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

2. The New Disease Paradigm: Developmental Origins of Disease The environment during development.. stress, nutrition, environmental exposures, infections and drugs: –Functional changes or aberrant developmental programming, permanently alters gland, organ or system potential Alter gene expression and/or protein regulation Persist throughout life –Developmental changes lead to increased susceptibility to disease A bad start…lasts a lifetime!

3. Developmental Basis of Disease: Obesity and Diabetes Does sensitivity to develop obesity and diabetes have their origins during development…and do environmental chemicals exposures play a role? Note: Obesity contributes to diabetes

4. Interrelationship: Obesity, Diabetes and Metabolic Syndrome Increased Adipose Tissue Altered Glucose Tolerance/Insulin Sensitivity Increased Lipids, Blood Pressure, Cardiovascular Disease Inflammation

5. Energy balance endocrine system is sensitive to disruption by endocrine disrupting chemicals. Obesity and Diabetes: Due to Disruption of the Endocrine System Controlling Energy Balance Badman and Flier science 2005

6. Energy balance endocrine system is sensitive to disruption by endocrine disrupting chemicals. Obesity/ Diabetes: Due to Disruption of the Endocrine System Environmental chemicals can alter the “setpoint” controlling energy balance: weight control and glucose tolerance/insulin sensitivity: how much food it takes to put on weight/and or alter glucose tolerance…. and also how much exercise is needed to reduce weight and improve glucose tolerance.. Environmental chemicals can alter the “setpoint” controlling energy balance: weight control and glucose tolerance/insulin sensitivity: how much food it takes to put on weight/and or alter glucose tolerance…. and also how much exercise is needed to reduce weight and improve glucose tolerance.. Badman and Flier science 2005

7. The Developmental Basis of Obesity/Diabetes: Obesogen or Metabolic Disruption Hypothesis We hypothesize that environmental agents and/or nutrition 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 –Control beta cell function and glucose tolerance and insulin sensitivity thereby altering the programming of the energy balance “setpoint” or sensitivity for developing metabolic derangement later in life leading to obesity and diabetes.

8. Obesogens – Just the Tip of the Iceberg? Tributyl Tin EstradiolPFOAGenisteinLead DES Phthalates Nicotine Air Pollution Benzo[a]pyrene (PAH)Monosodium Glutamate Bisphenol APBDEs?PCBs? Organophosphate Pesticides (Parathion, Diazinon, Chlorpyrifos) Fructose?

9. Environmental Exposures and 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) Type 2 DiabetesType 1 Diabetes

10. What are the Public Health Implications of this Hypothesis? Hypothesis changes focus: Obesity is set (programmed) during development…perhaps in utero. Changes focus 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 Focus on development of biomarkers to indicate developmental exposures and thereby increased susceptibility and on prevention as well as intervention strategies. Obesity is complex and due to multiple interacting factors…it is likely that environmental agents play a role in a subset of obese people. The size of this subset is unclear!

11. THE END… or just the beginning?