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