Detailed Review Paper State of the Science on Novel In Vitro and In Vivo Screening and Testing Methods and Endpoints for Evaluating Endocrine Disruptors

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Organisation de Coopération et de Développement Économiques

Organisation for Economic Co-operation and Development 21-Aug-2012 ___________________________________________________________________________________________

English - Or. English ENVIRONMENT DIRECTORATE

JOINT MEETING OF THE CHEMICALS COMMITTEE AND

THE WORKING PARTY ON CHEMICALS, PESTICIDES AND BIOTECHNOLOGY

DETAILED REVIEW PAPER ON THE STATE OF THE SCIENCE ON NOVEL IN VITRO AND IN VIVO SCREENING AND TESTING METHODS AND ENDPOINTS FOR EVALUATING ENDOCRINE DISRUPTORS

Series on Testing & Assessment No. 178

JT03325419

Complete document available on OLIS in its original format

This document and any map included herein are without prejudice to the status of or sovereignty over any territory, to the delimitation of international frontiers and boundaries and to the name of any territory, city or area.

ENV/JM/MONO(2012)23Unclassified English - Or. En

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OECD Environment, Health and Safety Publications Series on Testing and Assessment

No. 178

DETAILED REVIEW PAPER ON THE STATE OF THE SCIENCE ON NOVEL IN VITRO AND IN VIVO SCREENING AND TESTING METHODS AND ENDPOINTS FOR

EVALUATING ENDOCRINE DISRUPTORS

Environment Directorate

ORGANISATION FOR ECONOMIC CO-OPERATION AND DEVELOPMENT Paris 2012

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Also published in the Series on Testing and Assessment:

No. 1, Guidance Document for the Development of OECD Guidelines for Testing of Chemicals (1993; reformatted 1995, most recently revised 2009)

No. 2, Detailed Review Paper on Biodegradability Testing (1995)

No. 3, Guidance Document for Aquatic Effects Assessment (1995)

No. 4, Report of the OECD Workshop on Environmental Hazard/Risk Assessment (1995)

No. 5, Report of the SETAC/OECD Workshop on Avian Toxicity Testing (1996)

No. 6, Report of the Final Ring-test of the Daphnia magna Reproduction Test (1997)

No. 7, Guidance Document on Direct Phototransformation of Chemicals in Water (1997)

No. 8, Report of the OECD Workshop on Sharing Information about New Industrial Chemicals Assessment (1997)

No. 9, Guidance Document for the Conduct of Studies of Occupational Exposure to Pesticides during Agricultural Application (1997)

No. 10, Report of the OECD Workshop on Statistical Analysis of Aquatic Toxicity Data (1998)

No. 11, Detailed Review Paper on Aquatic Testing Methods for Pesticides and industrial Chemicals (1998)

No. 12, Detailed Review Document on Classification Systems for Germ Cell Mutagenicity in OECD Member Countries (1998) No. 13, Detailed Review Document on Classification Systems for Sensitising Substances in OECD Member Countries 1998)

No. 14, Detailed Review Document on Classification Systems for Eye Irritation/Corrosion in OECD Member Countries (1998) No. 15, Detailed Review Document on Classification Systems for Reproductive Toxicity in OECD Member Countries (1998)

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No. 16, Detailed Review Document on Classification Systems for Skin Irritation/Corrosion in OECD Member Countries (1998) No. 17, Environmental Exposure Assessment Strategies for Existing Industrial Chemicals in OECD Member Countries (1999) No. 18, Report of the OECD Workshop on Improving the Use of Monitoring Data in the Exposure Assessment of Industrial

Chemicals (2000)

No. 19, Guidance Document on the Recognition, Assessment and Use of Clinical Signs as Humane Endpoints for Experimental Animals used in Safety Evaluation (1999)

No. 20, Revised Draft Guidance Document for Neurotoxicity Testing (2004)

No. 21, Detailed Review Paper: Appraisal of Test Methods for Sex Hormone Disrupting Chemicals (2000)

No. 22, Guidance Document for the Performance of Out-door Monolith Lysimeter Studies (2000)

No. 23, Guidance Document on Aquatic Toxicity Testing of Difficult Substances and Mixtures (2000)

No. 24, Guidance Document on Acute Oral Toxicity Testing (2001)

No. 25, Detailed Review Document on Hazard Classification Systems for Specifics Target Organ Systemic Toxicity Repeated Exposure in OECD Member Countries (2001)

No. 26, Revised Analysis of Responses Received from Member Countries to the Questionnaire on Regulatory Acute Toxicity Data Needs (2001)

No 27, Guidance Document on the Use of the Harmonised System for the Classification of Chemicals which are Hazardous for the Aquatic Environment (2001)

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No 30, Detailed Review Document on Hazard Classification Systems for Mixtures (2001)

No 31, Detailed Review Paper on Non-Genotoxic Carcinogens Detection: The Performance of In-Vitro Cell Transformation Assays (2007)

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No. 42, Guidance Document on Reporting Summary Information on Environmental, Occupational and Consumer Exposure (2003)

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No. 160, Guidance Document on the Bovine Corneal Opacity and Permeability (BCOP) and Isolated Chicken Eye (ICE) Test Methods:

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© OECD 2012

Applications for permission to reproduce or translate all or part of this material should be made to: Head of Publications Service, RIGHTS@oecd.org. OECD, 2 rue André-Pascal, 75775 Paris Cedex 16, France

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ABOUT THE OECD

The Organisation for Economic Co-operation and Development (OECD) is an intergovernmental organisation in which representatives of 34 industrialised countries in North and South America, Europe and the Asia and Pacific region, as well as the European Commission, meet to co-ordinate and

harmonise policies, discuss issues of mutual concern, and work together to respond to international problems. Most of the OECD’s work is carried out by more than 200 specialised committees and working groups composed of member country delegates. Observers from several countries with special status at the OECD, and from interested international organisations, attend many of the OECD’s workshops and other meetings. Committees and working groups are served by the OECD Secretariat, located in Paris, France, which is organised into directorates and divisions.

