Perturbateurs endocriniens environnementaux et obésité
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Transcript of Perturbateurs endocriniens environnementaux et obésité
Perturbateurs endocriniens environnementauxet obésité
Perturbateurs endocriniens environnementauxet obésité
1er Congrès Santé-Environnement, Marseille, 2013
Charles Sultan
1 - Unité d’Endocrinologie - 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
Impact sur la santé / enfant
1. différenciation sexuelle masculine (vie fetale … )
2. croissance staturo-pondérale fetale, post-natale
3. développement psycho-moteur
4. Obésité5. 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
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
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 hormones2 – altered sensitivity to neurotransmittors3 – altered CNS activity
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
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
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
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
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
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 !
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 !
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)
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
Perturbateurs endocriniens environnementaux et obésité
Mechanisms of action
+ thyroid hormone receptor / antagonist . dev. Brain
. glucose oxydat
+ glucocorticoid horm. Rc / 11 OHSD / adipose tissue
+ Pregnane X Rc Constitutive Androstene-Rc energy metabolism Aryl hydrocarbone -Rc
Perturbateurs endocriniens environnementaux et obésité
Bisphenol A
EED 1 – ER agonist (ER, , ++)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
Perturbateurs endocriniens environnementaux et obésité
Brain / energy regul
EED
liver
stomach
pancreas
Adipocyte
Perturbateurs endocriniens environnementaux et obésité
Parabens /widely used as preservatives in
- cosmetics- toiletries- food- pharmaceuticals
Parabens 1 - promotes adipogenesis + adipocytes differentiation2 - activates glucocorticoid –Rc and PPAR
3 – promotes conversion of multipotent stromal cells adipocytes
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 > 6.10 yrs
6 – Association between phtalates and BMI (males)
* But confounding variables !
Perturbateurs endocriniens environnementaux et obésité
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
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)
OBESOGENS – JUST THE TIP OF THE ICEBERG ?
PFOA BISPHENOL A PCBs
PHTALATES ORGANOPESTICIDES
TRIBUTYLTIN
6
2009
10 !!
2013
Parabens