Hormone Disruptive Chemical Contaminants in Food Editors

Hormone Disruptive Chemical Contaminants in Food D ow nl oa de d on 1 2 F eb ru ar y 20 12 P ub li sh ed o n 28 O ct ob er 2 01 1 on h tt p pu bs r sc o rg | do i 10 1 03 9 97 81 84 97 32 97 0 F P 00 1 Issues in Toxicology Series Editors Professor Diana Anderson, University of Bradford, UK Dr Michael D Waters, Integrated Laboratory Systems, Inc, N Carolina, USA Dr Martin F Wilks, University of Basel, Switzerland Dr Timothy C Marrs, Edentox Associates, Kent, UK Titles in the Series 1 Hair in.

Downloaded on 12 February 2012 Published on 28 October 2011 on http://pubs.rsc.org | doi:10.1039/9781849732970-FP001 Hormone-Disruptive Chemical Contaminants in Food View Online Issues in Toxicology Downloaded on 12 February 2012 Published on 28 October 2011 on http://pubs.rsc.org | doi:10.1039/9781849732970-FP001 Series Editors: Professor Diana Anderson, University of Bradford, UK Dr Michael D Waters, Integrated Laboratory Systems, Inc, N Carolina, USA Dr Martin F Wilks, University of Basel, Switzerland Dr Timothy C Marrs, Edentox Associates, Kent, UK Titles in the Series: 1: Hair in Toxicology: An Important Bio-Monitor 2: Male-mediated Developmental Toxicity 3: Cytochrome P450: Role in the Metabolism and Toxicity of Drugs and other Xenobiotics 4: Bile Acids: Toxicology and Bioactivity 5: The Comet Assay in Toxicology 6: Silver in Healthcare 7: In Silico Toxicology: Principles and Applications 8: Environmental Cardiology 9: Biomarkers and Human Biomonitoring, Volume 1: Ongoing Programs and Exposures 10: Biomarkers and Human Biomonitoring, Volume 2: Selected Biomarkers of Current Interest 11: Hormone-Disruptive Chemical Contaminants in Food How to obtain future titles on publication: A standing order plan is available for this series A standing order will bring delivery of each new volume immediately on publication For further information please contact: Book Sales Department, Royal Society of Chemistry, Thomas Graham House, Science Park, Milton Road, Cambridge, CB4 0WF, UK Telephone: +44 (0)1223 420066, Fax: +44 (0)1223 420247, Email: books@rsc.org Visit our website at http://www.rsc.org/Shop/Books/ View Online Downloaded on 12 February 2012 Published on 28 October 2011 on http://pubs.rsc.org | doi:10.1039/9781849732970-FP001 Hormone-Disruptive Chemical Contaminants in Food Edited by Ingemar Pongratz and Linda Vikstroăm Bergander Department of Biosciences and Nutrition, Karolinska Institute, Huddinge, Sweden Downloaded on 12 February 2012 Published on 28 October 2011 on http://pubs.rsc.org | doi:10.1039/9781849732970-FP001 View Online Issues in Toxicology No 11 ISBN: 978-1-84973-189-8 ISSN: 1757-7179 A catalogue record for this book is available from the British Library r Royal Society of Chemistry 2012 All rights reserved Apart from fair dealing for the purposes of research for non-commercial purposes or for private study, criticism or review, as permitted under the Copyright, Designs and Patents Act 1988 and the Copyright and Related Rights Regulations 2003, this publication may not be reproduced, stored or transmitted, in any form or by any means, without the prior permission in writing of The Royal Society of Chemistry or the copyright, or in the case of reproduction in accordance with the terms of licences issued by the Copyright Licensing Agency in the UK, or in accordance with the terms of the licences issued by the appropriate Reproduction Rights Organization outside the UK Enquiries concerning reproduction outside the terms stated here should be sent to The Royal Society of Chemistry at the address printed on this page The RSC is not responsible for individual opinions expressed in this work Published by The Royal Society of Chemistry, Thomas Graham House, Science Park, Milton Road, Cambridge CB4 0WF, UK Registered Charity Number 207890 For further information see our web site at www.rsc.org Downloaded on 12 February 2012 Published on 28 October 2011 on http://pubs.rsc.org | doi:10.1039/9781849732970-FP005 Foreword Even though effects of both endogenous and exogenous endocrine disruptors were first observed and described a long time ago, it was not obvious that these effects