The Environment, Health and Safety Division publishes free-of-charge documents in ten different series:

Testing and Assessment; Good Laboratory Practice and Compliance Monitoring; Pesticides and Biocides; Risk Management; Harmonisation of Regulatory Oversight in Biotechnology; Safety of Novel Foods and Feeds; Chemical Accidents; Pollutant Release and Transfer Registers; Emission Scenario Documents; and Safety of Manufactured Nanomaterials. More information about the Environment, Health and Safety Programme and EHS publications is available on the OECD’s World Wide Web site (www.oecd.org/ehs/).

This publication was developed in the IOMC context. The contents do not necessarily reflect the views or stated policies of individual IOMC Participating Organisations.

The Inter-Organisation Programme for the Sound Management of Chemicals (IOMC) was

established in 1995 following recommendations made by the 1992 UN Conference on Environment and Development to strengthen co-operation and increase international co-ordination in the field of chemical safety. The Participating Organisations are FAO, ILO, UNEP, UNIDO, UNITAR, WHO, World Bank and OECD. UNDP is an observer. The purpose of the IOMC is to promote co-ordination of the policies and activities pursued by the Participating Organisations, jointly or separately, to achieve the sound management of chemicals in relation to human health and the environment.

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This publication is available electronically, at no charge.

For this and many other Environment, Health and Safety publications, consult the OECD’s

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OECD Environment Directorate, Environment, Health and Safety Division

2 rue André-Pascal 75775 Paris Cedex 16

France

Fax: (33-1) 44 30 61 80 E-mail: ehscont@oecd.org

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FOREWORD

This Detailed Review Paper (DRP) was developed as a follow-up to the workshop on OECD countries’

activities regarding testing, assessment and management of endocrine disrupters, which was held in Copenhagen (Denmark) on 22-24 September 2010 (see document No. 118 published in the Series on Testing and Assessment).

In 2010, the project was included in the Test Guideline workplan. It was led by the US, with the support of the European Commission (EC) and the Secretariat – the EC and the Secretariat led the development of the chapter on Endocrine Disrupters and the Epigenome, included in the annex of this DRP. The document was developed by consultants in close cooperation with an advisory group on testing and assessment of endocrine disrupters (EDTA AG). The outline of the DRP was discussed at the meeting of the EDTA AG in April 2011. The 1st draft DRP was then sent to the Working Group of National Coordinators of the Test Guidelines Programme and the EDTA AG for comments in July 2011. The draft was revised by the consultants on the basis of the comments received and a 2nd draft was developed and sent for WNT comments in autumn 2011. The 2nd draft DRP was also reviewed and revised at a meeting of the EDTA AG in December 2011. The draft chapter on Endocrine Disrupters and the Epigenome was circulated once more to the WNT after the December EDTA AG meeting, as its section on Recommendations (section 8 of the chapter) had been revised in depth by the EDTA AG.

The draft Detailed Review Paper was approved by the WNT at its meeting held in April 2012. It was declassified by the Joint Meeting of the Chemicals Committee and the Working Party on Chemicals, Pesticides and Biotechnology (hereafter Joint Meeting), on 7 August 2012. This document is published under the responsibility of the Joint Meeting.

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Detailed Review Paper State of the Science on Novel In Vitro and In Vivo Screening and Testing Methods and Endpoints for Evaluating Endocrine Disruptors

Contractor:

RTI International 3040 Cornwallis Road P.O. Box 12194 Research Triangle Park, NC 27709 Draft #3 February 2012 Authors

Gerald A. LeBlanc, Ph.D.

Department of Environmental and Molecular Toxicology

North Carolina State University Raleigh, NC

David O. Norris, Ph.D.

Department of Integrative Physiology University of Colorado

Boulder, CO

Werner Kloas, Ph.D.

Department of Ecophysiology and Aquaculture IGB

Endocrinology at Humboldt University Germany

Seth W. Kullman, Ph.D.

Department of Environmental and Molecular Toxicology

North Carolina State University Raleigh, NC

William S. Baldwin, Ph.D.

Department of Biological Sciences and Environmental Toxicology

Clemson University Clemson, SC

John M. Greally, Ph.D.

