Jean Baptiste Fini

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Embryonic Xenopus as a model for testing potential thyroid disrupting pesticides Jean-Baptiste Fini, PhD Evolution des régulations endocriniennes Muséum National d’Histoire Naturelle /CNRS UMR 7221 Paris 13/11/15

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Modern society’s diseases In Europe: sperm quality decreased by half in 50 years ( Carlsen 1992) 1/6 couple would use assisted reproduction (ESHRE 2014) Cryptorchidism affects 2-4% boys (+400% in Denmark ) 1/8 woman will develop breast cancer (cancer research UK 2014 ) Diabete risk has dobled between 1980 and 2008 (153 to 347 millions) Obesity is 5th mortality factor in the world Autistic risk in US 1/5000 in 1975 to 1/68 in 2014 Intoxication Stéphane Horel 2015

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Unexplained increase in neurodevelopmental disease (ADHD, ASD) Data from USA : incidence 2014 1 in 68 children 1 in 42 boys. From Demeneix B, Losing our minds OUP 2014 Less than 25% due to changed diagnosis Gene x Environment interactions strongly suspected Nearly half the children diagnosed have IQs < 70

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A 5 point IQ loss would result in a 57% increase of «  less gifted  » people

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Over 150 billion euro per annum in Europe For 4 chemicals

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Usual suspects: Endocrine disruptors Characteristics : Non monotonic dose response ( threshold ) Low dose effects Synergistic effects Critical windows of exposure

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The effects of early exposures to EDCs may be manifested any time in life Fœtal development is a critical window of exposure . TH crucial for normal brain development

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Thyroid Hormone signaling Tiré de Gilbert et al., 2011 (OMS2012)

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Iodine intake TH synthesis T4 in brain Circulating TH Cell response to T4 in brain Brain development Molecular Initiating Event Behavior cognition Adverse Outcome Absolute need of iodine Cretinism : Total lack of iodine

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Essential Role of TH for normal brain development Cretinism HT Maternal fetal HT Normal brain development TH Maternal fetal TH TH Maternal fetal TH HT Maternal fetal TH Maternal Hypothyroidism Congenital Hypothyroidism Consequences of Maternal hypothyroidism ?

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Low maternal free thyroxine concentrations during early pregnancy are associated with impaired psychomotor development in infancy . Pop VJ, Kuijpens JL et al. Clin Endocrinol ( Oxf ). 1999 Feb;50(2):149-55. Maternal hypothyroxinemia in early pregnancy predicts reduced reaction time tests in 5- 6 year offspring . Finken ME et al JCEM 2013 Hypo as hyperthyroxinemia during pregnancy are associated with lower IQ, lower white matter density and reduced cortical volume Korevaar et al. Oct 2015 (online) The Lancet Are there chemicals which affect TH signalling during development which ?

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Mean of 33 compounds measured in pregnant women Woodruff et al. 2011

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21,35 chemicals found in mean per woman 32 max in one sample 12 minimum 109 pg /g sample (24,14-387pg/g ) Générations furures 2015

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Howdeshell 2002

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BPA Triclosan Diethyl hexyl phtalate (DEHP) Dibutylphtalate PCB-153 Benzophenone-3 Perchlorate/ nitrate / thiocyanates Flame retardants Woodruff et al. 2011 Thyroid hormone disruptors found in maternal blood and urine are also present in amniotic fluid CHLORPYRIFOS AMITROLE 4-4’ DDE Hexachlorobenzen (HCB)

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How to detect effects of chemicals acting on Thyroid signaling on brain development ? Adapted model 2) Screen for thyroid hormone disrupting potential of chemicals 3 ) Expose embryos to the mixture and study the effects on mobility and gene expression

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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 1983

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0 20 40 60 80 100 Embryo Larvae Métamorphosis Concentration en T 3 et T 4 (Unités arbitraires) Larvae / adult transition = Perinatal period in mammals ( Leloup et Buscaglia , 1977) T 4 T 3 TH induce critical changes in all vertebrates

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Possible targets of thyroid disruptors From Gilbert et al., 2011 (OMS2012 ) TD TH/bZIP THb/ZIP GFP

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How to detect effects of chemicals acting on Thyroid signaling on brain development ? Adapted model 2) Screen for thyroid hormone disrupting potential of chemicals 3 ) Expose embryos to the mixture and study the effects on mobility and gene expression

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Screening thyroid disrupting compounds with XETA (OECD validation process ) Measurement (plate reading) 72h treatment renewal renewal 48h 24h n = 15 t per group 96 well plate 6 well plate T 3 T 3 EDC Fini et al., 2007

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Chlorpyrifos (CPF) N= 30 / column Non parametric ANOVA ( Kruskal Wallis) ctrl T3 T3 +CPF10-6M Potentializes T3 effect at 10-10M concentration CTRL T3 T3+CPF 10-10M 72h treatment renewal renewal 48h 24h n = 15 t per group Levels found in amniotic fluid : 9pg/g (0,2 10-13M)

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4-4’ DDE 72h treatment renewal renewal 48h 24h n = 15 t per group No significant effect on thyroid signaling Concentrations found in amniotic fluid : 0.21ng/ml (0,7 10-9M) (Foster et al., 2000) Anti ER known effect

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Amitrole Preliminary results to be confirmed / High T3 potentialisation 72h treatment renewal renewal 48h 24h n = 15 t per group Known to inhibit peroxidase ( thyroid peroxicase for Thyroid Hormone organification )

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U shape curve Significant effect at 10-10M 10-7M and 10-6M Potentialize effect with T3 72h treatment renewal renewal 48h 24h n = 15 t per group Hexachlorobenzen (HCB) Concentration found in cord serum : 0.48 10-7M. 0.023ng/ml (0,8 10-10M) in amniotic fluids. ( Luzardo et al, 2009)

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How to detect effects of chemicals acting on Thyroid signaling on brain development ? Adapted model 2) Screen for thyroid hormone disrupting potential of chemicals 3 ) Expose embryos to the mixture and study the effects on mobility and gene expression

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Exposure Exposition précoce à des perturbateurs affecte l’expression de gènes régulés par les HTs NF1 NF10 NF24 NF37 NF41 Thyroid gland formation Gastrulation Neurulation Organogenesis First trimester in Human qPCR 3 d 2 d 1 d CTRL, T3, amitrole , CPF, HCB, 4-4’ DDE Levels of gene transcripts ( Thyroid hormone signalling ) (neuronal markers)

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Currently : Long term effects following embryonic exposure NF1 NF10 NF24 NF37 NF41 NF45 NF46 NF 48 Thyroid gland formation Gastrulation Neurulation Organogenesis NF 51 NF 65 Comportement (mobilité) Histologie sur cerveaux

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Thanks Pr Barbara Demeneix Michelle LEEMANS (PhD Student ) Bilal MUGHAL (PhD student ) Sébastien LE MEVEL (IE) Melodie LETTMANN Petra ŠPIRHANZLOVÁ

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Part2: Apply active susbstances during embryonic development NF1 NF10 NF24 NF37 NF41 NF45 NF46 NF 48 Thyroid gland formation Gastrulation Neurulation Organogenesis "It is not birth, marriage, or death, but gastrulation, which is truly the most important time in your life."             Lewis Wolpert (1986) First trimester in Human

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72h treatment renewal renewal 48h 24h n = 15 t per group Amitrole Concentration found in blood :

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Phenotype observed at 10-6M with and without T3 Kruskal Wallis non parametric test (all data) Chlorpyrifos Measurement (plate reading ) 72h treatment renewal renewal 48h 24h n = 15 t per group

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