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ScienceDirect Endocrine disruptive compounds and cardio-metabolic risk factors in children Naila Khalil1, Aimin Chen2 and Miryoung Lee3,4 The endocrine disrupting chemicals (EDC) are exogenous chemicals that can disrupt hormonal signaling system. EDCs are ubiquitous in our environment and many EDC are detectable in humans. With the increasing obesity prevalence in children it is imperative to explore the role of EDC as obesogens. This review summarizes recent epidemiological evidence regarding impact of these EDC on weight gain and metabolic outcomes in children. The EDCs include pharmaceuticals, pesticides, industrial by-products, and cigarette smoke. Current evidence suggests a link between early life exposure to some industrial by-products, synthetic hormones and cigarette smoke with weight gain. However, there is inconclusive evidence of an association between exposure to fungicides, dioxin, phytoestrogens, flame retardants, heavy metals and childhood obesity. Addresses 1 3123 Research Blvd., Suite #200, Center for Global Health, Department of Community Health, Wright State University, Boonshoft School of Medicine, Dayton, OH, USA 2 Division of Epidemiology and Biostatistics, Department of Environmental Health, University of Cincinnati, College of Medicine, Cincinnati, OH 45267, USA 3 Lifespan Health Research Center, Department of Community Health, Wright State University, Boonshoft School of Medicine, Dayton, OH 45420-4006, USA 4 Department of Pediatrics, Wright State University, Boonshoft School of Medicine, Dayton, OH 45404-1815, USA Corresponding author: Khalil, Naila ([email protected])
Current Opinion in Pharmacology 2014, 19:120–124 This review comes from a themed issue on Endocrine and metabolic diseases Edited by Scott M Belcher
http://dx.doi.org/10.1016/j.coph.2014.09.015 1471-4892/# 2014 Elsevier Ltd. All right reserved.
Introduction The endocrine system secretes hormones which regulate the metabolic functions of the body. Endocrine disrupting chemicals (EDC) are substances that can alter endocrine system and subsequently cause adverse health effects in an intact organism, or its progeny according to World Health Organization (WHO) [1]. The EDCs are ubiquitous in our environment, and Current Opinion in Pharmacology 2014, 19:120–124
include pesticides, flame retardants, pharmaceuticals, and chemicals in personal care products and housewares. EDCs may be released from these products and absorbed through ingestion, inhalation and dermal contact. EDCs effects are critical during early life when rapid tissue development and metabolic pathways are programmed [2]. Since 1960s, potential harmful effects of EDCs on human, in particular on fetal and child growth and development, have been investigated. Early life exposure to EDCs has been associated with abnormalities in hypothalamic–pituitary–gonadal axis and hypothalamic–pituitary–thyroid axis consequently affecting reproductive, immune, and metabolic [3] or nervous systems [4]. In addition to disorders of sexual developments and various endocrine disorders, certain EDCs called obesogens are related to childhood obesity [5]. Obesogens influence fat accumulation and obesity [6] putatively by disrupting critical lipid and metabolic pathways in early life resulting in permanent changes in fat storage and metabolic homeostasis [3]. This review summarizes recent published epidemiologic research on various EDCs and obesogens in association with childhood obesity and metabolism.
Phthalate esters Phthalates are used as plasticizers in many consumer products such as personal care products, medical equipment, pharmaceuticals, children’s toys, and in food packaging. Children and adults are exposed via diet, dust ingestion and dermal contact [7]. Phthalate metabolites activate peroxisome proliferator-activated receptor and have anti-androgenic and thyroid effects, which may contribute to the development of obesity, more so with developmental exposure at low doses [8]. In addition to cross-sectional and short-term prospective epidemiological studies reporting positive association of phthalates metabolites with adult obesity, emerging evidence suggests similar association in children (reviewed in [8]). Hatch et al. reported association of measures of adiposity and urinary phthalates concentrations among girls in the United States [9]. Using data from National Health and Nutrition Examination Survey (NHANES) in the US, two recent studies indicate that urinary levels of phthalates were associated with higher risk of obesity in children and adolescents [10,11]. A short-term prospective study in children also reported a positive association between urinary phthalate metabolites and body mass index (BMI) in overweight children only [12]. The obesogen effect of phthalate exposure may differ www.sciencedirect.com
Endocrine disruptive compounds and childhood obesity Khalil, Chen and Lee 121
by type of phthalates ester, timing, duration and intensity of exposure, and genetic susceptibility. Furthermore, most evidence so far is based on cross-sectional studies, long term epidemiological studies that measure exposure and outcome at several critical developmental stages are needed to understand the variable obesogen effects of phthalates.