Department of Genetics

Albert Einstein College of Medicine Bronx, NY

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Table of Contents

ABOUT THE OECD ... 18 FOREWORD ... 20 ABSTRACT ... 32 INTRODUCTION ... 33 1.1 Relevance of this DRP to Diseases and Syndromes of Contemporary Concern ... 37 1.2 Relevance of this DRP to the Adverse Outcome Pathway approach ... 37 THE HYPOTHALAMUS:PITUITARY:ADRENOCORTICAL (HPA) AXIS ... 40 2.1 Overview ... 40 2.1.1 Corticotropin-Releasing Hormone (CRH) ... 41 2.1.2 Arginine Vasopressin (AVP)/Arginine Vasotocin (AVT) ... 42 2.1.3 Corticotropin (ACTH) ... 42 2.1.4 Luteinizing Hormone (LH) and Chorionic Gonadotropin (CG) ... 42 2.1.5 Glucocorticoids ... 42 2.1.5.1 Glucocorticoid Receptors (GRs)... 43 2.1.5.2 CRH and Glucocorticoid-Binding Protein (transcortinprotein and glucocorticoid-binding protein [transcortin]) ... 43 2.1.6. Neuroendocrine Regulation of the HPA Axis ... 43 2.2 Consequences of Disruption ... 44 2.3 Precedent Chemicals as Potential Disruptors of the HPA Axis... 44 2.3.1 Steroid Synthesis and Receptor Agonists and Antagonists ... 44 2.3.2 Metals ... 45 2.3.3 Neuroactive Chemicals ... 45 2.3.4 Vasopressin Receptor Agonists and Antagonists ... 45 2.3.5 CRH Receptor Antagonists ... 46 2.3.6 Pesticides ... 46 2.3.7 Arylhydrocarbon Receptor (AhR) Agonists ... 46 2.3.8 Estrogens and Androgens ... 46 2.4 In Vitro Assays ... 46 2.4.1 Transactivation Reporter Assays ... 46 2.4.2 Microarrays ... 47 2.4.3 Cell Culture Systems ... 47 2.4.3.1 Corticotropes ... 47 2.4.3.2 Adrenal Cortical Cells ... 47 2.4.3.3 Glucocorticoid Target Cells ... 47 2.5 In Vivo Assays ... 47 2.5.1 Mammals ... 48 2.5.2 Fish ... 48 2.5.2 Amphibians ... 48 2.6 Strengths, Challenges, and Limitations ... 48 2.6.1 Stress, the Adverse Outcome Pathway, and Assay Selection ... 49 HYPOTHALAMUS:PITUITARY:GONAD (HPG) AXIS ... 51 3.1 Overview ... 51 3.1.1 Structure of the HPG Axis ... 51 3.1.2 Structure and Actions of HPG Hormones ... 51

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3.1.3 Function of the HPG Axis... 53 3.2 Consequences of Disruption ... 53 3.2.1 (Anti)estrogens ... 53 3.2.1.1 Reproduction ... 54 3.2.1.2 Metabolism and Growth ... 55 3.2.1.3 Immune System ... 55 3.2.2 (Anti)androgens ... 55 3.2.2.1 Reproduction ... 55 3.2.2.2 Growth ... 56 3.2.3 (Anti)gestagens ... 56 3.2.3.1 Reproduction ... 56 3.2.3.2 Immune System ... 57 3.3 Precedent Chemicals ... 57 3.3.1 (Anti)estrogens ... 57 3.3.1.1 Bisphenol A (BPA) ... 57 3.3.1.2 Phthalate Esters ... 58 3.3.1.3 Polychlorinated Biphenyls (PCBs) ... 58 3.3.2 (Anti)androgens ... 59 3.3.2.1 Di-(2-ethylhexyl)phthalate (DEHP) ... 59 3.3.2.2 Flutamide ... 59 3.3.3 (Anti)gestagens ... 59 3.3.3.1 Levonorgestrel (LNG)... 59 3.4 In Vitro Assays ... 60 3.4.1 (Anti)estrogens ... 60 3.4.1.1 ER Transactivation Assays ... 60 3.4.1.2 Membrane Receptor Binding ... 60 3.4.1.3 Cell-based Microarrays ... 60 3.4.2 (Anti)androgens ... 61 3.4.2.1 AR Transactivation Assay ... 61 3.4.3 (Anti)gestagens ... 61 3.4.3.1 PR Transactivation Assays ... 61 3.4.3.2 mPR Binding Assays ... 61 3.4.3.3 Cell-based Microarrays ... 61 3.5 In Vivo Assays ... 61 3.5.1 (Anti)estrogens ... 61 3.5.1.1 Microarrays ... 61 3.5.1.2 Disruption of Brain and Gonad Differentiation ... 62 3.5.2 (Anti)androgens ... 62 3.5.2.1 Behavioral Changes ... 62 3.5.3 (Anti)gestagens ... 62 3.5.3.1 Germinal Vesicle Breakdown (GVBD) ... 62 3.5.3.2 Sperm Motility... 62 3.6 Strengths, Challenges, and Limitations ... 63 3.6.1 (Anti)estrogens ... 63 3.6.2 (Anti)androgens ... 64 3.6.3 (Anti)gestagens ... 64 THE SOMATOTROPIC AXIS ... 68 4.1 Overview ... 68 4.2 Consequences of Disruption ... 70 4.3 Precedent Chemicals ... 70

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4.3.1 Estrogenic Chemicals ... 70 4.3.2 Anti-thyroid Chemicals ... 70 4.3.3 Corticosteroid Stimulants ... 70 4.3.4 Chemicals that Directly Disrupt the Somatotropic Axis ... 71 4.4 In vitro Assays ... 71 4.5 In vivo Assays ... 72 4.6 Strengths, Challenges, and Limitations ... 72 THE RETINOID SIGNALING PATHWAY... 74 5.1 Overview ... 74 5.1.1 Retinoic Acid Receptor Signaling ... 74 5.1.2 The Retinoid X Receptor Signaling Network ... 74 5.1.2.1 Reproduction in Mammals ... 75 5.1.2.2 Development in Mammals ... 75 5.1.2.3 Lipid Homeostasis in Mammals ... 76 5.2 Consequences of Disruption ... 76 5.3 Precedent Chemicals ... 76 5.3.1 Reductions in Retinoid Levels ... 77 5.3.2 RAR Agonists ... 77 5.3.3 RXR Agonists/Antagonists ... 77 5.4 In Vitro Assays ... 78 5.4.1 AhR Transactivation Reporter Assay ... 78 5.4.2 RAR Transactivation Reporter Assay ... 79 5.4.3 RXR Transactivation Reporter Assay ... 79 5.4.4 Adipocyte Differentiation Assay ... 80 5.4.5 Cell-based Microarrays ... 81 5.5 In Vivo Assays ... 81 5.5.1 CYP 1A1 Induction ... 81 5.5.2 Alterations in Retinoid Levels and Metabolism ... 81 5.5.3 Alterations in Lipid Levels and Metabolism ... 82 5.6 Strengths, Challenges, and Limitations ... 82 THE HYPOTHALAMUS:PITUITARY:THYROID (HPT) AXIS ... 83 6.1 Overview ... 83 6.2 Consequences of Disruption ... 85 6.3 Precedent Chemicals ... 87 6.3.1 AhR and CAR Agonists ... 87 6.3.2 Deiodinase Inhibitors/Suppressors ... 88 6.3.3 Disruptors of TSH Signaling ... 88 6.3.4 Disruptors of TR Signaling ... 88 6.3.5 Disruptors of Iodine Uptake and Thyroid Hormone Synthesis ... 89 6.3.6 Disruptors of Plasma and Cross-Membrane Transport Proteins ... 89 6.4 In Vitro Assays ... 90 6.4.1 Transactivation Reporter Assays with TRα and TRβ ... 90 6.4.2 Two-hybrid Assays ... 91 6.4.3 DNA Binding Assays ... 92 6.4.4 Dendritic Arborization ... 92 6.4.5 Neurite Extension ... 93 6.4.6 Cell Proliferation Assay ... 93 6.4.7 Thyroid Peroxidase (TPO) Inhibition Assay ... 94 6.4.8 Iodide Uptake Assay ... 95

