Mechanisms of hormones in obesity. ROLE OF ENDOCRINE DISRUPTORS in OBESITY

Transcription

1 Mechanisms of hormones in obesity ROLE OF ENDOCRINE DISRUPTORS in OBESITY

2 Obesity prevalence WHO estimates doubled since 1980 In 2008, 10% of the men and 14% of the women in the world were obese, compared with 5% for men and 8% for women in 1980 at least 2.8 million adults die each year as a result of being overweight or obese Notably, prevalence has increased in children and adolescents in developed countries 23.8% of boys and 22.6% of girls were overweight or obese in 2013 World Health Organization. Obesity and Overweight Fact Sheet No Geneva, Switzerland: World Health Organization; 2015.

3 Epidemiology of Obesity In 2013, an estimated one in three adults worldwide was overweight or obese Adult obesity exceeded 50% in several countries around the globe Prevalence of adult obesity in the developed world seems to have stabilized Prevalence of obesity in children and adolescents globally, as well as adults obesity in developing countries, is still increasing The Epidemiology of Obesity: Pharmacoeconomics July ; 33(7):

4 Obesity in IRAN Above 18 as 21.7% (CI 95%: 18.5% - 25%) Below 18 as 6.1% (CI 95%: 6.8%-5.4%) An ascending trend in the prevalence of obesity in Iran Investigation of the Prevalence of Obesity in Iran: a Systematic Review and Meta- Analysis Study. Acta Med Iran Oct;53(10):

5 Obesity of children under 2 years Rise in obesity of children under 2 years of age unlikely that such young children would have been affected by eating so much more food and taking so much less exercise than in previous generations Altered environment in utero or postnatally which is affecting fat deposition in early life Kim J et al. Trends in overweight from 1980 through 2001 among preschool-aged children enrolled in a health maintenance organization. Obesity (Silver Spring). 2006;14: Koebrick C, et al. Prevalence of extreme obesity in a multi-ethnic cohort of children and adolescents. J Pediatr. 2010;157:26 31.e2

6 Etiology of obesity Energy imbalance when intake of energy is higher than expenditure Changes in lifestyle (eg, increase in stress or sedentary habits, changes in diet) Increased exposure to Gene-by- environment interaction (Studies of the heritability of obesity in monozygotic and dizygotic twins ) Segal NL, Allison DB. Twins and virtual twins: bases of relative body weight revisited. Int J Obes Relat Metab Disord. 2002;26:

7 Definition of EDCs An exogenous chemical, or mixture of chemicals, that interferes with any aspect of hormone action Zoeller RT, et al. Endocrine-disrupting chemicals and public health protection: a statement of principles from the Endocrine Society. Endocrinology. 2012;153:

8 Obesogens In 2002, Baillie-Hamilton hypothesized the obesogenic action of toxic chemicals, based on the parallel increase of pollutants and the incidence of obesity Baillie-Hamilton PF. Chemical toxins: a hypothesis to explain the global obesity epidemic. J Altern Complement Med. 2002;8: Heindel JJ. Endocrine disruptors and the obesity epidemic. Toxicol Sci. 2003;76:

9 Obesogen hypothesis Prenatal or early-life exposure to certain EDCs predisposes some individuals to gain fat mass and become obese Grün F, et al. Endocrine-disrupting organotin compounds are potent inducers of adipogenesis in vertebrates. Mol Endocrinol. 2006;20: Janesick A. Endocrine disrupting chemicals and the developmental programming of adipogenesis and obesity. Birth Defects Res C Embryo Today. 2011;93:34 50.

10 Developmental origins of health and disease (DOHaD) hypothesis An adverse environment experienced by a developing individual can increase the risk of disease later in life The DOHaD paradigm : Links between poor nutrition in utero and increased risk in offspring of obesity, CVD, and diabetes mellitus over a life span Barker DJ. The fetal and infant origins of adult disease. BMJ. 1990;301:1111.

