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Perturbateurs endocriniens environnementaux et
obésité
Charles Sultan 1 - Unité dEndocrinologie -
Gynécologie Pédiatriques, Service de Pédiatrie
I, Hôpital A. de Villeneuve, Montpellier,
France 2 - Service d Hormonologie
(Développement et Reproduction) , Hôpital
Lapeyronie, Montpellier, France 3 - Institut de
Génétique Humaine, CNRS UPR1142, Montpellier,
France
1er Congrès Santé-Environnement, Marseille, 2013
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Perturbateurs endocriniens environnementaux et
obésité
Impact sur la santé / enfant 1.
différenciation sexuelle masculine (vie fetale
) 2. croissance staturo-pondérale fetale,
post-natale 3. développement
psycho-moteur 4. Obésité 5. timing /
tempo de la puberté (fille) Impact sur la santé
/ adulte 5. Fréquence du cancer du testicule /
jeune 6 . Baisse de la spermatogénèse 7.
Fréquence du cancer de la prostate 8.
Fréquence du cancer du sein 9. Obésité/
troubles métaboliques/DS
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Perturbateurs endocriniens environnementaux et
obésité
Genetics nutrition
environment hunger /
satiety basal metabolic rate
carbohydrate / lipid
flux regulation of adipocyte
proliferation and differentiation
developmental programming of metabolic set
points obesity
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Perturbateurs endocriniens environnementaux et
obésité
2002-2003 Baillie-Hamilton postulated a role for
EED in the etiology of obesity The obesity
epidemic coincides with the marked increase of
industrial chemicals in the environment over the
past 30-40 years The obesity epidemic cannot be
explained only by alterations in food intake
and/or decreased physical activity She cited
numerous studies / EED -
pesticides - BCP -
Phtalates - Bisphénol A
- Solvents
1 weight controlling hormones 2 altered
sensitivity to neurotransmittors 3
altered CNS activity
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Perturbateurs endocriniens environnementaux et
obésité
The  environmental    basis of obesity 1 An
emerging hypothesis is that the obesity epidemic
could be due to the interaction of nutrition and
chemical exposures during vulnerable windows in
development 2 Environmental agents and/or
nutrition act during development to - Alter the
pathways responsible for control of adipose
tissue development - Increase the number of fat
cells - Alter food intake and metabolism -
Alter insulin sensitivity and lipid metabolism
via effects on pancreas, adipose tissue,
liver, Gl tract, brain and muscle
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Perturbateurs endocriniens environnementaux et
obésité

• There is accumulative evidence that factors that
  influence long-term risk of obesity begin very
  early in life
• - in utero nutrition
• - prenatal period an important window of
  vulnerability for adult obesity
• development origins of adult disease paradigm

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Perturbateurs endocriniens environnementaux et
obésité
Animal studies Mice treated in utero with -
DES - tributyltene (TBT) -
perfluorooctanoic acid (PFA) increase in
body weight as adults, . elevated lipid
accumulation in adult . low neonatal body
weight adult obesity
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Perturbateurs endocriniens environnementaux et
obésité
DES a good model compound to study the effects
of EED / obesity 1 Low dose of DES , prenatal
life pubertal obesity
excessive abdominal fat 2 Prior to overweight
/ obesity ? leptin ? adiponectin ?
IL-6 ? glucose levels 3 Balance of activity
levels / food intake ? food intake
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Perturbateurs endocriniens environnementaux et
obésité
DES a good model compound to study the effects
of EED / obesity 4 Developmental genes /
origin of obesity
alteration of gene expression involved in
programing adipocytes development
genes involved in fat distribution EED play a
role in regulating the expression of
obesity-related genes during development
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Perturbateurs endocriniens environnementaux et
obésité
Obesogens molecules that inappropriately
regulate lipid metabolism and adipogenesis to
promote obesity - DES - Bisphenol A -
Phtalates - organochlorine pesticides -
PCB The list continues to growth !
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Perturbateurs endocriniens environnementaux et
obésité
Mechanisms of action 1 most EED long half
life 2 some EED metabolized / more toxic
compounds 3 BPA, not persistent in the
environment but so widespread in their use
/ prevalent exposure humans and wild
life are exposed dayly to thousands of
compounds - if none reach an effective level /
toxic - the combination or mixture of chemicals
is dangerous !
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Perturbateurs endocriniens environnementaux et
obésité
Mechanisms of action age of exposure is
important (fetal, neonatal, infancy) alteration
of DNA sequences / gene mutation modification
of DNA methylation and histones acetylation /
dysregulation of gene expression (
epigenetics)
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Perturbateurs endocriniens environnementaux et
obésité
Mechanisms of action EED can interfere with
multiple hormonal systems estrogen receptor /
regulation . glucose transport .
mitochondrial activity . lipid
metabolism / modulation . neuronal
networks / food intake
/ insulin resistance impaired
glucose tolerance
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Perturbateurs endocriniens environnementaux et
obésité
Mechanisms of action thyroid hormone
receptor / antagonist . dev. Brain .
glucose oxydat glucocorticoid horm. Rc / 11b
OHSD / adipose tissue Pregnane X Rc
Constitutive Androstene-Rc energy metabolism
Aryl hydrocarbone -Rc
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Perturbateurs endocriniens environnementaux et
obésité
Bisphenol A EED 1 ER agonist (ERa, b, g
) 2 antiandrogen 3 recrutment of co
factors 4 non-genomic action
(GPR-30) Metabolic action 1 Glucose
homeostasis hyper Ins.
Ins. Resistance 2 adipose tissue
- -
adiponectine
- ? IL-6
- ? TNF a
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Perturbateurs endocriniens environnementaux et
obésité
Brain / energy regul
EED
stomach
liver
pancreas
Adipocyte
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Parabens /widely used as preservatives in -
cosmetics - toiletries - food -
pharmaceuticals Parabens 1 - promotes
adipogenesis adipocytes differentiation 2 -
activates glucocorticoid Rc and PPARg 3
promotes conversion of multipotent stromal
cells adipocytes
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Perturbateurs endocriniens environnementaux et
obésité
Role of EED in the development of obesity in
humans studies 1 Relation of OC pesticides and
BMI 2 Strong association prenatal DDE / BMI
child 3 Transplacental DDE / ? weight
adolescent males 4 2 fold higher risk of
obesity in children whose cord blood levels of OC
pesticides ? 5 Male offsprings of women who
worked in greenhouse during pregnancy
? BMI gt 6.10 yrs 6 Association between
phtalates and BMI (males) But confounding
variables !
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• Developmental exposure to EDD and adult obesity
• Conclusion
• 1 The EED that impact obesity have been
  referred to as  obesogens 
• 2 The obesity epidemic is recent in origin and
  is related to increased to man made chemicals /
  occupation al and environmental settings
• 3 Experimental evidence shows a role for
  increased exposures to EED in the etiology of
  obesity

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• Developmental exposure to EDD and adult obesity
• Conclusion
• 4 Many substances (DES, estrogens) have been
  used for decad to promote fattening / growth of
  farms animals
• 5 Increasing evidence in animal models (human)
  that in utero exposure to EED alters
  developmental programing
• - of adipose tissue development
• - of gastro-intestinal hypothalamic
  food intake regulatory
  system
• altered gene expression
  (epigenetics)

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OBESOGENS JUST THE TIP OF THE ICEBERG ?
PFOA BISPHENOL A
PCBs PHTALATES
ORGANOPESTICIDES TRIBUTYLTIN
6 2009
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Parabens
10 !! 2013
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