BPA or BADGE induce or antagonize RXR or PPAR-c activity in transient transfection assays. Collectively, these observations indicate that BPA, tributyltin (TBT) and di(2-ethylhexyl) phthalate (DEHP), and TBT modulate adipogenic commitment and differentiation in a stage- and compound-specific manner through PPAR-cdependent/independent signaling. Parabens are alkyl esters of p-hydroxybenzoic acid that are used primarily for their bactericidal and fungicidal properties in cosmetics, toiletries, pharmaceuticals, and food. Parabens (butylparaben and benzylparaben, in particular) promoted adipogenesis in human ADSCs. In murine 3T3-L1 cells, parabens induced adipocyte differentiation through PPAR-c as well as glucocorticoid receptor-like signaling. In contrast, the paraben metabolite 4-hydroxybenzoic acid was inactive in the promotion of 3T3-L1 adipocyte differentiation.129 While transcriptional regulation of MSCs appears to be a major driving force in the initiation of in utero and perinatal development of obesity, MSCs could also be biased toward differentiation into an adipocyte lineage through epigenetic modifications of the genome. Prenatal exposure of mouse ADSCs to TBT resulted in hypomethylation of

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the promoter/enhancer region of the Fapb4 locus and consequently overexpression of Fapb4.110 In conclusion, obesity is a global health problem. Prenatal exposure to endocrine disruptors induces reprogramming of adipogenesis, thus increasing the risk of obesity later in life. Reduction of early life exposure to these chemicals opens the door for new strategies in the prevention of obesity, especially during early life. Author Disclosure Statement The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review. This review did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.

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Address correspondence to: Enas Samir Nabih, MBBCh, MSc, PhD Department of Medical Biochemistry Faculty of Medicine Ain Shams University Cairo PO 38 Egypt E-mail: [email protected]