1. 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
FreedR05_2446 v04.ppt

2. 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% %–14% %–19% %–24% %–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
Insulin resistance
Glucose intolerance
Health Risks
Hypertension
Cardiovascular diseases
Caronary artery diseases
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 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…

6. 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

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 Week 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 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

14. 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.

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.
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.

17. 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

18. 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

19. 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

20. 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

21. 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.

22. 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

23. 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

24. 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

25. 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

26. 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

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?
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

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