Transcript No Slide Title

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
[email protected]
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
•Type II diabetes
Health Risks •PCOS
Insulin resistance
•Liver disease
Glucose intolerance
Hypertension
•Cardiovascular diseases
Caronary artery diseases
Stroke
•Many forms of cancer
endometrial
prostate
breast
colon
•Fatty liver
•Gallbladder disease
•Respiratory disease
•Sleep disorders
•Arthritis
•Edema
•Dislipidemia
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
•
•
•
•
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:
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 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
INDUSTRIAL CHEMICALS
Aldicarb
Bisphenol - A
beta-HCH
Polycarbonates
Carbaryl
Butylhydroxyanisole (BHA)
Chlordane
Cadmium
Chlordecone
Chloro- & Bromo-diphenyl
DBCP
Dioxins
Dicofol
Furans
Dieldrin
Lead
DDT and metabolites
Manganese
Endosulfan
Methyl mercury
Heptachlor / H-epoxide
Nonylphenol
Lindane (gamma-HCH)
Octylphenol
Malathion
PBDEs
Methomyl
PCBs
Methoxychlor
Pentachlorophenol
Oxychlordane
Penta- to Nonylphenols
Parathion
Perchlorate
Synthetic pyrethroids
PFOA
Transnonachlor
p-tert-Pentylphenol
Toxaphene
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)
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.
Epigenetic/Environmental Basis of Disease
Normal Stem Cell
CH3
Hormones
CG CG
CG CG
Normal Growth and
Development
CG CG
CG CG
EDCs
Disease/Dysfunction
EDCs
CH3
CG CG
Altered Gene Expression
persists
CH3
Changes in DNA
methylation pattern
CG CG
Abnormal Growth &
Development
Both Genetics and Epigenetics Control Our Health
Environmental
Stressors
Epigenetics
(Chemicals, diet, drugs,
(stable but plastic)
stress, infections)
Inter-individual variability
Susceptibility to Disease, Toxicants, Drugs,
Altered behavior
Shuk mei Ho
Genetic polymorphisms
(born with)
Developmental Basis of Disease: Obesity
• Are there data indicating that obesity has its origins during
development…and do environmental chemicals exposures
play a role?
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
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
Altered Programming
↑↑ Susceptibility
Weight loss
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
• 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
Prenatal/
Perinatal
Nicotine
Exposure
Atrophy and
apoptosis of
pancreatic
islets
Increased
adipogenesis
Increased b.w
and fat mass
Increased food
efficiency (high
fat diet)
Reduction of
physical activity
Glucose
intolerance
Reduction of
sensitivity to
insulin
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.
PFOA
Estradiol
Phthalates
Tributyl Tin
Genistein
DES
PBDEs
Lead
Nicotine
Fructose?
Air Pollution (PM2.5)
Bisphenol A
PCBs?
Organophosphate Pesticides (Parathion, Diazinon, Chlorpyrifos)
Monosodium Glutamate
Benzo[a]pyrene (PAH)
Obesogens –
Just the Tip of the Iceberg?
Environmental Exposures and Diabetes
Type 2 Diabetes
Type 1 Diabetes
• Bisphenol A, DES (estrogens)
• Nitrates/ nitrite/ nitroso compounds
(E/I)
• POPS (PCBS, dioxins, HCB, DDE)
• Organochlorine pesticides
– Oxychlordane
– Aldrin
– Nonachlor
• Arsenic
• Organophosphate pesticides
– Malathion
• Air pollutants (ozone, sulphates)
• PCBs (E/I)
• Phthalates (E/I)
• Mercury, Cadmium (E/I)
• Trichloroethylene (I)
• Dioxin (E/I)
– Diazinon
• Air pollution
Endocrine (E) Immune (I)
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…
or just the beginning?