were related to disturbances in hormone homeostasis The observations were not spelled out as disrupters of the endocrine systems Examples of such effects are milk production in young boys after consumption of milk from cows feeding on clover in the spring or the effects observed in birds of prey and their insufficiency to reproduce successfully Experimental studies in the early 1970’s induced a prolongation in the estrous cyclicity of mice However, over the last two decades endocrine disrupting chemicals and their effects have become more obvious and are now a matter of major concern Numerous national and international reports were produced to address this issue in the latter part of the 1990’s, including one from the UNEP/ WHO 2002.* Thereafter an intense amount of work was devoted to improving our knowledge and understanding of EDCs and their effects The present book ‘‘Hormone-disruptive Chemical Contaminants in Food ’’ is one of a few such attempts to summarize the current state-of-the science Focusing on EDCs in food is highly relevant since this is indeed the major source of human exposure to these chemicals Over the last decade the EU legislation on chemicals REACH (Registration, Evaluation and Authorization of Chemicals) has been agreed and now implemented Even though ED effects are not addressed as such, the endpoints regarding, e.g reproductive toxicity, are highly dependent on hormone regulations, as well as cancer In a recent global project related to REACH and EDCs, the EU have adopted a report on the ‘‘State of the Art * http://www.who.int/ipcs/publications/new_issues/endocrine_disruptors/en/ Issues in Toxicology No 11 Hormone-Disruptive Chemical Contaminants in Food Edited by Ingemar Pongratz and Linda Vikstroăm Bergander r Royal Society of Chemistry 2012 Published by the Royal Society of Chemistry, www.rsc.org v View Online vi Foreword Downloaded on 12 February 2012 Published on 28 October 2011 on http://pubs.rsc.org | doi:10.1039/9781849732970-FP005 nd w Assessment of Endocrine Disrupters; Interim report’’ The present book is timely and addresses natural and anthropogenic EDCs, verity of endocrine endpoints, hormone systems and novel methodology for studies of EDCs and their effects So far slightly more than 140,000 chemicals in commerce have been registered under REACH and by adding a number of natural endocrine active compounds; it is easy to understand the enormous complexity of possible chemical structures interacting The phrase herein defines, that metabolism is further contributing to the number of potential EDCs; a highly appropriate and relevant conclusion By looking into the number of endogenous and exogenous compounds plus their metabolites it is clear to see that a very complex exposure scenario exists Adding to this are two different situations numerous chemicals possessing both persistency and bioaccumulativity characteristics on one hand and chemicals characterized by their pseudopersistency, e.g exposure to polycyclic aromatic hydrocarbons and phthalate esters on the other The present book introduces the reader to the extensive complexity of the hormone systems through selected in-depth examples The important issues of reproduction, fertility-related issues, teratogenicity and cancer in offspring, are addressed and it reaches the conclusion that male reproductive function is at risk This is very much in agreement with findings of others and supported by both experimental data and observations in wildlife, a mirror of an endpoint that is devastating for populations, independent of species It is obvious that food contaminants are linked to sex hormones and their receptors as well as to the aryl hydrocarbon (Ah) receptor The authors visualize the complexity of compounds interacting with these receptors A notably high number of anthropogenic chemicals are binding to the Ah receptor Examples of some very different responses are also given, even though the structural changes in the chemicals exerting these effects are sometimes minimal Accordingly, it is important to discuss in silico methodologies for assessing endocrine effects of chemicals In view of all the complex results from both in vivo and in vitro