5/6/2005 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 FreedR05_2446 v04.ppt

Obesity Trends* Among U.S. Adults BRFSS, 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%

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 Insulin resistance Glucose intolerance Health Risks Hypertension Cardiovascular diseases Caronary artery diseases Stroke Many forms of cancer endometrial prostate breast colon

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

Current Paradigm Focus is on Genetics Focus is on treatment 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…

A bad start…lasts a lifetime! 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 Middle Life Later Life Environmental Exposures, drugs, diet, stress, microbiome

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.

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)

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

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

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.

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!

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 and metabolites 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 inhibitor Estrogen receptor agonist Thyroid hormone disruptor Androgen receptor antagonist

Developmentally-Induced Diseases (Human) 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) 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) Just a few examples of the toxicants that can cause the diseases via developmental exposures in animal models. The important point is that we can show, in animal models, increased incidence of ALL of these diseases with just developmental exposures to one environmental chemical at environmentally relevent doses. Look at the breadth of the diseases…note the ones that have increased in the past 40 years…like cancers, infertility, early puberty, obesity, ADHD, heart disease…The strength of the data varies…such that there are few data on stroke, alzheimers, heart disease and immune autoimmune.

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

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. The effects of developmental exposures persist because altered epigenetic signaling (developmental programming) persists. Examples include DNA methylation of CpG islands or “shores” and chromatin changes or remodeling. The developmental time period is the most sensitive to epigenetic alterations in gene expression that then persist throughout life. Early developmental exposures (along with nutrition, stress, infections) alter epigenetic marks which lead to functional changes which lead to abnormal tissues which lead to disease later in life.

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

Both Genetics and Epigenetics Control Our Health (stable but plastic) Genetic polymorphisms (born with) Inter-individual variability Environmental Stressors Susceptibility to Disease, Toxicants, Drugs, Altered behavior (Chemicals, diet, drugs, stress, infections) It is genentic and epigenetic influences that control our life. Born with genetics and can’t do much about it but epigenetic changes are due to environmental influences during development and also somewhat throughout life. Of importance is these is a whole system equivalent to genetic…epigenetic that is there soley to respond to environmental influences…some positive and many negative. This really shows importance of environment in diseases. Shuk mei Ho

Developmental Basis of Disease: Obesity 5/6/2005 Developmental Basis of Disease: Obesity Are there data indicating that obesity has its origins during development…and do environmental chemicals exposures play a role? FreedR05_2446 v04.ppt

Obesity: Due to Disruption of the Endocrine System 5/6/2005 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 FreedR05_2446 v04.ppt

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 Weight gain Weight loss Altered Programming ↑↑ Susceptibility 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.

The Developmental Basis of Obesity: Obesogen Hypothesis 5/6/2005 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 FreedR05_2446 v04.ppt

Meta-analysis of Smoking During Pregnancy vs. Overweight 5/6/2005 Meta-analysis of Smoking During Pregnancy vs. Overweight Oken et al, Int J Obes, 2008 FreedR05_2446 v04.ppt

Perinatal Nicotine Exposure Gestation Childhood Middle Life Later 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

Developmental Exposure to DES and Weight Gain Proof of Principle 5/6/2005 Developmental Exposure to DES and Weight Gain Proof of Principle 0.0 5.0 10.0 15.0 20 25.0 30.0 350 40.0 450 500 1 Month 4 Month Control DES 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. FreedR05_2446 v04.ppt

Obesogens – Just the Tip of the Iceberg? 5/6/2005 PFOA Estradiol Genistein Lead Fructose? Phthalates DES Nicotine Air Pollution (PM2.5) Tributyl Tin PBDEs Bisphenol A PCBs? Organophosphate Pesticides (Parathion, Diazinon, Chlorpyrifos) Monosodium Glutamate Benzo[a]pyrene (PAH) Obesogens – Just the Tip of the Iceberg? FreedR05_2446 v04.ppt

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)

Public Health Implications of Obesogen Hypothesis? 5/6/2005 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 FreedR05_2446 v04.ppt

THE END… or just the beginning? 5/6/2005 THE END… or just the beginning? FreedR05_2446 v04.ppt