Diethylstilbestrol (DES) A synthetic estrogen, DES, was commonly prescribed to prevent pregnancy related complications in 1950s and is no longer in use [13]. In vivo and in vitro studies report that prenatal and perinatal exposures to DES and environmental agents with weak estrogenic activity (Bisphenol A, genistein) are linked to increase in adiposity and alteration in adipogenesis and glucose metabolism (as reviewed by [14]). A recent paper on the Collaborative Perinatal Project (1959–1974) reported that DES, and lower dose pharmacologic sex hormone use during pregnancy was linked to offspring obesity [13].
Phytoestrogens Infants fed soy protein based formula consume higher levels of isoflavones, a class of phytoestrogens including weakly estrogenic genistein and daidzein compounds [15]. A recent review summarized the studies on soy intake and child growth to 36 months and found similar weight gain among soy fed children compared with children consuming breast milk or cow milk based formula [16]. Among children with different isoflavone intake levels, a study found no difference in baseline BMI at 7 years of age [17].
Pesticides (fungicides and herbicides, DDE) Biomonitoring studies have shown that various pesticides accumulate in humans [18,19]. While health effects of fungicides on various chronic diseases such as cardiovascular disease [20], research is limited on the obesogenic roles of fungicides. Two independent Spanish studies both demonstrated that hexachlorobenzene (HCB), one of persistent organic pollutants (POP) used as fungicide, was positively related to childhood obesity [21,22]. Higher prenatal exposure to HCB was associated with significantly increased risk of rapid growth in infancy, overweight at 14 months of age and childhood obesity at age 6.5 years [22]. DDE is the major metabolite of dichlorodiphenyltrichloroethane (DDT) and persists in the environment and humans. Several birth cohort studies have shown an association between prenatal exposure to DDT and increased childhood weight or BMI, although null findings have also been reported [17,18,23]. Two studies found that DDE exposure was associated with an increase in adiposity [24,25]. Research in Spain showed an association between cord blood DDE and the risk of being overweight at 6.5 years, but significant association was limited to the second tertile [21]. Other studies did not www.sciencedirect.com
found significant association between prenatal DDE concentrations and child BMI or the risk of obesity [23,26,27]. A study in the Faroe Islands found that increased BMI change from 5 to 7 years of age and increased waist circumference in girls was associated with prenatal DDE concentration [28]. Another study in Belgium also suggested a positive association between cord plasma DDE and waist circumference in girls at 7–8 years [29]. More research is needed to clarify the association and to examine postnatal exposures.
Polychlorinated biphenyls (PCBs) Exposure to PCBs during pregnancy has been examined in several cohort studies for the association with child obesity, as reviewed by two publications published in 2011 [25,30]. The literature is inconsistent, but the summarization by Tang–Pe´ronard suggests that prenatal total PCBs concentrations may be associated with an increase in childhood weight or BMI, especially in girls [25]. The analysis of U.S. Collaborative Perinatal Project did not find significant association between serum total PCBs concentrations at third trimester and child obesity or BMI [26]. However, a Spanish study published in 2012 showed the third tertile of cord PCB concentrations was associated with increased risk of being overweight or obese [21]. The latest study from the Faroe Islands found that among girls with pre-pregnant overweight mothers, the fourth quartile of maternal PCBs concentrations was associated with increased BMI at age 7 years compared with the lowest quartile [28]. There is a lack of studies of postnatal exposure to PCBs; also studies of cardiometabolic biomarkers in addition to anthropometric measurement are needed.
Dioxins and furans Exposure to dioxins and furans has been examined in very few epidemiological studies to determine associations with obesity and overweight in children [25,30]. Studies in the Netherlands and Belgium did not find significant associations between dioxin levels and weight in childhood [29]. A study in Russian boys reported reduced BMI z-score at age 11–12 years across quintiles suggesting of inverse relationships between serum dioxin levels and BMI measured three years later [31]. More research is needed to examine both background exposure and high local exposure to dioxins and furans on child growth.
Polybrominated diphenyl ethers (PBDEs) PBDE exposure is universal because of the release from carpet padding, furniture, and electronic products that contains PBDEs as flame retardants. However, epidemiologic study of prenatal and postnatal exposure to PBDEs and child obesity is in its infancy despite suggestive evidence from animal studies [30]. There is a significant need to examine the obesogenic roles of PBDEs, especially in the fact that toddlers and preschoolers have two to three times higher PBDE exposure than adults [32]. Current Opinion in Pharmacology 2014, 19:120–124
122 Endocrine and metabolic diseases
Bisphenol A (BPA)
Lead
BPA is a manmade polycarbonate resin used in plastic products and as coatings in food and beverage containers and is detectable in 93% of the US population, with children [33] having the highest urinary BPA exposure. Cross-sectional studies in children reported the positive association between BPA exposure and increased body weight [34] and higher waist circumference-to-height ratio [35]. However no significant association between BPA exposure and metabolic risk factors was noted. In a Spanish birth cohort study, prenatal (creatinine adjusted urinary) BPA exposure on postnatal growth and obesity was examined. Prenatal BPA was not associated with BMI at 14 months of age but was positively associated with BMI and waist circumference at four years of age [36]. In the CHAMACOS cohort study, however, increasing BPA concentrations in mothers during pregnancy were negatively associated with obesity measures; decreased BMI, body fat, and overweight/obesity among their daughters at nine years of age [37]. In this study, there was positive, cross-sectional relationship between children’s urinary BPA levels and increased adiposity measured at 9 years of age [37]. In overweight or obese Ohio children aged 3–8 years, BPA levels were associated with insulin resistance, higher blood pressure, and other adverse liver and metabolic effects [38]. A Chinese studies report similar associations as Khalil et al. [39]. This emerging evidence needs to be validated through long term prospective studies.