studies it seems appropriate to conclude as herein defined, that in silico methodology is a tool that requires interdisciplinary competence for relevant conclusions Even though the concept of epigenetics was generally understood some time ago it was not until the last decade that changes in the epigenome were first discussed in relation to ED and their effects in life The obvious changes in molecules due to methylations seem reasonable causes of changes in hormone system regulations The examples described indicate a mismatch between programming and real life which is striking To study and promote a better understanding of hormone function and the vast number of hormone systems, receptor proteins, transport proteins, and endpoints, it requires the development of new methods for experimental w http://www.who.int/ipcs/publications/new_issues/endocrine_disruptors/en/ Authored by: Richard Evans, Andreas Kortenkamp, Olwenn Martin, Rebecca McKinlay, Frances Orton, Erika Rosivatz, 2011 View Online Downloaded on 12 February 2012 Published on 28 October 2011 on http://pubs.rsc.org | doi:10.1039/9781849732970-FP005 Foreword vii studies The large number of chemicals, their metabolites and other potential abiotic transformation products requires methods that can be carried out over a short period of time but still give results from fully integrated organisms Hence financial as well as the ethical aspects need to be considered Examples of novel developments concerning test systems are given in the present book showing a positive development in this field of ED research ED effects in humans and well-established wildlife are a major threat to human health and the sustainable development of wildlife populations It is therefore urgent to intensify research efforts on EDCs, their effects, mechanisms of action and their synergies with natural and anthropogenic EDCs, in the complex mixtures we are exposed to via food and feed The issues that need to be solved will require competences from scientists with a deep knowledge in a variety of disciplines The issue of EDCs also needs to be communicated to policymakers, stakeholders and the public, to alert all of us that management of these chemicals is required This book ‘‘Hormone-disruptive Chemical Contaminants in Food ’’ serves, in my view, as a base for communicating the importance of this message of EDCs in food and their in vivo interactions A˚ke Bergman Professor in Environmental Chemistry Stockholm University Downloaded on 12 February 2012 Published on 28 October 2011 on http://pubs.rsc.org | doi:10.1039/9781849732970-FP005 View Online Downloaded on 12 February 2012 Published on 28 October 2011 on http://pubs.rsc.org | doi:10.1039/9781849732970-FP009 Preface Chemicals are an integral part of a modern society and consumers benefit from different chemicals on a daily basis However, there are a number of problems coupled with these products Because chemicals are present in a wide range of products and goods, consumers are under constant exposure to many of them In this book, we discuss the health problems that are associated with the presence of chemical contaminants in food We highlight some of the scientific challenges associated with the characterization of biological effects coupled to exposure to chemical contaminants and some of the needs for future research efforts in this scientific area We go through the scientific challenges associated with, for example, detection of chemical contaminants in a complex food matrix, and we discuss some of the problems associated with the current exposure scenarios to chemical contaminants in food, namely the presence of relatively low doses of chemicals with a prolonged exposure time In this book we have decided to focus our attention on chemicals that somehow have the potential to interfere with the endocrine axis, namely the hormonal pathways that are regulated by transcription factors of different families of proteins In addition, we also discuss how multidisciplinary scientific approaches are required to develop new knowledge in this area and how new scientific information needs to be ‘‘translated’’ into legislative action in order to develop relevant