11 EDCs exposure during ontogenesis Development is one-way street Hormones as well as exposures to exogenous environmental chemicals, alter this unidirectional process Effects are often permanent and can affect organ development and function Lifetime consequences

12 EDCs Adulthood exposure May elicit effects such as weight gain ( obesogens ) and/or insulin resistance and hyperinsulinemia ( diabetogens ) May be reversible if the insult is removed, exposure in the real world is more often continuous and to a mixture of chemicals

13 EDCs exposure Accidental release: into the air, food, and water leaching from the product they are contained in, volatilization (aerosolization), as food residues after agricultural application lipophilic distribution into milk from body stores Dermal absorption : Lotions, sunscreens, soaps, Occupational exposure : exposure to higher concentrations than the average resident Myers SL, Estrogenic and anti-estrogenic activity of off-theshelf hair and skin care products. J Expo Sci Environ Epidemiol. 2015;25(3):

14 EXPOSURE OF ENDOCRINE DISRUPTORS Food is the major route of exposure to endocrine disruptors a total of 32 food samples from three major supermarket chains in Dallas were contaminated with Polybrominated diphenyl ethers, mainly in fish, meat, and dairy products BPA exposure also occurs through diet, including contaminated food and water Schecter A,. Polybrominated diphenyl ethers contamination of United States food. Environ Sci Technol 2004;38: Cichna-Markl M. Sample clean-up by sol-gel immunoaffinity chromatography for the determination of bisphenol A in food and urine. Methods 2012;56:

15 Exposure sources and routes of endocrine disruptors in human

16 Exposure sources and routes of endocrine disruptors in human

17 Environmental obesogenic endocrine disruptors

18 Bisphenol A Bisphenol A (BPA) was first synthesized in 1891 and was discovered to be estrogenic in 1936 It is used in a very wide array of manufacturing, food packaging, toys, water bottles, linings of water pipes, coatings on food and beverage cans, thermal paper and dental sealants It can leach out from plastic containers Virtually everyone is exposed continuously Dodds EC. Synthetic oestrogenic agents without the phenanthrene nucleus. Nature. 1936;137:996. Meeker JD, Relationship between urinary phthalate and bisphenol A concentrations and serum thyroid measures in U.S. adults and adolescents from the National Health and Nutrition Examination Survey (NHANES) Environ Health Perspect. 2011; 119:

19 Phthalates In plastics, coatings, cosmetics, and medical tubing First introduced in 1920s Plasticizers to increase the flexibility, transparency and durability of plastic materials Not chemically bound to the plastic, can leach into the environment U.S. Environmental Protection Agency. Phthalates: TEACH Chemical Summary. Document #905B

20 Phthalates Adhesives, paints, packaging, children s toys, electronics, flooring, medical equipment, personal care products, air fresheners, food products, pharmaceuticals and textiles Detectable in human urine, serum, and milk samples U.S. Environmental Protection Agency. Phthalates: TEACH Chemical Summary. Document #905B WuMT, et al. The public health threat of phthalate-tainted foodstuffs in Taiwan: the policies the government implemented and the lessons we learned. Environ Int. 2012;44:75 79.

21 Atrazine (ATR) (2-chloro-4-ethylamino-6-isopropylamino-s-triazine) Widely used herbicide used to control broadleaf and grass weed growth on crops such as commercial corn, sorghum, and sugar cane Christmas tree farms, parks, and golf courses also use ATR Groundwater contaminants and the most commonly detected pesticide in US surface waters, including drinking water Agency for Toxic Substances and Disease Registry. Toxicological Profile for Atrazine. Atlanta, GA: U.S. Department of Health and Human Services, Public Health Service; 2003.

22 Polychlorinated biphenyls ethers PCBs were mass-produced globally from the late 1920s until they were banned in 1979 plasticizers in rubber and resins, carbonless copy paper, adhesives, and paints and inks Widespread environmental contamination, including buildings and schools Herrick RF, An unrecognized source of PCB contamination in schools and other buildings. Environ Health Perspect. 2004;112: Lauby-Secretan B, et al. Carcinogenicity of polychlorinated biphenyls and polybrominated biphenyls. Lancet Oncol. 2013;14:

23 These persistent organic pollutants (POPs) bioaccumulate in the environment and are stored in body fat They have thyroidogenic, estrogenic, and antiandrogenic actions Agency for Toxic Substances and Disease Registry. Toxicological Profile for Polybrominated Biphenyls and Polybrominated Diphenyl Ethers (PBBs and PBDEs). Atlanta, GA: U.S. Department of Health and Human Services, Public Health Service; 2004.