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6.4.9 Thyroid Hormone Binding Protein Assays ... 95 6.5 In Vivo Assays ... 95 6.5.1 Modification of Long Term In Vivo Assays ... 95 6.5.2 Organ Culture ... 96 6.5.3 Additional In Vivo Models ... 97 6.5 Strengths, Challenges and Limitations ... 97 THE VITAMIN D SIGNALING PATHWAY ... 100 7.1 Overview ... 100 7.1.1 Synthesis ... 100 7.1.2 Catabolism ... 102 7.1.3 Calcium and Skeletal Maintenance ... 102 7.1.4 Immune System Function ... 102 7.1.5 Cancer ... 102 7.1.6 Neurodevelopment ... 103 7.1.7 Cardiac Function ... 103 7.1.8 Metabolism of Secondary Bile Acids ... 103 7.2 Consequences of Disruption ... 104 7.3 Precedent Chemicals ... 105 7.3.1 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) ... 105 7.3.2 Polychlorinated Biphenyls (PCBs) ... 105 7.3.3 Ethanol ... 106 7.3.4 Lead ... 106 7.4 In Vitro Assays ... 106 7.4.1 Transactivation VDR Reporter Assays ... 106 7.4.2 AhR Transactivation Reporter Assays ... 106 7.5 In Vivo Assays ... 107 7.5.1 Serum Vitamin D Levels ... 107 7.5.2 Microarrays ... 107 7.5.3 Skeletal Morphology and Bone Densitometry ... 107 7.5.4 Histology ... 108 7.6 Current Challenges and Limitations ... 108 7.6.1 Limited Knowledge Regarding Non-mammalian Vertebrates ... 108 7.6.2 Broaden Focus beyond Skeletal Effects ... 109 THE PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR SIGNALING PATHWAY ... 110 8.1 Overview ... 110 8.1.1 PPARs in Non-Mammalian Species ... 111 8.2 Consequences of Disruption ... 111 8.2.1 PPARα ... 112 8.2.2 PPARβ/δ ... 113 8.2.3 PPARγ... 114 8.2.4 PPAR Disruption in Wildlife ... 115 8.3 Precedent Chemicals ... 116 8.3.1 PPAR Activators in Non-Mammalian Species ... 118 8.4 In Vitro Assays ... 118 8.4.1 Transactivation Reporter Assays ... 118 8.4.2 3T3-L1 Cell Differentiation Assay ... 119 8.5 In Vivo Assays ... 119 8.5.1 Peroxisome Proliferation ... 119 8.5.2 Lipid Accumulation ... 120

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8.5.3 Microarrays ... 120 8.6 Strengths, Challenges, and Limitations ... 120 SUMMARY, CONCLUSIONS, AND CONSIDERATIONS ... 122 9.1 Summary and Conclusions ... 122 9.1.1 Cross Talk among Signaling Pathways ... 122 9.1.2 Assays ... 122 9.2 Next Steps for Further Consideration ... 125 9.2.1 Hypothalamus:Pituitary:Adrenocortical Axis ... 125 9.2.2 Hypothalamus:Pituitary:Gonadal Axis ... 126 9.2.3 Somatotropic Axis ... 126 9.2.4 Retinoid Signaling Pathway ... 127 9.2.5 Hypothalamus:Pituitary:Thyroid Axis ... 127 9.2.6 Vitamin D Signaling Pathway ... 127 9.2.7 Peroxisome Proliferator-Activated Receptor Signaling Pathway ... 128 9.2.8 Adverse Outcome Pathway approach and the Conceptual Framework... 128 ACKNOWLEDGEMENTS ... 129 REFERENCES ... 130 ANNEX 1: ENDOCRINE DISRUPTERS AND THE EPIGENOME ... 172 1.0 Introduction ... 172 2.0 Definitions ... 172 3.0 Potential effects ... 178 4.0 Evidence for endocrine disruption being mediated by epigenomic processes ... 178 5.0 Assay methods ... 181 6.0 Challenges ... 188 7.0 Conclusions and testing recommendations ... 189 8.0 Recommendations ... 197

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Acronyms and Abbreviations

3β-HSD 3β-hydroxysteroid dehydrogenase 3,3’,5-triClBPA 3,3’,5-trichlorobisphenol A 17,20β-P 17,20β-dihydroxypregn-4-en-3-one 17,20β-S 17,20β,21-trihydroxypregn-4-en-3-one ACTH corticotropin