safety margins of exposure to contaminants in food and food items In our opinion, future research efforts in this scientific area face several key challenges, not only of a scientific nature but also other aspects will require considerable attention by all parties in this field One key aspect is, for example, the need to find new innovative channels of communication between research providers and research users There is a critical need to shorten the time frame between scientific discovery regarding potential health hazards and legislative implementation Issues in Toxicology No 11 Hormone-Disruptive Chemical Contaminants in Food Edited by Ingemar Pongratz and Linda Vikstroăm Bergander r Royal Society of Chemistry 2012 Published by the Royal Society of Chemistry, www.rsc.org ix View Online Downloaded on 12 February 2012 Published on 28 October 2011 on http://pubs.rsc.org | doi:10.1039/9781849732970-FP009 x Preface Communication with the larger community is also an area that requires special attention New ways to share scientific information and risk information need to be developed so that non-experts are able to digest the information that is provided and to make informed decisions regarding risks and benefits coupled with food consumption These issues represent new challenging and important areas that will require considerable attention in the future We would like to thank all the authors that have contributed their expertise that is presented in this book and we hope that the readers will find our views interesting and worthy of further thought Linda Bergander and Ingemar Pongratz View Online -Zurich on 12 February 2012 Published on 28 October 2011 on http://pubs.rsc.org | doi:10.1039/9781849732970-00216 222 endocrine disrupter chemicals (EDCs) 53–5 see also specific compounds accumulation 5, 154, 167, 199 adverse effects androgen receptor (AR) 26, 39 biological pathway targets 2–3, 8–9 breast cancer 63 characteristics 29, 199–200 chronic low-concentration exposure 6, 10, 11 classes 3–4 combinational exposure definition DNA methylation 57 DNA methyltransferases (DNMTs) 58–9 effects on epigenome 56, 59 fertility 63 fetal exposure 44 food chains 199–210 hydrophobic tendency Leydig cells 29, 37–9 medaka fish (Oryzias latipes) 139–40 metabolic pathways 205 phytoestrogens 206–7 screening methods 170–82 in silico research 170–82 sources steroid hormone receptors 63 steroidogenesis 38 synthetic vitamin A 207–8 zebrafish (Danio rerio) 139–40 Endocrine-disrupting chemicals.Diet Interaction Database (EDID) 208 endocrine disruptor hypothesis Endocrine Society endocrine system 2–3 endogenous ligands endoplasmic reticulum 94 enterohepatic circulation 95 Environmental Protection Agency, USA (EPA) Subject Index epigenome adult onset disease causes 63 definition 45 developmental environment 50–3, 63 disease risk 50, 63 endocrine disrupter chemicals (EDCs) 56, 59 environmental factors 44–64 epoxide hydrolase 100 equol 72, 73, 83, 96–8, 108 ERE-Luc reporter mice bioluminescence imaging 157–8 cadmium 163–7 daidzein (Daid) 163 diets 156, 158 estradiol 164 estrogen receptor (ER) effects 159–62 estrogen responsive element (ERE) 158–9 experimental treatments 156–8 generation 158 genistein (GEN) 162–3, 164, 207 8-prenylnaringenin (8PN) 86 soy milk 162–3, 164 17b-estradiol 33, 35 estradiol binding 98 equol effect 98 ERE-Luc reporter mice 164 estrogen receptor (ER) 62–3, 161, 163, 164 gene expression 62–3 genistein (GEN) 207 postmenopausal levels 86 trace elements 208 estragole (1-allyl-4-methoxybenzene) 189, 190, 191, 192–7 estrogen receptor (ER) activity variations 160–2 cadmium 163–7 daidzein 72 3,3 -diindolylmethane (DIM) 125 DNA methylation 59, 62–3 View Online -Zurich on 12 February 2012 Published on 28 October 2011 on http://pubs.rsc.org | doi:10.1039/9781849732970-00216 Subject Index equol 98 estradiol 62–3, 161, 163, 164 estrous cycle changes 159 gene silencing 63 genistein (GEN) 72, 164 Leydig cells 35 methoxychlor 106 model organisms 137 phytoestrogens 70, 86 polybromodiphenyl ethers (PBDEs) 102 polychlorinated biphenyls (PCBs) 100, 102 prenylflavonoids 85 red clover isoflavones 73 resveratrol 127 signalling complexities 167 in silico research 