Jerrold J. Heindel PhDScientific Program Administrator
National Institute of Environmental Health SciencesNational Institutes of Health/DHHS
Developmental and Environmental Origins of Obesity: A Bad Start
Lasts a Lifetime
1999
Obesity Trends* Among U.S. AdultsBRFSS, 1990, 1999, 2008
(*BMI 30, or about 30 lbs. overweight for 5’4” person)
2008
1990
No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30%
Why Do We Care About Obesity??Why Do We Care About Obesity??
Health Health RisksRisks
Hypertension•Cardiovascular diseases
Caronary artery diseasesStroke
•Many forms of cancerendometrialprostatebreastcolon
•Reproductive disease
•PCOS
•Liver disease
•Fatty liver
•Gallbladder disease
•Respiratory disease
•Sleep disorders
•Arthritis
•Edema
•Dislipidemia
•Type II diabetesInsulin resistanceGlucose intolerance
Proposed Causes of ObesityProposed 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 ParadigmCurrent 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…
Developmental Origins of Disease: Developmental Origins of Disease: Altered Developmental Programming Lead to Disease Throughout Life 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.
Stages of Prenatal and Postnatal Organ DevelopmentStages of Prenatal and Postnatal Organ Development
Central nervous system (3wks - 20 years)Central nervous system (3wks - 20 years)
Ear (4-20 wks)Ear (4-20 wks)
Kidneys (4-40 wks)Kidneys (4-40 wks)
Heart (3-8)Heart (3-8)
Immune system (8-40 wks; competence & memory birth-10yrs)Immune system (8-40 wks; competence & memory birth-10yrs)
Adipose tissueAdipose tissue
Lungs (3-40 wks; alveoli birth-10yrs)Lungs (3-40 wks; alveoli birth-10yrs)
Reproductive system (7-40wks; maturation in puberty)Reproductive system (7-40wks; maturation in puberty)
Skeleton (1-12 wks)Skeleton (1-12 wks)
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: Developmental Origin of Adult Disease: Barker HypothesisBarker 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
D. Barker, Trends in Endocrinology and Met. (2010)
Fetal Origin of Adult Disease (FEBAD) confirmed for:
• Coronary heart disease• Hypertension• Type II diabetes/obesity
Developmental Origins of Obesity: Role of Nutrition in Developmental Origins of Obesity: Role of Nutrition in HumansHumans
• 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 Transgenerational ObesityObesity
Waterland et al, Int J Obesity 2008
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.
Endocrine Control of Development and Tissue Endocrine Control of Development and Tissue FunctionsFunctions
• 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!
HERBICIDES2,4,-D2,4,5,-TAlachlorAmitroleAtrazineLinuronMetribuzinNitrofenTrifluralin
FUNGICIDESBenomylEthylene thioureaFenarimolHexachlorobenzeneMancozebManebMetiram - complexTri-butyl-tinVinclozolinZineb
METALS
INSECTICIDESAldicarbbeta-HCHCarbarylChlordaneChlordeconeDBCPDicofolDieldrinDDT and metabolitesEndosulfanHeptachlor / H-epoxideLindane (gamma-HCH)MalathionMethomylMethoxychlorOxychlordaneParathionSynthetic pyrethroidsTransnonachlorToxaphene
INDUSTRIAL CHEMICALSBisphenol - A PolycarbonatesButylhydroxyanisole (BHA)CadmiumChloro- & Bromo-diphenylDioxinsFuransLeadManganeseMethyl mercuryNonylphenolOctylphenolPBDEsPCBsPentachlorophenolPenta- to NonylphenolsPerchloratePFOAp-tert-PentylphenolPhthalatesStyreneTestosterone synthesis inhibitor Estrogen receptor agonist
Thyroid hormone disruptor Androgen receptor antagonist
Endocrine Disrupting Chemicals
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)
Why are There Sensitive Windows and Why are There Sensitive Windows and Persistent effects?Persistent effects?
A Paradigm Shift in ToxicologyEpigenetics
•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: EpigeneticsDevelopmental 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.
Normal Stem Cell
CG CG
CG CG
Normal Growth and Development
CG CG
CG CG
CH3
Hormones
Disease/Dysfunction
Altered Gene Expression persists
Abnormal Growth & Development
EDCs
EDCs
Changes in DNA methylation pattern CG CG
CG CG
CH3
CH3
Epigenetic/Environmental Basis of DiseaseEpigenetic/Environmental Basis of Disease
Epigenetics(stable but plastic)
Genetic polymorphisms(born with)
Inter-individual variability
Environmental Stressors
Susceptibility to Disease, Toxicants, Drugs, Altered behavior
(Chemicals, diet, drugs,
stress, infections)
Both Genetics and Epigenetics Control Our HealthBoth Genetics and Epigenetics Control Our Health
Shuk mei Ho
Developmental Basis of Disease: ObesityDevelopmental Basis of Disease: Obesity• Are there data indicating that obesity has its origins during
development…and do environmental chemicals exposures play a role?
Endocrine system controls metabolism/weight and is therefore sensitive to disruption by endocrine disrupting
chemicals leading to obesity.
Obesity: Due to Disruption of the Endocrine SystemObesity: Due to Disruption of the Endocrine System
Badman and Flier science 2005
Metabolic Set Point Programmed by Chemical Metabolic Set Point Programmed by Chemical Exposures During DevelopmentExposures During Development
Hypothesis: Developmental chemical exposures may induce metabolic shifts that alter regulation of energy balance weight gain
Weight gain Weight loss
Altered Programming↑↑ SusceptibilityCertainly 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 The Developmental Basis of Obesity: Obesogen HypothesisHypothesis
• 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
Meta-analysis of Smoking During Pregnancy vs. Overweight
Oken et al, Int J Obes, 2008
Increased adipogenesis
Reduction of sensitivity to insulin
Increased food efficiency (high fat diet)
Reduction of physical activity
Glucose intolerance
Increased b.w and fat mass
Atrophy and apoptosis of pancreatic islets
PrenatalPrenatal//PerinataPerinatal l Nicotine Nicotine ExposurExposuree
Developmental Exposure to DES and Weight GainDevelopmental Exposure to DES and Weight Gain Proof of Principle Proof of Principle
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.
0.05.010.015.02025.030.035040.0450500
1 Month 4 Month
ControlDES
Obesogens – Just the Tip of the Iceberg?
Tributyl Tin
EstradiolPFOA Genistein Lead
DESPhthalates Nicotine Air Pollution (PM2.5)
Benzo[a]pyrene (PAH)Monosodium Glutamate
Bisphenol APBDEs PCBs?
Organophosphate Pesticides (Parathion, Diazinon, Chlorpyrifos)
Fructose?
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 Diabetes Type 1 Diabetes
Public Health Implications of Obesogen Hypothesis?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
THE END…THE END…
or just the beginning?or just the beginning?