A recent epidemiologic study reported significant associations of maternal lead biomarkers with preterm birth and low birth weight/fetal growth [50]. However, the human evidence for lead exposure and its effect on obesity is inconsistent overall, especially in children as reviewed by La Merrill et al. [30]. Mice exposed to lead in early development manifested increased food intake, weight, and changes in glucose tolerance and insulin response in adulthood [51]. Whereas, results from a human longitudinal study suggested that chronic lead exposure in childhood may result in obesity that persists into adulthood [52]. More research is clearly needed to understand the association between heavy metal exposure in children and obesity.
Perfluorinated alkyl substances Perfluorinated alkyl substances (PFAS) are man-made chemicals, used widely because of their heat stable, non-flammable properties and are detectable globally in human serum, and are associated with increased lipid, and diabetes in adults (reviewed by Steenland et al. [40]) and children [41]. In the US adolescents, increasing serum PFAS levels were related to elevated blood sugar levels, decreased blood insulin, and impaired b-cell function (borderline significance) [42]. In a Danish study, prenatal PFOA exposure was associated with adiposity, and higher insulin and leptin, and inversely associated with adiponectin levels in female children at age 20 [43], other studies reported null association [44,45]
Heavy metals Arsenic
Arsenic exposures through water and food consumption (e.g., rice) are associated with diabetes, metabolic syndrome, and obesity risk in adults [46,47]. Epidemiological data regarding arsenic exposure and its association with metabolic effects in children are sparse. A recent study reported that total urinary arsenic was negatively associated with the BMI in Taiwanese adolescents [48]. In a study of Bangladeshi infants/children, postnatal arsenic exposure was associated with lower body weight and length among girls at age 2 [49]. Current Opinion in Pharmacology 2014, 19:120–124
Organotins
Organotins are tin compounds, widely used in industrial processes, polyvinyl chloride (PVC) plastic manufacturing, and used as biocides. While organotins are found in humans, there are no known population studies showing their association with body mass or adiposity at present [30,53]. Cigarette smoking
Tobacco or nicotine use influences the endocrine system, including body weight, glucose and lipid homeostasis [54]. Prenatal smoking exposure is associated with consequent childhood obesity (reviewed by Ino et al.) [55]. This effect is dose-dependent and is significant even in exposure to paternal smoking (i.e. passive exposure) [56].
Conclusion Current evidence suggests a link between early life exposure to some industrial by-products, synthetic hormones and cigarette smoke with weight gain. However, there is inconclusive evidence of an association between exposure to fungicides, dioxin, phytoestrogens, flame retardants, heavy metals and childhood obesity. The worldwide prevalence of childhood overweight and obesity has increased from 4.2% in 1990 to 6.7% in 2010 [57]. Children who are overweight or obese have a higher risk of being overweight as adults and to suffer from obesity-related morbidity and mortality including cardiometabolic disorders such as hyperlipidaemia, hyperinsulinaemia, hypertension, and atherosclerosis [58]. Around 800 chemicals in current use are thought to be capable of influencing endocrine control of human metabolism [59]. However, significant gaps in knowledge exist in understanding associations between exposures to EDCs and early onset of obesity or diabetes especially in children [1]. These research needs can be addressed by prospective epidemiological studies. www.sciencedirect.com
Endocrine disruptive compounds and childhood obesity Khalil, Chen and Lee 123
Conflict of interest statement All authors declare that they do not have a conflict of interest.
Acknowledgement This was a non-funded review.
References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as: of special interest of outstanding interest 1.
WHO: Endocrine disrupters and child health. Possible developmental early effects of endocrine disrupters on child health. 2012. This is currently the most detailed review that discusses the association between reproductive child health and endocrine disruptors.