AhR aryl hydrocarbon receptor

AND androstenedione

ANSA 8-anilina-1-napthalenesulfonic acid

AOP adverse outcome pathway

AR androgen receptor

AR STTA AR transactivation assay

ARNT aryl hydrocarbon receptor nuclear translocator

ATPase adenosine triphosphatase

AVP arginine vasopressin

AVT argonine vastocine

BDE brominated diphenyl ether

BDE-47 2,2',4,4'-tetrabromodiphenylether

BDNF brain-derived neutrophic factor

BFR brominated flame retardant

BIAC Business and Industry Advisory Committee BKME bleached kraft mill effluent

BMI body mass index

BNF β-naphthoflavone

BNST bed nucleus of the stria terminalis

BPA bisphenol A

BTEB basic transcription element binding protein

cAMP cyclic adenosine monophosphate

CAR constitutive androstane receptor

CARLA co-activator-dependent receptor ligand assays

CAT chloramphenicol actyltransferase

CBG corticosteroid binding globulin CBP/p300 CREB binding protein

CCD charged couple device

CDCA chenodeoxycholic acid

CG chorionic gonadotropin

CHIP chromatin immunoprecipitation

CHO Chinese hamster ovary cells

CNS central nervous system

CoR co-repressors CPT1 carnitine palmitoyl transferase 1 CREB cAMP-responsive element binding

CRH corticotropin-releasing hormone

CRH-BP corticotropin-releasing hormone binding protein

CV coefficient of variation

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DBD DNA binding domain

DBP di-n-butyl phthalate

DEHP di[2-ethylhexyl] phthalate

DES diethylstilbestrol DEX dexamethasone DHEA dehydroepiandrosterone

DHEAS DHEA sulfate

DHRA 9-cis-4-oxo-13,14-dihydroretinoic acid

DHT dihydrotestosterone

DIDP diisodecyl phthalate

DIT di-iodothyronine

DMBPA 3,3'-dimethylbisphenol A

DNHP di-n-hexyl phthalate

DnOP di-n-octyl phthalate

DPSA Differential Protease Sensitivity Assay

DRE dioxin response element

DRP detailed review paper

DUOX/ThOX dinucleotide phosphate oxidase

DXA dual-emission X-ray absorptiometry

EAT estrogen, androgen, and thyroid

EDC endocrine disrupting chemical

EDTA Endococrine Disrupter Testing and Assessment EE2 ethinylestradiol

EHA 2-ethylhexanoic acid

EMSA electrophoretic mobility shift assay ENCODE Encyclopedia of DNA Elements EPA U.S. Environmental Protection Agency

ER estrogen receptor

ERRγ estrogen-related receptor γ

FITC fluorescein isothiocyanate

FRET fluorescence resonance energy transfer

FSH follicle stimulating hormone

FXR farnesoid X receptor

GABAergic gamma-amino butyric acid

GHRH growth hormone releasing hormone

GH growth hormone

GHRH growth hormone releasing hormone

GnRH gonadotropin-releasing hormones

GPR30` G-protein-coupled receptor 30

GR glucocorticoid receptor

GR1 mineral corticoid receptor

GRE glucocorticoid response elements

GFP Green Fluorescent Protein

GST glutathione S-transferase

GSUα glycoprotein-hormone α-subunit

GVBD germinal vesicle breakdown

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H3K9me 3histone H3 lysine 9 trimethylation HBCD 1,2,5,6,9,10-αHexabromocyclododecane HCBD hexabromocyclododecane HHPS hypothalamo-hypophysial portal system Hnpc human neural progenitor cell

HPA hypothalamus-pituitary-adrenocortical HPG hypothalamo-pituitary-gonadal HPI hypothalamic-pituitary-interrenal HPT hypothalamo-pituitary-thyroidal

hrTPO human recombinant TPO

IGF-1 insulin-like growth factor 1 IGF-2 insulin-like growth factor 2

IHEC International Human Epigenome Consortium IL interleukins

IP3 inositol trisphosphate

IPS induced pluripotent stem

JAK/STAT Janus Kinase/Signal Transducer and Activator of Transcription

K+ potassium ion

LBD ligand-binding domain

LC locus caeculeus

LCA lithocholic acid

LH luteinizing hormone

LICA ligand induced complex assay

LNG levonorgestrel

LUMA luminometric methylation analysis

LXR liver X receptor

MBP mono-n-butyl phthalate

MC2R melanocortin receptor

MCPA 2-methyl-4-chlorophenoxyacetic acid

MCT monocarboxylate transporter

MCT8 monocarboxylate transporter 8

ME malic enzyme

MEHP mono-2-ethylhexylphthalate MIT mono-iodothyronine

MMGT medaka multi-generation test

MMI methimazole

mPR membrane-G-protein-coupled gestagen receptor

MPS massively-parallel sequencing

MR mineralocorticoid receptor

MUFA monounsaturated fatty acid

Na+ sodium ion

NCoR nuclear receptor corepressor

NGF nerve growth factor

NIH National Institutes of Health

NIS sodium-iodide symporter

NR nuclear receptor

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OATP organic ion transport proteins

OECD Organization for Economic Cooperative Development

P4 progesterone

PACAP pituitary adenylate cyclase-activating peptide PAH polycyclic aromatic hydrocarbon