24 Polybrominated diphenyl ethers(pbdes) Began in the late 1970s They were used as Flame retardants in upholstered products, mattresses, and clothing Agency for Toxic Substances and Disease Registry. Toxicological Profile for Polybrominated Biphenyls and Polybrominated Diphenyl Ethers (PBBs and PBDEs). Atlanta, GA: U.S. Department of Health and Human Services, Public Health Service; 2004

25 4-Nonylphenol Used as a surfactant in industrial and domestic applications White R, Jobling S, Hoare SA, et al. Environmentally persistent alkylphenolic compounds are estrogenic. Endocrinology. 1994;135:

26 Parabens (alkyl esters of p-hydroxybenzoic acid) Used as antimicrobial agents for the preservation of personal care products, foods, pharmaceutical products and paper products Widely present in human tissues including breast tissue Have estrogenic properties Darbre PD, Harvey PW. Parabens can enable hallmarks and characteristics of cancer in human breast epithelial cells: a review of the literature with reference to new exposure data and regulatory status. J Appl Toxicol. 2014;34:

27 Phytoestrogens Ingested by humans in the diet in edible plant material Isoflavones such as genistein and daidzein are found in soybeans, legumes, lentils and chickpeas

28 TBT (tributyltin) Widely used as an pesticide in marine paints or as an antifungal for textiles Acts as an agonist of PPAR and retinoid X receptor (RXR) Promotes adipogenesis in the preadipocyte Kanayama T, Organotin compounds promote adipocyte differentiation as agonists of the peroxisome proliferatoractivated receptor #/retinoid X receptor pathway. Mol Pharmacol. 2005;67:

29 DDT and DDE DDT is a synthetic industrial and household insecticide with a long half-life, extensive use, and lipophilic nature Banned in 1972 Associated with endocrine-related diseases such as testicular tumors endometrial cancer, pancreatic cancer,t2d and breast cancer McGlynn KA, Persistent organochlorine pesticides and risk of testicular germ cell tumors. J Natl Cancer Inst. 2008;100: Hardell L, et al. Adipose tissue concentrations of p,p -DDE and the risk for endometrial cancer. Gynecol Oncol. 2004;95:

30 BPA and phthalates body burden Serum or urine levels of these chemicals, reflect the total amounts of these chemicals present in the human body

31 PCBs, PBDEs, DDT, and DDE body burden Persistent organic pollutants (POPs) Highly lipophilic and accumulate in the food chain and in white adipose tissue (WAT) Limit the ability to estimate the real burden of these chemicals from measurements in serum or urine WAT contains a large reservoir of POPs that are liberated into blood, especially during weight loss periods

32 Diethylstilbestrol and beyond Potent synthetic nonsteroidal estrogen taken by pregnant women from the 1940s to 1975 to prevent miscarriage Its use was discontinued when a subset of exposed daughters presented with earlyonset vaginal clear-cell adenocarcinoma, with a 40-fold increase in risk Herbst AL, Ulfelder H, Poskanzer DC. Adenocarcinoma of the vagina. Association of maternal stilbestrol therapy with tumor appearance in young women. N Engl J Med. 1971;284:

33 Exposure to diethylstilbestrol (DES)during the neonatal period predisposes to obesity in mice at 4 6months of age

34 Endocrine systems interactions by EDCs Some EDCs, bind to hormone receptors (as agonists or antagonists) Alter number of hormone receptors Alter concentration of hormones Xu XB, He Y, et al. Bisphenol A regulates the estrogen receptor $ signaling in developing hippocampus of male rats through estrogen receptor. Hippocampus. 2014;24: Martinez-Arguelles DB, et al. In utero exposure to the endocrine disruptor di-(2-ethylhexyl) phthalate induces long-term changes in gene expression in the adult male adrenal gland. Endocrinology. 2014;155:

