Mechanisms of hormones in obesity

ROLE OF ENDOCRINE DISRUPTORS in OBESITY

Obesity prevalence• WHO estimates doubled since 1980

• In 2008, 10% of the men and 14% of the womenin the world were obese, compared with 5% formen and 8% for women in 1980

• at least 2.8 million adults die each year as a resultof being overweight or obese

• Notably, prevalence has increased in children andadolescents in developed countries

• 23.8% of boys and 22.6% of girls were overweightor obese in 2013

World Health Organization. Obesity and Overweight Fact Sheet No. 311. Geneva, Switzerland: World Health Organization; 2015.

Epidemiology of Obesity

– In 2013, an estimated one in three adults worldwide was overweight or obese

– Adult obesity exceeded 50% in several countriesaround 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. 2015 July ; 33(7): 673–689.

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. 2015 Oct;53(10):596-607

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;14:1107–12.

Koebrick C, et al. Prevalence of extreme obesity in a multi-ethnic cohort of children and adolescents. J Pediatr. 2010;157:26–31.e2

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;26:437–441

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;153:4097–4110.

“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;8:185–192.

Heindel JJ. Endocrine disruptors and the obesity epidemic. Toxicol Sci. 2003;76:247–249.

“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: 2141–2155.

Janesick A. Endocrine disrupting chemicals and the developmental programming of adipogenesis

and obesity. Birth Defects Res C Embryo Today. 2011;93:34 –50.

Developmental origins of health anddisease (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.

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

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

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 EnvironEpidemiol. 2015;25(3):271–277.

EXPOSURE OFENDOCRINE 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;38:5306-11.

Cichna-Markl M. Sample clean-up by sol-gel immunoaffinity chromatography for the determination of bisphenol A in food and urine. Methods 2012;56:186-91.

Exposure sources and routes of endocrine disruptors in human

Exposure sources and routes of endocrine disruptors in human

Environmental obesogenic endocrine disruptors

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 continuouslyDodds 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) 2007–2008. Environ Health Perspect. 2011; 119:1396–1402

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 #905B07006. 2007

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 #905B07006. 2007

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.

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.

Polychlorinated biphenyls ethers

• PCBs were mass-produced globally from the late1920s 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;112:1051–1053.

Lauby-Secretan B, et al. Carcinogenicity of polychlorinated biphenyls and polybrominated biphenyls. Lancet Oncol. 2013;14:287–288.

• 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.

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

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;135:175–82.

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;34:925–38.

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

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;67:766–774.

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;100:663–671.

Hardell L, et al. Adipose tissue concentrations of p,p’-DDE and the risk for endometrial cancer. Gynecol Oncol. 2004;95:706–711

BPA and phthalates “body burden”

• Serum or urine levels of these chemicals, reflect the total amounts of these chemicals present in the human body

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

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 early-onset 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;284:878–881

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

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;24:1570–1580.

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;155:1667–1678.

Inhibition of endocrine receptors

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;79:1147–56.

Obesity mechanism

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, 1999–2002. Environ Health. 2008;7:27.

Summary of the mechanisms of action of obesogenic endocrine disruptors

“Vicious

Spiral”

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

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;53:345–353.

Neel BA, Brady MJ,.The endocrine disrupting chemical tolylfluanid alters adipocyte metabolism via glucocorticoid receptor activation. Mol Endocrinol. 2013; 27:394–406.

• 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

• Reduced energy expenditure and impaired thermogenesis :

perinatal exposure to environmentally

relevant doses of DDT

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

Epigenetic changes Mechanisms

• Methylation of cytosine residues on

DNA

• Post-translational modification of histones

• Altered microRNA expression

This important body of work has shown

• Ancestral environmental exposures may influence the predisposition to obesity even without direct exposure to the environ-mental compound

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.

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.

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