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14. Newbold RR, Padilla-Banks E, Jefferson WN: Environmental estrogens and obesity. Mol Cell Endocrinol 2009, 304:84-89. 15. Chen A, Rogan WJ: Isoflavones in soy infant formula: a review of evidence for endocrine and other activity in infants. Annu Rev Nutr 2004, 24:33-54. 16. Vandenplas Y et al.: Safety of soya-based infant formulas in children. Br J Nutr 2014, 111:1340-1360. 17. Cheng G et al.: Relation of isoflavones and fiber intake in childhood to the timing of puberty. Am J Clin Nutr 2010, 92:556564. 18. Chevrier C et al.: Environmental determinants of the urinary concentrations of herbicides during pregnancy: the PELAGIE mother–child cohort (France). Environ Int 2014, 63:11-18. 19. Morgan MK, Wilson NK, Chuang JC: Exposures of 129 preschool children to organochlorines, organophosphates, pyrethroids, and acid herbicides at their homes and daycares in North Carolina. Int J Environ Res Public Health 2014, 11:3743-3764. 20. Mostafalou S, Abdollahi M: Pesticides and human chronic diseases: evidences, mechanisms, and perspectives. Toxicol Appl Pharmacol 2013, 268:157-177.
Vandenberg LN et al.: Hormones and endocrine-disrupting chemicals: low-dose effects and nonmonotonic dose responses. Endocr Rev 2012, 33:378-455. Comprehensive discussion of mechanism of action of endocrine disruptors.
21. Valvi D et al.: Prenatal concentrations of polychlorinated biphenyls, DDE, and DDT and overweight in children: a prospective birth cohort study. Environ Health Perspect 2012, 120:451-457.
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22. Smink A et al.: Exposure to hexachlorobenzene during pregnancy increases the risk of overweight in children aged 6 years. Acta Paediatr 2008, 97:1465-1469.
Wang G et al.: Early life origins of metabolic syndrome: the role of environmental toxicants. Curr Environ Health Rep 2014, 1:78-89. A outstanding review of recent literature regarding exposure to endocrine disruptors and early life development of metabolic syndrome. 4.
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DiVall SA: The influence of endocrine disruptors on growth and development of children. Curr Opin Endocrinol Diabetes Obes 2013, 20:50-55. Schell LM, Gallo MV: Relationships of putative endocrine disruptors to human sexual maturation and thyroid activity in youth. Physiol Behav 2010, 99:246-253.
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Janesick A, Blumberg B: Obesogens, stem cells and the developmental programming of obesity. Int J Androl 2012, 35:437-448. Reviews research regarding obesogens exposure during early life and their plausible mechanism of action in childhood obesity.
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Langer S et al.: Phthalate metabolites in urine samples from Danish children and correlations with phthalates in dust samples from their homes and daycare centers. Int J Hyg Environ Health 2014, 217:78-87.
23. Warner M et al.: In utero DDT and DDE exposure and obesity status of 7-year-old Mexican-American children in the CHAMACOS cohort. Environ Health Perspect 2013, 121:631-636. 24. Warner M et al.: Prenatal exposure to dichlorodiphenyltrichloroethane and obesity at 9 years of age in the CHAMACOS study cohort. Am J Epidemiol 2014, 179:1312-1322. 25. Tang-Peronard JL et al.: Endocrine-disrupting chemicals and obesity development in humans: a review. Obes Rev 2011, 12:622-636. 26. Cupul-Uicab LA et al.: Prenatal exposure to persistent organochlorines and childhood obesity in the US collaborative perinatal project. Environ Health Perspect 2013, 121:1103-1109. 27. Hoyer BB et al.: Body mass index in young school-age children in relation to organochlorine compounds in early life: a prospective study. Int J Obes (Lond) 2014, 38:919-925 http:// dx.doi.org/10.1038/ijo.2014.58. Epub 2014 Apr 10.
8. Kim SH, Park MJ: Phthalate exposure and childhood obesity. Ann Pediatr Endocrinol Metab 2014, 19:69-75. Nice review-discussing plausible mechanism of action of phthlates on childhood obesity.
28. Tang-Peronard JL et al.: Association between prenatal polychlorinated biphenyl exposure and obesity development at ages 5 and 7 y: a prospective cohort study of 656 children from the Faroe Islands. Am J Clin Nutr 2014, 99:5-13.
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29. Delvaux I et al.: Prenatal exposure to environmental contaminants and body composition at age 7–9 years. Environ Res 2014, 132C:24-32.
Hatch EE et al.: Association of urinary phthalate metabolite concentrations with body mass index and waist circumference: a cross-sectional study of NHANES data, 1999–2002. Environ Health 2008, 7:27.