PAX8 paired box gene 8

PBB polybrominated biphenyl

PBPK physiologically based pharmacokinetic

PCB polychlorinated biphenyl

PCDD polychlorinated dibenzo-p-dioxin

PCDF polychlorinated dibenzofuran

PFOA perfluorooctanoic acid

PFOS perfluorooctane sulfonate

PGJ2 prostaglandin J2

PKA phosphokinase A

PKC protein kinase C

PLC phospholipase C

PPAR peroxisome proliferator activated receptor

pQCT peripheral quantitative computed tomography

PR progesterone receptor

PRL prolactin

PTH parathyroid hormone

PTU propylthiouracil PUFA polyunsaturated fatty acid

PVN paravocellular nucleus

PXR pregnane X receptor

qPCR real-time polymerase chain reaction RAR retinoic acid receptor

RIA radioimmunoassay

RIC20 relative inhibitory concentration

RN raphe nucleus

RU486 mifepristone

RXR retinoid X receptor

SEXDAMAX Sexual differentiation and metamorphosis assaywith Xenopus

siRNA short interfering RNA

SMRT silencing mediator for retinoid and thyroid hormone receptors

SON supraoptic nucleus

SRIF somatotropin release inhibiting factor SRC-1 steroid receptor coactivator-1

SRC-2 steroid receptor coactivator-2

STAR steroidogenic acute regulatory protein

T3 thyroid hormone, triiodothyronine

T4 thyroid hormone, thyroxine

TBBPA 3,3’,5,5’-tetrabromobisphenol A

TBG Thyroid hormone-binding globulin

TBTO tributyltin oxide

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TCBPA 3,30,5,50-tetrachlorobisphenol A TCDD tetrachlorodibenzo-p-dioxin

TCGA The Cancer Genome Atlas

TD thyroid disruptor

TDC thyroid disrupting compound

TDS testicular dysgenesis syndrome

TG test guideline

TH tyrosine hydroxylase

TIF2 transcriptional intermediary factor

TIQDT T4 immunofluorescence quantitative disruption test

TMBPA tetramethylbisphenol A

TMTU N,N,N’,N’-tetramethylthiourea

TPO thyroid peroxidase

TR thyroid hormone receptor

TRAP tartrate-resistant acid phosphatase

TRE thyroid response element

TRH thyrotropin releasing hormone

TRHR thyrotropin-releasing hormone receptor

TRIAC T3 signaling agonist

TSH thyrotropin stimulating hormone

TTF1 transcription termination factor 1 TTF2 transcription termination factor 2 TTR transthyretin Ucn Urocortin

V1aR vasopressin-1

VDBP vitamin D binding protein

VDR vitamin D receptor

VDRE vitamin D response element VTG vitellogenin

WHO World Health Organization

ZF zona fasciculata

ZG zona glomerulosa

ZR zona reticularis

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ABSTRACT

Increasing incidents of disorders such as obesity/diabetes/metabolic syndrome, reproductive dysfunction, and neuro-developmental abnormalities in some human populations have raised concern that disruption of key endocrine-signaling pathways by exposure to environmental chemicals may be involved. This Detailed Review Paper describes some endocrine pathways that have been shown to be susceptible to environmental endocrine disruption and whose disruption could contribute to increasing incidents of some disorders in humans and wildlife populations. Assays and endpoints are described that could be used in new or existing Organization for Economic Cooperative Development (OECD) Test Guidelines for evaluating chemicals for endocrine-disrupting activity. Endocrine pathways evaluated were the hypothalamus:pituitary:adrenocortical (HPA) axis, the hypothalamus:pituitary:gonad (HPG) axis, the somatotropic axis, the retinoid signaling pathway, the hypothalamus:pituitary:thyroid (HPT) axis, the vitamin D signaling pathway, and the peroxisome proliferator-activated receptor (PPAR) signaling pathway. In addition, the potential role of chemical-induced epigenetic modifications to endocrine signaling pathways, during sensitive windows of exposure, was evaluated as a mechanism of endocrine disruption, along with the examination of potential methods for assessing such disruption. This section is provided as an annex to the document (Annex 1). Potential targets of disruption along putative adverse outcome pathways associated with the signaling pathways were identified, along with assays that show promise in evaluating the target in a screening and testing program. Disruption of the HPA or retinoid X receptor signaling pathways could contribute to disorders of emerging concern, and adverse outcome pathways are well defined. However, assays for the assessment of disruption of these pathways are less well developed, and in some cases, are not specific to the pathway. Several new assays were described for the detection of disruption of the HPT axis. These assays may complement assays in the existing Test Guidelines and strengthen the adverse outcome pathway lineage. Assays for the detection of vitamin D signaling disruption and novel aspects of the HPG axis (membrane receptor signaling, progestin signaling) require further development and refinement prior to consideration for incorporation into Test Guidelines. Disruption of the somatotropic axis is likely to occur through disruption of other signaling pathways that cross-talk with the somatotropic axis. Disruption of the somatotropic axis may thus provide a more holistic view of the general integrity of the endocrine system. PPARs are involved in lipid and glucose homeostasis, inflammation, and aspects of development. The adverse outcome pathway for PPARγ is well established. Assays used to assess disruption of PPAR signaling are well developed, and many are suitable for incorporation into existing OECD Test Guidelines. In conclusion, OECD Test Guidelines could be modified to include new assays or the incorporation of novel endpoints into existing assays that would expand the repertoire of endocrine signaling pathways included in the screening and testing regimen.

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INTRODUCTION

1. The endocrine system consists of an assemblage of ductless glands that secrete hormones directly into the blood or lymph, which regulate a wealth of biological processes.1 The endocrine system is comprised of multiple pathways, or axes, each consisting of different groupings of organs and hormones with distinct regulatory functions. These pathways are intricately involved in organizational, or programming, events during fetal development, as well as in the maintenance of homeostasis in the adult organism.

