Perturbation de l axe thyroïdien maternel et risque de maladie neurodéveloppementale chez l enfant

Transcription

1 Perturbation de l axe thyroïdien maternel et risque de maladie neurodéveloppementale chez l enfant Barbara Demeneix Evolution des Régulations Endocriniennes Muséum National d Histoire Naturelle Paris Novembre 2016 Responsable scientifique:

2 Disclosure I am a co-founder of Watchfrog- but receive no financial compensation

3 Iodine discovered in 1813 BUT iodine deficiency still a major cause of preventable intellectual retardation Thyroid hormone isolated in 1912 Cretinism virtually eradicated world wide due to postnatal T4 therapy 1970s Without a minimum of thyroid hormone, at the right time, a tadpole fails to become a frog and a human baby becomes a cretin. Jacques Legrand 1976

4 Cependant

5 Unexplained increase in neurodevelopmental disease >50% due to unknown factors (Weintraub, Nature 2011) Gene x Environment interactions strongly suspected Up to 40% of children diagnosed have IQs < 70 Data from USA : 2014 & in 68 children 1 in 42 boys From Demeneix B, Losing our Minds

6 Production by the Chemical industry set to increase 300 fold between

7 Linda Birnbaum Director NIEHS Exposure to multiple chemicals is inevitable we live in a chemical soup Hypothesis : many of these industrial chemicals are halogenated and have the capacity to interfere with thyroid hormone signalling Thyroid hormone is the most complex halogenated molecule synthetized by vertebrates Only one to contain iodine, both iodine and thyroid hormone are essential for brain development

8 Take home message It is thought that thyroid hormone production and signalling is prone to disruption by more chemicals than any other endocrine system Envir Health Perspectives Howdeshell 2002

9 In the last twenty years we have witnessed a revolution in understanding thyroid hormone signalling Cell specific membrane transporters MCT8, OATP1C1, etc Discovery of TRa as well as TRb mutations in humans Need for tight control of maternal levels of thyroid hormone in early pregnancy Serum levels do not necessarily reflect tissue levels (tissue specific availability ) Role in control of stem cell activity and lineage decisions

10 THREE Tim Korevaar Robin Peters, Lancet Diabetes Endocrinology , Generation R Study (Rotterdam) Maternal thyroid hormone/tsh levels > 18 weeks of pregnancy Thyroid Peroxidase antibodies Child IQ at 6-8 yrs old MRI scans at 8 years old

11 Mean Child IQ 6-8 years Child IQ < 85 Similar results for grey matter and cortex volume.

12 On average pregnant women carry 33 compounds out of 52 analysed, 15 are ubiquitous Woodruff et al. 2011

13 Levels of the 15 common contaminants found in human amniotic fluid Phenolic compounds Bisphenol A (BPA) M Triclosan M Benzophenone M Organochlorine pesticides HCB M 4-4 DDE 10-9 M Phthalates DBP M DEHP M Polyaromatic hydrocarbons 2-Napthol M Perfluorinated compounds PFOS M PFOA M Halogenated compounds PCB M BDE M Sodium perchlorate 10-8 M Heavy metals Methyl Mercury 10-7 M Lead M Many of these compounds individually have been shown to act as thyroid hormone disruptors and to cause IQ loss

14 How many chemicals affect Thyroid Hormone signalling during development? How can they be identified? What is their impact on neurogenesis?

15 Levels of interaction of EDCs with thyroid signalling Modification of transcription of target genes TH/bZIP THb/ZIP GFP From Gilbert et al., 2011 (redrawn)

16 Screening thyroid disrupting compounds with Xenopus embryonic thyroid assay (XETA) T 3 T 3 ED C Treatment Renewal Renewal Measurement (plate reading) 24h 48h 72h 6 well plate Three concentrations: 0.1x, 1x and 10x Fini et al., 2007

17 Perfluorinated compounds (surfactants) N oublions pas que l hyper est aussi néfaste que l hypo..

18 Natural hormones Estrogen Testosterone Thyroids. etc. Lower birth weight Language delay EDCs Anti-androgens Thyroid active etc. Shorter AGD Selma > 2000 mother child pairs CG Bornehag & Ake Bergmann. SWETOX, Stockholm

19 x x 1 0 x 1 x x x 1 0 x 1 x EDC-MixRisk testing neurodevelopmental delay mix N Seven independent experiments n=15/group. Non parametric One way ANOVA Kruskall Wallis with Dunn s post test significance *p<0.05, **p<0.01, ***p<0.001, ****p< TH/bZIP GFP 1000x N (mol/l) 100x N (mol/l ) MEP 2.7E E- 06 MBP 2.26E E- 06 MBzP 1.05E E- 06 MINP 2.06E E- 06 BPA 4.0E E- 07 PFHxS 3.20E E- 07 PFNA 1.10E E- 07 PFOS 1.03E E x N (mol/l) 2.7E E E E E E E E-07 1x N (mol/l) 2.7E E E E E E E E-08 F lu o re s c e n c e n o rm a lis e d o n T **** 0 M ix N (in te rm s o f h u m a n e x p o s u re ) - - ** **** T 3 5 n M *** 19

20 F lu o re s c e n c e n o r m a lis e d o n T 3 EDC-MixRisk testing growth delay mix G T3 Modification of transcription of target genes TH/bZIP GFP T3 NH3 Five independent experiments n=15/group. Non parametric One way ANOVA Kruskall Wallis with Dunn s post test significance *p<0.05, **p<0.01, ***p<0.001, ****p< Growth and metabol ism 1000x M&G (mol/l) 100x M&G (mol/l) 10x M&G (mol/l) 1x M&G (mol/l) MEP 2.3E E E E-08 MBP 2.0E E E E-08 MBzP 9.1E E E E-09 MEHP 1.2E E E E-08 MINP 1.8E E E E-08 Triclosan 2.6E E E E-09 PFHxS 2.8E E E E-09 PFOA 2.9E E E E-09 PFOS 8.9E E E E M ix M & G - in t e r m s o f h u m a n e x p o s u r e T 3 5 n M *** ** * **** - 1 x 1 0 x x x - 1 x 1 0 x x x *

21 What might be the consequences of these exposures? 14 IQ point loss

22 Clinical and public health implications? Socio-economic costs?

23 n Leo Transande

24 Conclusions Over 15 chemical classes are found in most adults world wide These chemicals pass the placenta and are found in amniotic fluid Many of these 15 chemicals disrupt thyroid hormone signalling. Increasing numbers of studies show the importance of thyroid hormone signalling in early fœtal development for later brain development Maternal exposure to some of these chemicals is well documented as increasing risk of neurodevelopmental disease or IQ loss No data on combined cocktail effects. Legislation in EU currently blocked by lobbying by the chemical industry. Iodine supplementation for women of child bearing age and children

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26 Acknowledgements Dr Jean-Baptiste FINI Sébastien LE MEVEL Michelle LEEMANS Mélodie LETTMANN Bilal MUGHAL Petra ŠPIRHANZLOVÁ Sylvie REMAUD Laurent COEN Jean-David GOTHIÉ Lindsey MARSHALL Isabelle SEUGNET Louise PERICARD Karine LEBLAY Fabrice GIRARDOT Marie Steph CLERGET-FROIDEVAUX Jean-Stéph JOLY Pierre AFFATICATI Laurie RIVIERE Elodie De JOB

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