10. Buser MC, Murray HE, Scinicariello F: Age and sex differences in childhood and adulthood obesity association with phthalates: analyses of NHANES 2007–2010. Int J Hyg Environ Health 2014, 217:687-694. 11. Trasande L et al.: Race/ethnicity-specific associations of urinary phthalates with childhood body mass in a nationally representative sample. Environ Health Perspect 2013, 121:501-506. 12. Teitelbaum SL et al.: Associations between phthalate metabolite urinary concentrations and body size measures in New York City children. Environ Res 2012, 112:186-193. 13. Jensen ET, Longnecker MP: Pharmacologic sex hormones in pregnancy in relation to offspring obesity. Obesity (Silver Spring) 2014 http://dx.doi.org/10.1002/oby.20778. A nice summary of evidence linking synthetic sex hormone use in mothers with childhood obesity. www.sciencedirect.com
30. La Merrill M, Birnbaum LS: Childhood obesity and environmental chemicals. Mt Sinai J Med 2011, 78:22-48. A comprehensive review paper that discusses endocrine disrupting effects of some chemicals in children. 31. Burns JS et al.: Serum dioxins and polychlorinated biphenyls are associated with growth among Russian boys. Pediatrics 2011, 127:pe59-pe68. 32. Toms LM et al.: Serum polybrominated diphenyl ether (PBDE) levels are higher in children (2–5 years of age) than in infants and adults. Environ Health Perspect 2009, 117:1461-1465. 33. Calafat AM et al.: Exposure of the U.S. population to bisphenol A and 4-tertiary-octylphenol: 2003–2004. Environ Health Perspect 2008, 116:39-44. 34. Trasande L, Attina TM, Blustein J: Association between urinary bisphenol A concentration and obesity prevalence in children and adolescents. JAMA 2012, 308:1113-1121. Current Opinion in Pharmacology 2014, 19:120–124
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An excellent research paper that presents evidence for childhood obesity related to not only BPA but a few other endocrine disruptors. 35. Eng DS et al.: Bisphenol A and chronic disease risk factors in US children. Pediatrics 2013, 132:e637-e645. 36. Valvi D et al.: Prenatal bisphenol a urine concentrations and early rapid growth and overweight risk in the offspring. Epidemiology 2013, 24:791-799. 37. Harley KG et al.: Prenatal and postnatal bisphenol A exposure and body mass index in childhood in the CHAMACOS cohort. Environ Health Perspect 2013, 121:514-520. 520e1-6. 38. Khalil N et al.: Bisphenol A and cardiometabolic risk factors in obese children. Sci Total Environ 2014, 470–471:726-732. 39. Wang HX et al.: Association between bisphenol A exposure and body mass index in Chinese school children: a cross-sectional study. Environ Health 2012, 11:p79. 40. Steenland K, Fletcher T, Savitz DA: Epidemiologic evidence on the health effects of perfluorooctanoic acid (PFOA). Environ Health Perspect 2010, 118:1100-1108. 41. Timmermann CA et al.: Adiposity and glycemic control in children exposed to perfluorinated compounds. J Clin Endocrinol Metab 2014, 99:E608-E614. 42. Lin CY et al.: Association among serum perfluoroalkyl chemicals, glucose homeostasis, and metabolic syndrome in adolescents and adults. Diabetes Care 2009, 32:702-707. 43. Halldorsson TI et al.: Prenatal exposure to perfluorooctanoate and risk of overweight at 20 years of age: a prospective cohort study. Environ Health Perspect 2012, 120:668-673. 44. Andersen CS et al.: Prenatal exposures to perfluorinated chemicals and anthropometry at 7 years of age. Am J Epidemiol 2013, 178:921-927. 45. Barry V et al.: Early life perfluorooctanoic acid (PFOA) exposure and overweight and obesity risk in adulthood in a community with elevated exposure. Environ Res 2014, 132:62-69. 46. Brauner EV et al.: Long-term exposure to low-level arsenic in drinking water and diabetes incidence: a prospective study of the diet. Cancer and health cohort. Environ Health Perspect 2014, 122:1059-1065.
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47. Wang W et al.: Association of inorganic arsenic exposure with type 2 diabetes mellitus: a meta-analysis. J Epidemiol Community Health 2014, 68:176-184. 48. Su CT et al.: The relationship between obesity, insulin and arsenic methylation capability in Taiwan adolescents. Sci Total Environ 2012, 414:152-158. 49. Saha KK et al.: Pre- and postnatal arsenic exposure and body size to 2 years of age: a cohort study in rural Bangladesh. Environ Health Perspect 2012, 120:1208-1214. 50. Afeiche M et al.: Windows of lead exposure sensitivity, attained height, and body mass index at 48 months. J Pediatr 2012, 160:1044-1049. 51. Faulk C et al.: Perinatal lead (Pb) exposure results in sexspecific effects on food intake, fat, weight, and insulin response across the murine life-course. PLOS ONE 2014, 9:e104273. 52. Kim R et al.: A longitudinal study of chronic lead exposure and physical growth in Boston children. Environ Health Perspect 1995, 103:952-957. 53. Grun F: The obesogen tributyltin. Vitam Horm 2014, 94:277-325. 54. Tweed JO et al.: The endocrine effects of nicotine and cigarette smoke. Trends Endocrinol Metab 2012, 23:334-342. 55. Ino T: Maternal smoking during pregnancy and offspring obesity: meta-analysis. Pediatr Int 2010, 52:94-99. 56. Koshy G, Delpisheh A, Brabin BJ: Dose response association of pregnancy cigarette smoke exposure, childhood stature, overweight and obesity. Eur J Public Health 2011, 21:286-291. 57. de Onis M, Blossner M, Borghi E: Global prevalence and trends of overweight and obesity among preschool children. Am J Clin Nutr 2010, 92:1257-1264. 58. Reilly JJ, Kelly J: Long-term impact of overweight and obesity in childhood and adolescence on morbidity and premature mortality in adulthood: systematic review. Int J Obes (Lond) 2011, 35:891-898. 59. UNEP/WHO: State of the science of endocrine disrupting chemicals. Geneva, Switzerland: United Nations Environment Programme/World Health Organization; 2012, . A compilation of current scientific evidence linking endocrine disruptors with human and animal health.