177, 180–1 soy milk 164 tissue-specific behaviour 159–60, 167–8 vinclozolin 105 zebrafish (Danio rerio) 142 estrogenic activities animal studies 74–5, 148–50 methoxychlor 32 prenylflavonoids 85, 86 red clover 72–8 soy milk 162–3 estrogenic compounds 8, 35–6, 53, 159–62, 167 see also phytoestrogens estrous cycle changes 159, 160 ethyl carbamate 95 17a-ethynylestradiol 35 European diet 4, 202, 206 excretion exposure factors 200 famine 51 fast-food meals 202 fat cells feed additives 124 fertility genistein (GEN) 79 hormonal function of Leydig cells 35–6 223 methoxychlor 107 transgenerational effects 64 fetal development, male 26–7, 29, 30–1 fetal exposure 6, see also placenta DES dioxin-like compounds 121 dioxins 34 endocrine disrupter chemicals (EDCs) 29 environmental factors 44 linuron 31 methoxychlor 54 organophosphates 203 phthalates 31, 32–4 polychlorinated biphenyls (PCBs) 121 procymidone 30–1 tetrachlorodibenzo-p-dioxin (TCDD) 54 vinclozolin 30, 53, 104 fetal Leydig cells (FLC) androgens 28 development 28 dysfunction 27, 38 endocrine disrupter chemicals (EDCs) 29, 38 estrogen receptor (ER) 35 insulin-like factor (Insl3) 28, 33 phthalates effect 31, 32–4, 37–8 species-dependent differences 37 steroidogenesis 28, 31, 32–3, 37 Finland first-pass effect 94 fish see also seafood arsenic 204 Baltic Sea 15–16 consumption advice 201–2, 205 DDE dioxins 124, 202 hexachlorobenzene 206 iodine 206 mercury persistent organic pollutants (POPs) levels 15 PFOS View Online -Zurich on 12 February 2012 Published on 28 October 2011 on http://pubs.rsc.org | doi:10.1039/9781849732970-00216 224 fish see also seafood (continued) polychlorinated biphenyls (PCBs) 5, 206 recommended consumption levels 16 fish liver 16 fish model organisms 137–40 see also medaka fish (Oryzias latipes); zebrafish (Danio rerio) flavonoids 126–7 see also isoflavones; prenylflavonoids cancers 126, 206–7 classes 35 consumption cytochrome P450-dependent monooxygenases (CYPs) 127 fruit 35, 203 gene expression 126 soy 35 sulfotransferases (SULTs) 127, 203 thyroid hormone (TH) 203 flavorings 184 flax 167 flexible docking 178 folic acid 54–5 food chains 1, 5, 199–210 food consumption food contaminating chemicals accumulation 154, 199 sources 2, 5–6 toxicity 93–4, 154 food hygiene 210 food packaging 32 food production chemicals 200 food safety challenges 9–12 formononetin (FOR) 62, 71, 72, 73–4, 76–8, 97 formula milk DDE 18, 20 DDT 18, 20 cis-heptachlorepoxide 20, 21 hexachlorocyclohexane (HCH) 18, 20 hypoallergenic formula 21–2 lindane (g-HCH) 18, 20 Subject Index organochlorine pesticides (OCPs) 23 persistent organic pollutants (POPs) levels 22 polychlorinated biphenyls (PCBs) 19, 23 polychlorinated dibenzo-p-dioxins (PCDDs) 19, 23 polychlorinated dibenzofurans (PCDFs) 19, 23 soy 6, 22, 36, 78–83, 87, 201 usage in Europe and USA 16–17 French paradox 127 fruit 203–4 fruitfly (Drosophila melanogaster) 138 fungicides 5–6 see also procymidone; vinclozolin furans 119–20 furocoumarins 203 galangin 127 gene expression aryl hydrocarbon receptor (AhR) 116–19, 128 carotenoids 128 CpG islands 45 developmental environment 45, 63 diethylstilbestrol (DES) 53 estradiol 62–3 flavonoids 126 formononetin (FOR) 62 linuron 31 modulation paternal high fat diet effects 56 polybromodiphenyl ethers (PBDEs) 103 prenylflavonoids 86 red clover extracts 73 retinoids 128 tetrachlorodibenzo-p-dioxin (TCDD) 54 vinclozolin 58 gene imprinting 47, 52, 53–4 gene knock-down 140–2 gene repression 62 gene silencing 45, 63 View Online -Zurich on 12 February 2012 Published on 28 October 2011 on http://pubs.rsc.org | doi:10.1039/9781849732970-00216 Subject Index gene transcription 34, 45, 47, 49, 59–62 genistein (GEN) see also 8-prenylgenistein; soy cancers 206–7 developmental environment 37, 80–2 dietary exposure 206 DNA methylation 207 epigenome effect 61 ERE-Luc reporter mice 162–3, 164, 207 estradiol 207 estrogen receptor (ER) 162–3, 164 hypospadia 207 liver 207 obesity 55 red clover extracts 71–2, 73, 76–8 soy 35–6, 78 soy infant formula 36, 79, 83, 201 thyroid hormone (TH) 206 zebrafish (Danio rerio) 142 genistin 78, 79, 80–2 germ cell maturation 55 GFP see green fluorescence protein (GFP) reporter gene glucaronic