Mounting evidence has shown that aspects of the endocrine system are susceptible to perturbation by exogenous chemicals, resulting in the disruption of those processes under endocrine control. Evidence to date indicates that hormone nuclear receptors are a major target of endocrine disrupting chemicals (EDCs) because these receptors are designed to bind small, lipoidal molecules (i.e., steroid hormones), which can be mimicked by many environmental chemicals. These nuclear receptors, once activated by their ligand, regulate the transcription of target genes. Xenobiotics can disrupt normal nuclear receptor function by inappropriately activating the nuclear receptor (hormone receptor agonist) or by inhibiting the action of the nuclear receptor (hormone receptor antagonist). Some environmental chemicals also can disrupt normal endocrine function by altering circulating hormone levels. Accordingly, the World Health Organization (WHO) has defined an endocrine disruptor as an exogenous substance or mixture that alters functions(s) of the endocrine system and, consequently, causes adverse health effects in an intact organism, or its progeny, or (sub)populations.2 In this detailed review paper (DRP), an EDC is defined as a chemical substance that meets this definition of an endocrine disruptor.

2. At the request of member countries and its Business and Industry Advisory Committee, the Organization for Economic Cooperative Development (OECD) established a Special Activity on Endocrine Disrupter Testing and Assessment (EDTA) in 1996. The objective of the Special Activity was to coordinate the development of Test Guidelines to detect endocrine disruptors and to harmonize risk characterization approaches for such chemicals. As a result, several Test Guidelines have been developed or are presently in development. These guidelines have been integrated into a Conceptual Framework that can be used to evaluate chemicals for endocrine-disrupting activity. The Framework (http://www.oecd.org/document/58/0,3343,en_2649_34377_2348794_1_1_1_1,00.html) organizes tests into five levels of complexity dealing largely with the ability of chemicals to disrupt estrogen, androgen, and thyroid (EAT) signaling processes and steroidogenesis. Level 1 consists of the compilation of all existing test data, physical-chemical properties of the chemical, and various model predictions of activity.

Level 2 consists of in vitro screening assays that provide information on potential interactions between the chemical and specific endocrine target (e.g., receptors, enzymes). Level 3 consists of whole-organism screening assays that provide insight into chemical interactions with single selected endocrine mechanism(s) / signaling pathways. Level 4 consists of whole-organism assays that provide data on adverse effects on endocrine-relevant endpoints. These assays provide insight into chemical interactions with multiple endocrine signaling pathways or endpoints. Level 5 consists of whole-organism assays that are designed to provide more comprehensive data on adverse effects on endocrine-relevant endpoints over more extensive parts of the life cycle of the organism.

3. This Conceptual Framework provides a rational, step-wise approach to evaluating chemicals for their ability to disrupt signaling pathways, with emphasis on EAT endocrine pathways. However, the EAT pathways represent three of many endocrine pathways, and recent evidence indicates that other endocrine pathways also are susceptible to the disrupting effects of environmental chemicals. Accordingly, the OECD recognizes the need to have Guidance Documents in place that also would serve to evaluate the effects of chemicals on non-EAT endocrine pathways. This DRP describes assays that have been used to detect endocrine-disrupting effects of chemicals on non-EAT pathways, atypical EAT pathways (e.g., estrogen signaling via membrane receptors), and neuroendocrine pathways. In addition, new approaches to assessing chemical effects on EAT pathways are discussed. The neuro-endocrine pathways discussed may function upstream to regulate the production of hormones that interact with nuclear receptors, or may

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function through the production of peptide hormones, which contribute directly to endocrine signaling.

(Note: The term neuro-endocrine is used in this document to denote both neuroendocrine and endocrine components to signaling pathways).

4. In 2007, the National Research Council published Toxicity Testing in the 21st Century: A Vision and a Strategy.3 This document served to redirect the standard toxicity testing paradigm, which consists of a patchwork of disparate tests performed largely with animals, to a more organized approach that makes extensive use of in vitro assays to identify and characterize toxicity pathways. The authors argue that the use of in vitro tests, coupled with modeling approaches (e.g., physiologically based pharmacokinetic [PBPK] modeling), could reduce the time and expense of chemical toxicity characterization and would relegate the use of whole-animal studies, mainly to the validation of toxicity predictions. Adverse outcome pathways (AOP) have been used as a tool to formulate pathway linkages among molecular events and toxicity. An AOP is a conceptual framework that integrates molecular events initiated by exposure to chemicals or other physiologic stressor to adverse biological outcomes at relevant levels of biological organization (Figure 1-1).4 In line with this emerging paradigm, assays described in this DRP are divided into in vitro screening assays designed to identify interactions of chemicals with specific components of toxicity pathways (OECD Conceptual Framework Level 2) and in vivo assays that would provide a more holistic evaluation of the chemical effects on endocrine signaling processes (OECD Conceptual Framework Levels 3–5). AOPs presented in the DRP are not meant to be definitive but are structured to define linkages between in vitro screening assays, which identify molecular initiating events, and in vivo toxicity tests that describe toxic events related to the initiating events. Readers are directed to Ankley et al.4 for the discussion and presentation of detailed AOPs.

5. Interaction of EDCs with nuclear receptors stands prominent among the molecular events that initiate adverse outcomes. The nuclear receptor family has 48 functionally distinct members in humans.5 In addition to the receptors involved in EAT signaling, hormone-activated nuclear receptors in vertebrates include the corticosteroid receptors (e.g., mineralocorticoid, glucocorticoid), retinoic acid receptor (RAR), retinoid X receptor (RXR), vitamin D receptor (VDR), and peroxisome proliferator activated receptor (PPAR). Ligands to some of these receptors (e.g., vitamin D binding to the VDR, retinoids binding to the RAR, fatty acids binding to PPAR) may not fit the conventional view of a hormone. Nonetheless, these ligands do fit the broad definition of a hormone as a substance, originating in one tissue and conveyed by the bloodstream to another to effect physiological activity,1 and this document will address the pathways to which these hormones and receptors contribute and their susceptibility to disruption by environmental chemicals.