www.sciencedirect.com
ScienceDirect Endocrine disruptive compounds and cardio-metabolic risk factors in children Naila Khalil1, Aimin Chen2 and Miryoung Lee3,4 The endocrine disrupting chemicals (EDC) are exogenous chemicals that can disrupt hormonal signaling system. EDCs are ubiquitous in our environment and many EDC are detectable in humans. With the increasing obesity prevalence in children it is imperative to explore the role of EDC as obesogens. This review summarizes recent epidemiological evidence regarding impact of these EDC on weight gain and metabolic outcomes in children. The EDCs include pharmaceuticals, pesticides, industrial by-products, and cigarette smoke. Current evidence suggests a link between early life exposure to some industrial by-products, synthetic hormones and cigarette smoke with weight gain. However, there is inconclusive evidence of an association between exposure to fungicides, dioxin, phytoestrogens, flame retardants, heavy metals and childhood obesity. Addresses 1 3123 Research Blvd., Suite #200, Center for Global Health, Department of Community Health, Wright State University, Boonshoft School of Medicine, Dayton, OH, USA 2 Division of Epidemiology and Biostatistics, Department of Environmental Health, University of Cincinnati, College of Medicine, Cincinnati, OH 45267, USA 3 Lifespan Health Research Center, Department of Community Health, Wright State University, Boonshoft School of Medicine, Dayton, OH 45420-4006, USA 4 Department of Pediatrics, Wright State University, Boonshoft School of Medicine, Dayton, OH 45404-1815, USA Corresponding author: Khalil, Naila ([email protected])
Current Opinion in Pharmacology 2014, 19:120–124 This review comes from a themed issue on Endocrine and metabolic diseases Edited by Scott M Belcher
http://dx.doi.org/10.1016/j.coph.2014.09.015 1471-4892/# 2014 Elsevier Ltd. All right reserved.
Introduction The endocrine system secretes hormones which regulate the metabolic functions of the body. Endocrine disrupting chemicals (EDC) are substances that can alter endocrine system and subsequently cause adverse health effects in an intact organism, or its progeny according to World Health Organization (WHO) [1]. The EDCs are ubiquitous in our environment, and Current Opinion in Pharmacology 2014, 19:120–124
include pesticides, flame retardants, pharmaceuticals, and chemicals in personal care products and housewares. EDCs may be released from these products and absorbed through ingestion, inhalation and dermal contact. EDCs effects are critical during early life when rapid tissue development and metabolic pathways are programmed [2]. Since 1960s, potential harmful effects of EDCs on human, in particular on fetal and child growth and development, have been investigated. Early life exposure to EDCs has been associated with abnormalities in hypothalamic–pituitary–gonadal axis and hypothalamic–pituitary–thyroid axis consequently affecting reproductive, immune, and metabolic [3] or nervous systems [4]. In addition to disorders of sexual developments and various endocrine disorders, certain EDCs called obesogens are related to childhood obesity [5]. Obesogens influence fat accumulation and obesity [6] putatively by disrupting critical lipid and metabolic pathways in early life resulting in permanent changes in fat storage and metabolic homeostasis [3]. This review summarizes recent published epidemiologic research on various EDCs and obesogens in association with childhood obesity and metabolism.
Phthalate esters Phthalates are used as plasticizers in many consumer products such as personal care products, medical equipment, pharmaceuticals, children’s toys, and in food packaging. Children and adults are exposed via diet, dust ingestion and dermal contact [7]. Phthalate metabolites activate peroxisome proliferator-activated receptor and have anti-androgenic and thyroid effects, which may contribute to the development of obesity, more so with developmental exposure at low doses [8]. In addition to cross-sectional and short-term prospective epidemiological studies reporting positive association of phthalates metabolites with adult obesity, emerging evidence suggests similar association in children (reviewed in [8]). Hatch et al. reported association of measures of adiposity and urinary phthalates concentrations among girls in the United States [9]. Using data from National Health and Nutrition Examination Survey (NHANES) in the US, two recent studies indicate that urinary levels of phthalates were associated with higher risk of obesity in children and adolescents [10,11]. A short-term prospective study in children also reported a positive association between urinary phthalate metabolites and body mass index (BMI) in overweight children only [12]. The obesogen effect of phthalate exposure may differ www.sciencedirect.com
Endocrine disruptive compounds and childhood obesity Khalil, Chen and Lee 121
by type of phthalates ester, timing, duration and intensity of exposure, and genetic susceptibility. Furthermore, most evidence so far is based on cross-sectional studies, long term epidemiological studies that measure exposure and outcome at several critical developmental stages are needed to understand the variable obesogen effects of phthalates.