acid 97 glucocorticoid receptor (GR) 52, 59, 62, 102 glucose 94 glucosinolates 203 glucuronic acid 96 glucuronidation 94–5 daidzein (Daid) 97 equol 96 methoxychlor 105 polychlorinated biphenyls (PCBs) 100 vinclozolin 104 Xenopus laevis (African clawed frog) 139 glutamic acid decarboxylase gene promoter 52 glutathione (GSH) 57, 58, 94–5, 96, 100 225 glutathione S-transferases (GSTs) 95, 96, 100 glycetin 78 b-glycosidases 97 b-glycosides 97 gonadal differentiation methoxychlor effect 54 vinclozolin 104 vinclozolin effect 53, 55–6, 58 Gothenburg, Sweden 16 grandchildren 56, 64 grapefruit 203 green fluorescence protein (GFP) reporter gene 149, 150 green tea 127 Greenland Inuits 55 GSH see glutathione (GSH) GSTs see glutathione S-transferase gubernacular cords 33 gut bacteria 72, 86, 95, 97, 108, 204 HACCP: Hazard Analysis Critical Control Point 210 halogenated aromatic hydrocarbons (HAHs) 115 see also polychlorinated biphenyls (PCBs); polychlorinated dibenzo-p-dioxins (PCDDs); polychlorinated dibenzofurans (PCDFs); tetrachlorodibenzo-p-dioxin (TCDD) hCG see human chorionic gonadotropin heat shock element (HSE) 150 heat shock proteins (HSPs) 150 heat shock transcription factors (HSFs) 150 heavy metal pollution 208 cis-heptachlorepoxide commercial baby food levels 20, 21 infant formula 20, 21 herbicides see also linuron herring Baltic Sea 16 DDE View Online -Zurich on 12 February 2012 Published on 28 October 2011 on http://pubs.rsc.org | doi:10.1039/9781849732970-00216 226 herring (continued) PFOS polychlorinated biphenyls (PCBs) heterochromatin 45 hexachlorobenzene 206 hexachlorocyclohexane (HCH) 18, 20, 207 histone code 50 histones acetylation 49, 59 amino acid residue charges 49 cancer effects 50 diethylstilbestrol (DES) 63 methylation 59 modifications 47–50 homeostasis homocysteine 57, 58 homology modelling 178 honey 127 hops (humulus lupulus) 36, 83–4, 85 hormone receptors see also specific receptors hormone replacement therapy (HRT) 71 HPG see hypothalamic–pituitary– gonadal (HPG) axis HSPs see heat shock proteins (HSPs) human chorionic gonadotropin (hCG) 28, 33, 34, 36 human migration 44 human studies 76–8 humulus lupulus (common hop) 36, 83–4, 85 Hygiene Package, Europe 210 hypergonadotropism 31 hyperplasia 75 hypomethylation see also DNA methylation arsenic effect 57 benzene 55 bisphenol A (BPA) 55 famine during early gestation 51 hypospadia 26–7 DDE effect 32 diethylstilbestrol (DES) 35 Subject Index genistein (GEN) effect 207 linuron effect 31 phthalates effect 33 procymidone effect 30 vinclozolin effect 30, 207 hypothalamic–pituitary–gonadal (HPG) axis breast milk phthalate exposure 32 vinclozolin effect 30 imprinted genes 47, 52, 53–4 in silico research advantages 10, 170–1, 177, 179, 182 disadvantages 10–11, 171, 177, 182 estrogen receptor (ER) 180–1 methodologies 172–3 regulatory use 170–1 in vitro screening methods advantages 137 compared to in vivo 142 dietary extracts 73 disadvantages 137, 154 non-feeding embryos 139 in vivo studies advantages 137, 167 disadvantages 137 gene knock-down 141 metabolized compounds 73 indoles 125–6 industrial chemicals 9, 15 infant formula DDE 18, 20 DDT 18, 20 cis-heptachlorepoxide 20, 21 hexachlorocyclohexane (HCH) 18, 20 hypoallergenic 21–2 lindane (g-HCH) 18, 20 organochlorine pesticides (OCPs) 23 persistent organic pollutants (POPs) levels 22 polychlorinated biphenyls (PCBs) 19, 23 View Online 227 -Zurich on 12 February 2012 Published on 28 October 2011 on http://pubs.rsc.org | doi:10.1039/9781849732970-00216 Subject Index polychlorinated dibenzo-p-dioxins (PCDDs) 19, 23 polychlorinated dibenzofurans (PCDFs) 19, 23 soy 6, 22, 36, 78–83, 87, 201 usage in Europe and USA 16–17 infants see also breast milk; infant formula bisphenol A (BPA) exposure comparison of formula and breast milk 22, 201 dairy products 204 DDE 16 dioxins 16 endocrine disrupter chemicals (EDCs) exposure 7, 200–1 genistein (GEN) 201 isoflavone exposure 6, 78–83, 87 neurological status 16 perchlorate 144–5 persistent organic pollutants (POPs) 17, 21–2 polychlorinated biphenyls (PCBs) 16 ingenuity pathway analysis (IPA) 189, 192, 194 inositol hexaphosphate (phytic acid) 208, 209–10 insecticides 7, 206 see also