6. Members of the nuclear receptor family all share a common domain structure (Figure 1-2). The A/B domains are highly variable among the nuclear receptors, but contain a transcriptional activation function (AF-1) that is vital to receptor activity. The C or DNA-binding domain (DBD) is highly conserved among the nuclear receptors, containing two zinc finger motifs that are responsible for recognition of specific DNA binding sites. The D domain functions as a hinge between the DBD and the ligand-binding domain (LBD). The LBD or E domain contains a hydrophobic ligand-binding pocket, which provides specific ligand recognition to the receptor. The E domain mediates dimerization and ligand-dependent transcriptional activation functions (AF-2). The F domain is not present on all nuclear receptors, and its function is not clear.

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Figure 1-1 Adverse outcome pathway structure depicting the realms of in vitro and in vivo assays, site of initial interaction with toxicant (initiating event), and site of the typical initial

adverse outcome (Adapted from Ankley et al.4)

Figure 1-2. Domain structure of hormone nuclear receptors.

7. The susceptibility of peptide hormones, largely of neuroendocrine origin, to the action of EDCs has received relatively little attention. This may be because receptor proteins designed to recognize and bind peptide hormones are less likely to recognize typical environmental chemicals. However, precedent does exist for environmental chemicals modulating the secretion of peptide hormones (e.g., Fraites et al.6);

therefore, assays for the detection of such disruption will be described in this document. Endocrine signaling pathways for which evidence of endocrine disruption is limited to in vitro observations (e.g., MAP kinases) were not included in the DRP. Several endocrine pathways, that contribute to the regulation of apical processes relevant to this DRP (e.g., ghrelin and leptin signaling pathways), are not addressed since no data of endocrine disruption was revealed in our literature search. However, exclusion of such pathways likely indicates the absence of evaluation rather than the absence of disruption by environmental chemicals.

8. The intent of this DRP is to provide methods for both the mechanistic evaluation of the action of EDCs, as advocated in Toxicity Testing in the 21st Century: A Vision and a Strategy,3 and for the assessment of physiological consequences. This document is not all inclusive of neuro-endocrine pathways or the physiological processes regulated by the pathways. Rather, the document covers those neuro-endocrine pathways for which (a) significant evidence of susceptibility to disruption by environmental chemicals with potential for adverse outcome exists; and (b) assay procedures for the detection of environmental endocrine disruption are sufficiently developed for protocol standardization and validation. Chemicals that are known to disrupt each pathway are described in the respective sections.

These are not exhaustive lists of known EDCs, but rather are examples of chemicals that may serve as reference compounds in future standardization and validation of the assays. These pathways are diagrammed in Figure 1-3.

A/B C E

LBD AF-2

AF-1 DBD Hinge

F

Chemical properties

Receptor- ligand interactions Enzyme inhib.

Oxidative damage, etc.

Gene express.

Protein synth.

Altered signaling, etc.

Altered physiology, homeostasis, development, function

Lethality Impaired development, growth, reproduction

Altered structure, recruitment, Extinction

Toxicant Cellular

responses Macro-molecular

interactions Organ

responses Organism

responses Population responses

In vivo assays In vitro assays

Initiating event Apical event

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Figure 1-3. Some examples of neuro-endocrine pathways that are affected by EDCs, resulting in symptoms of metabolic syndrome and disruptions in reproduction, growth, and development.

Black arrows denote contiguous pathways. Red arrows highlight examples of cross-talk between pathways.

9. The overall intent of this DRP is to provide guidance on testing approaches that can be used for assessing the actions and toxicity of environmental chemicals on neuro-endocrine pathways not addressed in current Test Guidelines. This DRP is not intended to introduce a new patchwork of disparate tests to add to the existing complement of testing procedures. Whenever possible, approaches for the integration of tests are described so that the greatest amount of information can be derived with the least investment of time, resources, and animals. Effort was made to minimize redundancy among assays; however, the assays are presented in the context of pathways, and pathways are typically branched, rather than linear, with various intersections among different pathways (Figure 1-3). Accordingly, some redundancy in assay descriptions was warranted to maintain the integrity of individual pathways. The DRP does not specifically address temporal aspects of susceptibility to EDCs such as effects in old animals exposed in utero (e.g. earlier menopause, reduced testosterone in old males) or hormonally induced cancers (e.g.

breast cancer, testicular cancer, prostate cancer), although such considerations are warranted in studies designed to identify “no effect” levels of the chemical. There exist many assays for the clinical evaluation of endocrine function. These assays are typically not addressed in this DRP unless they have been used to assess environmental endocrine disruption. However, such assays do hold promise for incorporation into testing schemes following evaluation for such application.

10. The OECD Guidance Document on the Validation and International Acceptance of New or Updated Test Methods for Hazard Assessment (ENV/JM/MONO(2005)14 describes eight criteria for test method validation. Assays recommended in this DRP were derived from the peer-reviewed research literature and generally do not formally meet criteria such as inter-laboratory reproducibility, extensive use of reference chemicals to determine assay performance, and assay performance under Good Laboratory Practices guidelines. However, assays recommended in the DRP do meet criteria such as existing rationale for the use of the assay, established relationship between the assay endpoint and the relevant biological response, and (reasonably) detailed assay protocols. These criteria are either evident in the descriptions of the assays or in the references provided.

metabolism reproduction growth development

fatty acids vitamin A retinoic acid

corticotropin

releasing hormone arginine vasopressin

ACTH

corticosteroids

thyroid releasing hormone

thyroid stimulating hormone

thyroid hormone vitamin D

somatostatin GHRH

growth hormone

IGF-1 gonadotropin releasing hormone

gonadotropin

testosterone estradiol

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