Diethylstilbestrol (DES) A synthetic estrogen, DES, was commonly prescribed to prevent pregnancy related complications in 1950s and is no longer in use [13]. In vivo and in vitro studies report that prenatal and perinatal exposures to DES and environmental agents with weak estrogenic activity (Bisphenol A, genistein) are linked to increase in adiposity and alteration in adipogenesis and glucose metabolism (as reviewed by [14]). A recent paper on the Collaborative Perinatal Project (1959–1974) reported that DES, and lower dose pharmacologic sex hormone use during pregnancy was linked to offspring obesity [13].
Phytoestrogens Infants fed soy protein based formula consume higher levels of isoflavones, a class of phytoestrogens including weakly estrogenic genistein and daidzein compounds [15]. A recent review summarized the studies on soy intake and child growth to 36 months and found similar weight gain among soy fed children compared with children consuming breast milk or cow milk based formula [16]. Among children with different isoflavone intake levels, a study found no difference in baseline BMI at 7 years of age [17].
Pesticides (fungicides and herbicides, DDE) Biomonitoring studies have shown that various pesticides accumulate in humans [18,19]. While health effects of fungicides on various chronic diseases such as cardiovascular disease [20], research is limited on the obesogenic roles of fungicides. Two independent Spanish studies both demonstrated that hexachlorobenzene (HCB), one of persistent organic pollutants (POP) used as fungicide, was positively related to childhood obesity [21,22]. Higher prenatal exposure to HCB was associated with significantly increased risk of rapid growth in infancy, overweight at 14 months of age and childhood obesity at age 6.5 years [22]. DDE is the major metabolite of dichlorodiphenyltrichloroethane (DDT) and persists in the environment and humans. Several birth cohort studies have shown an association between prenatal exposure to DDT and increased childhood weight or BMI, although null findings have also been reported [17,18,23]. Two studies found that DDE exposure was associated with an increase in adiposity [24,25]. Research in Spain showed an association between cord blood DDE and the risk of being overweight at 6.5 years, but significant association was limited to the second tertile [21]. Other studies did not www.sciencedirect.com
found significant association between prenatal DDE concentrations and child BMI or the risk of obesity [23,26,27]. A study in the Faroe Islands found that increased BMI change from 5 to 7 years of age and increased waist circumference in girls was associated with prenatal DDE concentration [28]. Another study in Belgium also suggested a positive association between cord plasma DDE and waist circumference in girls at 7–8 years [29]. More research is needed to clarify the association and to examine postnatal exposures.
Polychlorinated biphenyls (PCBs) Exposure to PCBs during pregnancy has been examined in several cohort studies for the association with child obesity, as reviewed by two publications published in 2011 [25,30]. The literature is inconsistent, but the summarization by Tang–Pe´ronard suggests that prenatal total PCBs concentrations may be associated with an increase in childhood weight or BMI, especially in girls [25]. The analysis of U.S. Collaborative Perinatal Project did not find significant association between serum total PCBs concentrations at third trimester and child obesity or BMI [26]. However, a Spanish study published in 2012 showed the third tertile of cord PCB concentrations was associated with increased risk of being overweight or obese [21]. The latest study from the Faroe Islands found that among girls with pre-pregnant overweight mothers, the fourth quartile of maternal PCBs concentrations was associated with increased BMI at age 7 years compared with the lowest quartile [28]. There is a lack of studies of postnatal exposure to PCBs; also studies of cardiometabolic biomarkers in addition to anthropometric measurement are needed.
Dioxins and furans Exposure to dioxins and furans has been examined in very few epidemiological studies to determine associations with obesity and overweight in children [25,30]. Studies in the Netherlands and Belgium did not find significant associations between dioxin levels and weight in childhood [29]. A study in Russian boys reported reduced BMI z-score at age 11–12 years across quintiles suggesting of inverse relationships between serum dioxin levels and BMI measured three years later [31]. More research is needed to examine both background exposure and high local exposure to dioxins and furans on child growth.
