Jerrold J. Heindel PhD Scientific Program Administrator

1. Developmental and Environmental Origins of Obesity: A Bad Start Lasts a Lifetime Jerrold J. Heindel PhD Scientific Program Administrator National Institute of Environmental Health Sciences National Institutes of Health/DHHS heindelj@niehs.nih.gov

2. Obesity Trends* Among U.S. AdultsBRFSS,1990, 1999, 2008 (*BMI 30, or about 30 lbs. overweight for 5’4” person) 1990 1999 2008 No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30%

3. Why Do We Care About Obesity?? • Reproductive disease • PCOS • Liver disease • Fatty liver • Gallbladder disease • Respiratory disease • Sleep disorders • Arthritis • Edema • Dislipidemia • Type II diabetes • Insulinresistance • Glucose intolerance Health Risks Hypertension • Cardiovasculardiseases • Caronaryarterydiseases Stroke • Many forms of cancer • endometrial • prostate • breast • colon

4. Proposed Causes of Obesity • Genetic factors • Environmental factors (nutrition, exercise) • Psychological factors • Stress • Lack of sleep • Illness (hypothyroidism, Cushing’s syndrome) • Drugs (steroids, antidiabetic, antidepressants) • Viruses (adenovirus 36) • Environmental Chemicals

5. Current Paradigm • Focus is on Genetics • Obese at birth or at age 6-10….obese as adult • Some people eat and don’t gain weight • It can’t be only due to genetic mutations….timing! • All diseases have both genetic and environmental component! • Focus is on treatment • Reduce food intake and increase exercise • Highly intractable (90% regain wt in a year) suggesting a “set point” • Programming a “set point” occurs during development • Current approaches are not working…

6. Developmental Origins of Disease: Altered Developmental Programming Lead to Disease Throughout Life A bad start…lasts a lifetime! It is likely that all non infectious complex diseases have their origins during development. Gestation Childhood Puberty Reproductive Life MiddleLife Later Life Environmental Exposures, drugs, diet, stress, microbiome

7. Stages of Prenatal and Postnatal Organ Development Early Prenatal Mid-Late Prenatal Postnatal Central nervous system (3wks - 20 years) Ear (4-20 wks) Kidneys (4-40 wks) Heart (3-8) Adipose tissue Immune system (8-40 wks; competence & memory birth-10yrs) Skeleton (1-12 wks) Lungs (3-40 wks; alveoli birth-10yrs) Reproductive system (7-40wks; maturation in puberty) Week 1-16 Week 17-40 Birth – 25 years Source: Altshuler, K; Berg, M et al. Critical Periods in Development, OCHP Paper Series on Children's Health and the Environment, February 2003.

8. Developmental Origin of Adult Disease: Barker Hypothesis • 1989 David Barker: inverse relationship b/w birth weight and death from heart disease in England and Wales • “Dutch Hunger Winter”: food supply to the Netherlands was cut off by Nazis • Individuals born during this time had increased insulin-resistance as adults • Fetal Origin of Adult Disease (FEBAD) confirmed for: • Coronary heart disease • Hypertension • Type II diabetes/obesity D. Barker, Trends in Endocrinology and Met. (2010)

9. Developmental Origins of Obesity: Role of Nutrition in Humans • Low birth weight (due to nutritional deficiency) results in increased incidence of adult obesity if there is catch-up growth in first few years of life. • Excess Weight gain first 6 months: fat that lasts forever. • Breastfeeding for 4-6 months is protective against childhood obesity. • High birth weight….increased incidence of adult obesity. • Overweight mothers • Gestational diabetes

10. Transgenerational Obesity In a population with a genetic tendency for obesity, effects of maternal obesity accumulate over successive generations to shift the population distribution toward increased adult body weight, and suggest that epigenetic mechanisms are involved in this process. Waterland et al, Int J Obesity 2008

11. Endocrine Control of Development and Tissue Functions • Estrogens • Androgens • Thyroid • Others • Steroid – Glucocorticoid, Vit D, etc. • Non-Steroid – Prolactin, Insulin, etc. • Non-Classical Hormones – Vit A, etc.

12. Some Chemicals Disrupt the Endocrine System “Endocrine Disruptors” Exogenous agents that interfere with the production, release, transport, metabolism, binding, action, or elimination of the natural hormones …a “new” type of toxicity Active at environmentally relevant doses (ppb) Conservation of hormone receptors and pathways across species!

13. Endocrine Disrupting Chemicals HERBICIDES 2,4,-D 2,4,5,-T Alachlor Amitrole Atrazine Linuron Metribuzin Nitrofen Trifluralin FUNGICIDES Benomyl Ethylene thiourea Fenarimol Hexachlorobenzene Mancozeb Maneb Metiram - complex Tri-butyl-tin Vinclozolin Zineb METALS INSECTICIDES Aldicarb beta-HCH Carbaryl Chlordane Chlordecone DBCP Dicofol Dieldrin DDT andmetabolites Endosulfan Heptachlor / H-epoxide Lindane (gamma-HCH) Malathion Methomyl Methoxychlor Oxychlordane Parathion Synthetic pyrethroids Transnonachlor Toxaphene INDUSTRIAL CHEMICALS Bisphenol - A Polycarbonates Butylhydroxyanisole (BHA) Cadmium Chloro- & Bromo-diphenyl Dioxins Furans Lead Manganese Methyl mercury Nonylphenol Octylphenol PBDEs PCBs Pentachlorophenol Penta- to Nonylphenols Perchlorate PFOA p-tert-Pentylphenol Phthalates Styrene Testosterone synthesis inhibitorEstrogen receptor agonist Thyroid hormone disruptor Androgen receptor antagonist

