Perturbateurs endocriniens environnementaux et obésité

1. Perturbateurs endocriniens environnementaux et obésité 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 1er Congrès Santé-Environnement, Marseille, 2013

2. 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

5. 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

7. 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

8. 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

9. 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

10. 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

12. 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

14. 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

15. 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 !

16. 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 !

17. 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)

18. 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

19. 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

20. 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

22. Perturbateurs endocriniens environnementaux et obésité Brain / energy regul EED stomach liver pancreas Adipocyte

23. 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

24. 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 > 6.10 yrs 6 – Association between phtalates and BMI (males) * But confounding variables !

32. 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

33. 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)

34. OBESOGENS – JUST THE TIP OF THE ICEBERG ? PFOA BISPHENOL A PCBs PHTALATES ORGANOPESTICIDES TRIBUTYLTIN 6 2009

35. Parabens 10 !! 2013