Polybrominated diphenyl ethers (PBDEs) PBDE exposure is universal because of the release from carpet padding, furniture, and electronic products that contains PBDEs as flame retardants. However, epidemiologic study of prenatal and postnatal exposure to PBDEs and child obesity is in its infancy despite suggestive evidence from animal studies [30]. There is a significant need to examine the obesogenic roles of PBDEs, especially in the fact that toddlers and preschoolers have two to three times higher PBDE exposure than adults [32]. Current Opinion in Pharmacology 2014, 19:120–124
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Bisphenol A (BPA)
Lead
BPA is a manmade polycarbonate resin used in plastic products and as coatings in food and beverage containers and is detectable in 93% of the US population, with children [33] having the highest urinary BPA exposure. Cross-sectional studies in children reported the positive association between BPA exposure and increased body weight [34] and higher waist circumference-to-height ratio [35]. However no significant association between BPA exposure and metabolic risk factors was noted. In a Spanish birth cohort study, prenatal (creatinine adjusted urinary) BPA exposure on postnatal growth and obesity was examined. Prenatal BPA was not associated with BMI at 14 months of age but was positively associated with BMI and waist circumference at four years of age [36]. In the CHAMACOS cohort study, however, increasing BPA concentrations in mothers during pregnancy were negatively associated with obesity measures; decreased BMI, body fat, and overweight/obesity among their daughters at nine years of age [37]. In this study, there was positive, cross-sectional relationship between children’s urinary BPA levels and increased adiposity measured at 9 years of age [37]. In overweight or obese Ohio children aged 3–8 years, BPA levels were associated with insulin resistance, higher blood pressure, and other adverse liver and metabolic effects [38]. A Chinese studies report similar associations as Khalil et al. [39]. This emerging evidence needs to be validated through long term prospective studies.
A recent epidemiologic study reported significant associations of maternal lead biomarkers with preterm birth and low birth weight/fetal growth [50]. However, the human evidence for lead exposure and its effect on obesity is inconsistent overall, especially in children as reviewed by La Merrill et al. [30]. Mice exposed to lead in early development manifested increased food intake, weight, and changes in glucose tolerance and insulin response in adulthood [51]. Whereas, results from a human longitudinal study suggested that chronic lead exposure in childhood may result in obesity that persists into adulthood [52]. More research is clearly needed to understand the association between heavy metal exposure in children and obesity.
Perfluorinated alkyl substances Perfluorinated alkyl substances (PFAS) are man-made chemicals, used widely because of their heat stable, non-flammable properties and are detectable globally in human serum, and are associated with increased lipid, and diabetes in adults (reviewed by Steenland et al. [40]) and children [41]. In the US adolescents, increasing serum PFAS levels were related to elevated blood sugar levels, decreased blood insulin, and impaired b-cell function (borderline significance) [42]. In a Danish study, prenatal PFOA exposure was associated with adiposity, and higher insulin and leptin, and inversely associated with adiponectin levels in female children at age 20 [43], other studies reported null association [44,45]
Heavy metals Arsenic
Arsenic exposures through water and food consumption (e.g., rice) are associated with diabetes, metabolic syndrome, and obesity risk in adults [46,47]. Epidemiological data regarding arsenic exposure and its association with metabolic effects in children are sparse. A recent study reported that total urinary arsenic was negatively associated with the BMI in Taiwanese adolescents [48]. In a study of Bangladeshi infants/children, postnatal arsenic exposure was associated with lower body weight and length among girls at age 2 [49]. Current Opinion in Pharmacology 2014, 19:120–124
Organotins
Organotins are tin compounds, widely used in industrial processes, polyvinyl chloride (PVC) plastic manufacturing, and used as biocides. While organotins are found in humans, there are no known population studies showing their association with body mass or adiposity at present [30,53]. Cigarette smoking
Tobacco or nicotine use influences the endocrine system, including body weight, glucose and lipid homeostasis [54]. Prenatal smoking exposure is associated with consequent childhood obesity (reviewed by Ino et al.) [55]. This effect is dose-dependent and is significant even in exposure to paternal smoking (i.e. passive exposure) [56].
Conclusion Current evidence suggests a link between early life exposure to some industrial by-products, synthetic hormones and cigarette smoke with weight gain. However, there is inconclusive evidence of an association between exposure to fungicides, dioxin, phytoestrogens, flame retardants, heavy metals and childhood obesity. The worldwide prevalence of childhood overweight and obesity has increased from 4.2% in 1990 to 6.7% in 2010 [57]. Children who are overweight or obese have a higher risk of being overweight as adults and to suffer from obesity-related morbidity and mortality including cardiometabolic disorders such as hyperlipidaemia, hyperinsulinaemia, hypertension, and atherosclerosis [58]. Around 800 chemicals in current use are thought to be capable of influencing endocrine control of human metabolism [59]. However, significant gaps in knowledge exist in understanding associations between exposures to EDCs and early onset of obesity or diabetes especially in children [1]. These research needs can be addressed by prospective epidemiological studies. www.sciencedirect.com
Endocrine disruptive compounds and childhood obesity Khalil, Chen and Lee 123
Conflict of interest statement All authors declare that they do not have a conflict of interest.
Acknowledgement This was a non-funded review.
References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as: of special interest of outstanding interest 1.
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