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


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


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


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


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


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


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


Obesogens = molecules that inappropriately regulate lipid metabolism

and adipogenesis to promote obesity

- DES- Bisphenol A- Phtalates- organochlorine pesticides- PCB

The list continues to growth !


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 !



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)



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



+ 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


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


Brain / energy regul

EED

liver

stomach

pancreas

Adipocyte


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 !


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

Documents

Perturbateurs endocriniens environnementaux et obésité