35 Inhibition of endocrine receptors

36 Obesogens Acting through Interference with PPARs PPARs act as lipid sensors PPARγ functions in energy storage adipogenesis PPARs act by heterodimerisation with retinoid X receptors (RXRs) Activation of RXR-PPARγ favours the differentiation of adipocyte progenitors and preadipocytes in adipose tissue and regulates lipid biosynthesis and storage Tontonoz P,. Stimulation of adipogenesis in fibroblasts by PPAR gamma2, a lipid-activated transcription factorcell. 1994;79:

37 Obesity mechanism

38

39 Any ligand which can bind to the PPARγ will be able to influence adipogenesis and obesity BPA Nonylphenol Fungicide triflumizole Phthalate metabolite Parabens Hatch EE, et al. Association of urinary phthalate metabolite concentrations with body mass index and waist circumference: a cross-sectional study of NHANES data, Environ Health. 2008;7:27.

40 Summary of the mechanisms of action of obesogenic endocrine disruptors

41 Vicious Spiral

42 The Vicious Spiral of Obesogenic EDC Actions and Human Health Many EDCs are lipophilic POPs in particular are known to accumulate in body fat Link of obesity to disease relates not just simply to the deposition of fat but to the increased retention of lipophilic pollutants in the greater volume of fat Obesogens may be self-fulfilling and be able to increase capacity for their own retention

43 Other mechanisms: Cellular models DES and BPA through ERs Binding of EDCs to GRs pesticide tolylfluanid, widely used in Europe, bound to GR and promoted preadipocyte differentiation in vitro. It also increased insulin-stimulated lipogenesis Ohlstein JF. Bisphenol A enhances adipogenic differentiation of human adipose stromal/stem cells. J Mol Endocrinol. 2014;53: Neel BA, Brady MJ,.The endocrine disrupting chemical tolylfluanid alters adipocyte metabolism via glucocorticoid receptor activation. Mol Endocrinol. 2013; 27:

44 BPA decreased locomotor activity, a measure of energy expenditure, after 8 days of exposure in adult male mice, suggesting that it alters central energy regulatory pathways

45 Reduced energy expenditure and impaired thermogenesis : perinatal exposure to environmentally relevant doses of DDT

46 Epigenetics and transgenerational effects of EDCs Some EDCs may cause epigenetic changes, which in turn may lead to Trans generational effects During early development OR During adulthood a mix of plastic derivatives used in consumer and industrial applications (BPA, and phthalate) promotes the epigenetic trans generational inheritance of adult-onset obesity in rats

47 Epigenetic changes Mechanisms Methylation of cytosine residues on DNA Post-translational modification of histones Altered microrna expression

48 This important body of work has shown Ancestral environmental exposures may influence the predisposition to obesity even without direct exposure to the environmental compound

49 OBESITY : Storage of lipophilic environmental pollutants Non-obesogenic EDCs Non-obesogenic non-edc environmental chemicals some xenobiotics are known to form fatty acid conjugates which themselves exert local toxicities Ansari GAS, et al. Fatty acid conjugates of xenobiotics. Toxicol Lett. 1995;75:1 17.

50 Breastfeeding Early-life exposure to obesogens could result in a greater life- time burden of lipophilic pollutants Whilst the release of lipophilic pollutants in breast milk fat during breastfeeding may serve to detoxify the mother s breasts, adverse consequences for the baby have long been a concern Van den Berg M, et al. WHO/UNEP global surveys of PCDDs, PCDFs, PCBs and DDTs in human milk and benefit-risk evaluation of breastfeeding. Arch Toxicol. 2017;91:83 96.

51 Sudden weight loss Such as through dieting, could also cause the release of lifetime bioaccumulated pollutants from body fat with untoward consequences if the release were too fast for the body to eliminate the compounds sufficiently quickly