14. Developmentally-Induced Diseases (Human) • Pulmonocardiovascular • Asthma(Air Pollution) • Heart disease/hypertension (BPA) • Stroke (PCBs) • Brain/Nervous System • Alzheimer's disease (Lead) • Parkinson’s disease (Pesticides) • ADHD/learning disabilities (PCBs, Lead, Ethanol, Organochlorine Pesticides) • Reproductive/Endocrine • Breast/prostate cancer (BPA) • Endometriosis (Dioxin, PCBs) • Infertility (Phthalates, Estrogens, Pesticides) • Diabetes/metabolic syndrome (BPA) • Early Puberty (Estrogens, BPA) • Obesity(BPA, Tributyl Tin, Organochlorine Pesticides) • Immune/Autoimmune • Susceptibility to infections (Dioxin) • Autoimmune Disease (Dioxin)

15. Why are There Sensitive Windows and Persistent effects? A Paradigm Shift in Toxicology • Epigenetics • Modifications of DNA and chromatin which can be heritable and affect genome function (transcription, replication, recombination, but don’t affect DNA backbone • Controls cell and tissue differentiation

16. Developmental Programming: Epigenetics • The effects of developmental exposures, persist because they alter epigenetic signaling, which lasts throughout life • DNA methylation of CpG islands or “shores” • Chromatin changes/remodeling • siRNA • The developmental time period is the most sensitive to epigenetic alterations…when tissues are forming.

17. Epigenetic/Environmental Basis of Disease Normal Stem Cell CH3 Normal Growth and Development Hormones EDCs CG CG CG CG CG CG Disease/Dysfunction CG CG CG CG CG CG EDCs CH3 Altered Gene Expression persists Abnormal Growth & Development CH3 Changes in DNA methylation pattern

18. Both Genetics and Epigenetics Control Our Health Environmental Stressors Epigenetics (stable but plastic) (Chemicals, diet, drugs, stress, infections) Genetic polymorphisms (born with) Inter-individual variability Susceptibility to Disease, Toxicants, Drugs, Altered behavior Shuk mei Ho

19. Developmental Basis of Disease: Obesity • Are there data indicating that obesity has its origins during development…and do environmental chemicals exposures play a role?

20. Obesity: Due to Disruption of the Endocrine System Endocrine system controls metabolism/weight and is therefore sensitive to disruption by endocrine disrupting chemicals leading to obesity. Badman and Flier science 2005

21. Altered Programming ↑↑ Susceptibility Weight gain Weight loss Metabolic Set Point Programmed by Chemical Exposures During Development Hypothesis: Developmental chemical exposures may induce metabolic shifts that alter regulation of energy balance  weight gain Certainly food intake and exercise are important but environmental chemicals can alter the “setpoint” for gaining weight…how much food it takes to put on weight…. and also how much exercise is needed to reduce weight.

22. The Developmental Basis of Obesity: Obesogen Hypothesis • We hypothesize that environmental agents act during development to • Control adipose tissue development • Via an increase the number of fat cells • Control food intake and metabolism • Via effects on pancreas, adipose tissue, liver, GI tract, brain and/or muscle thereby altering the programming of the obesity “set-point” or sensitivity for developing obesity later in life

23. Meta-analysis of Smoking During Pregnancy vs. Overweight Oken et al, Int J Obes, 2008

24. Gestation Later Life Childhood Middle Life Prenatal/ Perinatal Nicotine Exposure Increased b.w and fat mass Increased food efficiency (high fat diet) Atrophy and apoptosis of pancreatic islets Reduction of physical activity Glucose intolerance Increased adipogenesis Reduction of sensitivity to insulin

25. Developmental Exposure to DES and Weight Gain Proof of Principle 500 Control 450 DES 40.0 350 30.0 25.0 20 15.0 10.0 5.0 0.0 1 Month 4 Month Exposure of CD-1 mice to DES for 5 days at birth results in increased weight gain starting at puberty in female mice. No change in food intake or exercise. Newbold et al.

26. PFOA Estradiol Genistein Lead Fructose? Phthalates DES Nicotine Air Pollution (PM2.5) PBDEs Tributyl Tin Bisphenol A PCBs? Organophosphate Pesticides (Parathion, Diazinon, Chlorpyrifos) Monosodium Glutamate Benzo[a]pyrene (PAH) Obesogens – Just the Tip of the Iceberg?

27. Environmental Exposures and Diabetes Type 2 Diabetes Type 1 Diabetes • Bisphenol A, DES (estrogens) • POPS (PCBS, dioxins, HCB, DDE) • Organochlorine pesticides • Oxychlordane • Aldrin • Nonachlor • Arsenic • Organophosphate pesticides • Malathion • Diazinon • Air pollution • Nitrates/ nitrite/ nitroso compounds (E/I) • Air pollutants (ozone, sulphates) • PCBs (E/I) • Phthalates (E/I) • Mercury, Cadmium (E/I) • Trichloroethylene (I) • Dioxin (E/I) • Endocrine (E) Immune (I)

28. Public Health Implications of Obesogen Hypothesis? • Hypothesis changes focus from • intervention in adults to prevention during development • from genetics to gene-environment interactions • Changes the focus to prevention • Focus on pregnancy, early childhood and puberty as sensitive periods • Reduced exposures to environmental agents during development • Improved nutrition during development

29. THE END… or just the beginning?