Developing AOPs from PPAR Activation Leading to Reproductive Toxicity PDF
Preview Developing AOPs from PPAR Activation Leading to Reproductive Toxicity
Peroxisome proliferator-activated receptors (PPARs) activation leading to reproductive toxicity in rodents Małgorzata Nepelska www.jrc.ec.europa.eu Adverse Outcome Pathways: From Research to Regulation September 3-5, 2014 Serving society Stimulating innovation Supporting legislation DISCLAIMER: This presentation and its contents do not constitute an official position of the European Commission or any of its services. Neither the European Commission nor any person acting on behalf of the Commission is responsible for the use which might be made of this presentation or its contents At the beginning We had an AIM To develop a strategy for building a MoA based chemical category chemical structure f( ) = toxicity f(MoA)= How? 2 Building MoA-based chemical category for toxicity prediction STEP 1. Chose endocrine active, data rich chemicals STEP 2. MoA matrix display of experimental data MIE KE AO Phthalates ER PPAR AR AhR Sertoli spermato Leydig Decreased stereodo oestrus reprModaulect ive Sperm Decreased cells genesis cells testosterone genesis cycle parameters AGD tract DEP 0 1 1 1 0 0 / 0 DiBP 1 1 1 1 1 1 1 1 1 DPP 0 1 1 1 1 1 1 1 DCHP 0 0 1 1 1 1 1 1 1 1 1 DHP 0 / 1 1 1 1 1 1 1 1 DINP 0 0 0 1 1 1 1 1 0 1 / DIDP 0 0 1 0 0 / 1 0 DnOP 0 1 0 0 / BBP 1 1 1 1 1 1 1 1 1 1 1 DprP 1 1 1 MEHP 1 1 1 1 1 1 1 1 1 1 DEHP / 1 / 1 1 1 1 1 1 1 1 1 STEP 3. Mechanistic "blueprint" of phthalates STEP 4. Search for mechanistic analogues (other chemicals that have similar MoA) 3 PPAR activation leading to reproductive toxicity in rodents MIE KE Adverse Outcome AOP-linked chemical initiators PPAR cholesterol Hormone H ormone Reproductive activation transport synthesis levels toxicity 4 MIE PPARs peroxisome proliferator-activated receptors Nutrients Fatty acids Xenobiotics family comprises the types α, γ and β/δ Growth factors Endocrine disruptors are nuclear receptor superfamily of transcription factors that respond to specific ligands regulate lipid and carbohydrate metabolism PPARα,γ β/δ embryonic and foetal development regulated genes cholesterol uptake and transport embryonic and foetal vascular functions development represent a potential molecular link between intracellular trafficking of lipids reproductive function and carbohydrate and Lipids and carbohydrates metabolism lipid metabolism inflammatory responses 5 MMIIEE PPAR activation: evidence Chemical In vitro in vitro Knock-out/inhibition/increased initiator binding transactivation expression Experiments with PPARα-null mice DEHP - + indicate involvement of the receptor in reproductive toxicity of phthalates Inhibition studies MEHP + + + BBP +/- To be verified + DBP +/- To be verified + Increased expression PPARγ Bisphenol A - Increased expression Butylparaben - + PPARγ 6 KE Altered steroidogenic pathway 3 β -HSD-III pregnenolone progesterone P450scc cholesterol Chemical StAR androstenedione cholesterol initiator TSPO aromatase 17β-HSD IV estrone PPAR testosterone binding&activation estradiol aromatase KKEE AO Chemical Decreased Malformation of Testicular toxicity Initiator testosterone levels reproductive organs + + + (Howdeshell et al., (Gray et al., 2000) DEHP (Kwack et al., 2009) 2008) (Parks, 2000) + + + (Howdeshell et al., (Gray et al., 2000) BBP (Gray et al., 2000) 2008) (Nagao et al., 2000) + + + (Howdeshell et al., (Barlow et al., 2003) (Mylchreest, 2000) DBP 2008) (Mylchreest, 2000) (Barlow et al., 2003) (Mylchreest, 2000) + +/- + (Tanaka et al., 2006) (Takagi et al., 2004) (Talsness et al., 2000) (Nakamura et al., (Kobayashi et al., 2002) Bisphenol A 2010) (Talsness et al., 2000) (Talsness et al., 2000) (Tinwell et al. 2002) + + + Butyl (Zhang et al., 2014) (Zhang et al., 2014) paraben (Oishi et al., 2001) + effect present / no change ? no information 8 *testosterone production PPAR activation leading to reproductive toxicity in rodents MIE KE Adverse Outcome cholesterol PPAR t ransport to Hormone H ormone Reproductive activation synthesis levels toxicity mitochondria Altered oestrus cycle Malformation of Decreased ovary weight reproductive organs Decreased AGD Hypospadias 9 PPAR activation leading to reproductive toxicity in rodents cholesterol PPAR Estradiol Hormone Reproductive transport to activation synthesis levels toxicity mitochondria p cholesterol r AOP 1 PPAR t ransport to t e stosterone Hormone Reproductive en activation synthesis levels malformations t mitochondria a l cholesterol AOP 2 PPAR t ransport to Estradiol Hormone Altered activation synthesis levels estrus cycle mitochondria a d u l t cholesterol AOP 3 PPAR t ransport to t e stosterone Hormone Testicular activation synthesis levels toxicity mitochondria 10
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