methoxychlor; pesticides insulin-like factor (Insl3) 28, 33 interstitial cell tumors 31 intestine 97 intracellular signaling 38 iodine 201, 202, 206 Iraq 5–6 Ireland pork contamination 124 irilone 72 iron 209 isoflavones see also flavonoids bioavailability 71–2 composition 71–2 equol production 96–7 infant exposure male phenotype development 36 metabolism 71–2 osteoporosis prevention 75 postmenopausal health effects 74 red clover 72–4 soy infant formula 78–83 isothiocyanates 203, 205 isoxanthohumol (IX) 36, 83, 84, 85 Japan rice oil contamination 124 Japanese mulberry tree (Morus alba L.) 84 Japanese population 35 kaempferol 125, 126, 127 kidneys 167 Korea infants daily exposure 22 Kyushu, Japan 124 Lake Apoka, USA legislation see regulation legumes 209 Leningrad siege 51 Leydig cells androgens 29 bisphenol A (BPA) effects 36 dioxins 34–5 dysfunction 38 endocrine disrupter chemicals (EDCs) 37–9 estrogen receptor (ER) 35 fetal see fetal Leydig cells genestein 36 isoflavones 36 phthalates 31, 32–4, 37–8 procymidone effect 31 steroidogenesis 26, 28, 31–3, 34, 37, 38 LH see luteinizing hormone (LH) LHR see luteinizing hormone receptor libido suppression 38 life stages 7–8, 200 lignans lindane (g-HCH) 18, 20 see also hexachlorocyclohexane linuron 31, 37 lipid uptake View Online -Zurich on 12 February 2012 Published on 28 October 2011 on http://pubs.rsc.org | doi:10.1039/9781849732970-00216 228 liver dioxins 207 estragole (1-allyl-4methoxybenzene) 196 estrogenic compounds exposure 159, 160, 161, 167 Percellome toxicogenomics 185–8 peroxisome proliferator activated receptor alpha (PPAR-alpha) 192 tetrachlorodibenzo-p-dioxin (TCDD) 15 vitamin A 207 zinc protection 209 lock-and-key model luciferase ERE-Luc reporter mice 157, 158, 161, 162, 165 zebrafish (Danio rerio) 148–9 lung cancers 55 lutein 128 luteinizing hormone (LH) dioxins effect 34–5 phthalates effect 32–3 procymidone effect 31 reproductive development 28 vinclozolin effect 30 luteinizing hormone receptor (LHR) 28 lysine acetylation 49 methylation 49–50 male phenotype development androgens 27–9 disruption 26 endocrine disrupter chemicals (EDCs) 37–8 isoflavones 36 species-dependent differences 37 vinclozolin effect 30 mammary gland 54, 74, 77, 86 marine animals see also fish; seafood masculinization 27–9, 30, 37–8 Subject Index MAT see methionine adenosyltransferase maternal diet advice 201–2 cardiovascular disease 51 dairy products 16 effect on epigenome 44, 50 famine 51 fat levels 16 fish 16 protein restriction 52 maternal stress hormones 44 maximal tolerated dose (MTD) 184–5, 188 maximum residue limits (MRL) 18 MBP see monobutyl phthalate (MBP) MC see methoxychlor MD (Molecular Dynamics) 178 medaka fish (Oryzias latipes) 138, 139–40, 148, 149 MEHP see monoethylhexyl phthalate membranes depolarization Menoflavon (MF11RCE) 76, 77 menopause 71, 74, 76–7, 86–7 menstrual cycle 84, 202 mercapturic acids 95, 96, 100 mercury 4, 5–6, 61, 150 metabolic diseases 51 see also specific diseases metabolic dysfunction 56 metabolism bioactivation 95–6, 107–8 detoxification 93–5, 108 isoflavones 71–2 phthalates 108 polychlorinated biphenyls (PCBs) 99–102 metals 4, 55, 150, 208 methionine 57, 58 methionine adenosyltransferase (MAT) 57, 58 methoxychlor androgen receptor (AR) 106 cancers 207 DNA methyltransferases (DNMTs) 58 View Online 229 -Zurich on 12 February 2012 Published on 28 October 2011 on http://pubs.rsc.org | doi:10.1039/9781849732970-00216 Subject Index epigenome effect 60 estrogen receptor (ER) 54, 106 fertility 107 gene imprinting 53–4 glucaronic acid conjugation 105 metabolism 105–7 steroidogenesis 107 testosterone 107 methoxychlor (MC) 32 3-methylcholanthrene (3-MC) 57 methylmercury (MeHg) 5–6, 55, 205 methyltransferase 54 MF11RCE 76, 77 microbial system microRNA (mRNA) 45, 57 gene knock-down 140–1 MIF (Molecular Interaction Fields) 175–6 milk see also infant formula children’s consumption 201 contaminants from pasture and feed 204 dioxins 16, 23, 202 iodine 206 perchlorate 144–5 mismatch hypothesis 51 mixture effects see combinational exposure (cocktail effect) MM (Molecular Mechanics) 178 model organisms see small model organisms (SMOs) molecular descriptors 173, 174, 176 Molecular Dynamics (MD) 178 Molecular Interaction Fields (MIF) 175–6 Molecular Mechanics (MM) 178 mono(2-ethylhexyl) phthalate (MEHP) 192, 195 monobutyl phthalate (MBP) 33 monoethylhexyl phthalate (MEHP) 32 Monte Carlo sampling 178 morpholinos 140–1 Morus alba L (Japanese mulberry tree) 84 MRL see maximum residue limits mulberry tree 84 Muăllerian duct 27 mycotoxins 200, 202 naphthoavones 126 2-naphthylamine 96 6-[1,1-dimethylallyl]naringenin (6DMAN) 83, 84, 85 National Center for Toxicological Research (NCTR) 180–1 nematode (Caenorhabitis elegans) 138 Netherlands 16, 51 neurotoxicants 55 no adverse effect level (NOAEL) 6, 15, 155, 184 Novagen 77 nuclear receptor signalling 1, 140 nuclear receptors 59–62 nucleotide bases 45 obesity 9, 51, 64 OCPs see organochlorine pesticides OECD amphibian metamorphosis test (OECD 231) 143–4 olive oil organochlorine pesticides (OCPs) see also hexachlorocyclohexane commercial baby food levels 20, 23 infant formula 23 infants daily exposure 18, 22 organophosphates 203 organophosphorus insecticides 206 organotins 199, 204 Oryzias latipes (medaka fish) 138, 139–40, 148, 149 osteoporosis 75, 77–8, 86, 205 ovaries 54 oxychlordane 18–21, 20 P-07 red clover extract 77 packaging 32 View Online -Zurich on 12 February 2012 Published on 28 October 2011 on http://pubs.rsc.org | doi:10.1039/9781849732970-00216 230 PAHs see polycyclic aromatic hydrocarbons; polycyclic aromatic hydrocarbons (PAHs) PAPS see phosphoadenosinephosphosulfate parathyroid hormone 59 Partial Least Square (PLS) 176 pasture contamination 204 paternal diet 56 PBDEs see polybromodiphenyl ethers PCA (Principal Component Analysis) 176 PCBs see polychlorinated biphenyls PCDDs see polychlorinated dibenzo-p-dioxins PCDFs see polychlorinated dibenzofurans Percellome database 186–7 Percellome Explorer (PE) program 192, 193, 194 Percellome toxicogenomics 184–97 perchlorate 144–5, 206 perfluorooctanesulfonic acid (PFOS) 4, perfluorooctanoic acid (PFOA) 146–7 perflurooctanesulfonate (PFOS) 146–7 peroxisome proliferator activated receptor alpha (PPAR-alpha) 52, 185, 189–97 persistent organic pollutants (POPs) see also specific chemicals chlorination degree 15 commercial baby food levels 17–23 epigenome effect 50, 61 historical perspective 14 hydrophobicity 15 hypomethylation 55 infants exposure 15–17, 21–2 regulation 15 Stockholm Convention 15 pesticides 7, 96, 203 see also DDT Stockholm Convention 15 Subject Index PFOS see perfluorooctanesulfonic acid phenobarbital 192 phenotype development 50 phenotypic plasticity 50 phenylpropanoid pathway 70 PhIP see 2-amino-1-methyl-6phenylimidazo[4,5-b]pyridine (PhIP) phosphoadenosine-phosphosulfate (PAPS) 95 photon emission 158, 162 phthalates 5a-reductase (5aR) effect 33 anti-androgenic effects 32–4 antioxidant vitamins 208 cholesterol transport 33 dairy products 204 DNA methyltransferases (DNMTs) 58–9 fetal exposure 31, 32–4, 37–8 gubernacular cords 33 iodide uptake 206 levels in women 29, 32 luteinizing hormone (LH) 32–3 male phenotype development 37 metabolism 108 olive oil pasture contamination 204 pregnancy exposure 32 steroidogenesis 31, 32–4 thyroid gland 206 Wolffian duct 33 phytic acid (inositol hexaphosphate) 208, 209–10 phytochemicals aryl hydrocarbon receptor (AhR) 116, 129 dioxins 129 polycyclic aromatic hydrocarbons (PAHs) 129 phytoestrogens 35–6, 70–87 alternative therapies 202 behaviour cAMP levels 36 cancers 202, 205, 206–7 View Online -Zurich on 12 February 2012 Published on 28 October 2011 on http://pubs.rsc.org | doi:10.1039/9781849732970-00216 Subject Index classes 35 consumption levels definition endocrine disrupter chemicals (EDCs) 206–7 estrogen receptor (ER) binding 70 female diet 202 human chorionic gonadotropin (hCG) effect 36 Leydig cells 36 menstrual cycle 202 osteoporosis prevention 205 red clover 71–8 sources 35 steroidogenesis 36 testosterone levels 36 thyroid hormone (TH) 202, 206 vegetables 203 vegetarianism 202 placenta 16, 52, 54 plankton plasticizers see phthalates PLS (Partial Least Square) 176 PMTI (Provisional Monthly Tolerable Intake) 22 polybromodiphenyl ethers (PBDEs) 5, 102–3, 208 polychlorinated biphenyls (PCBs) accidental human exposure 124 animal feed 204 antioxidant vitamins 208 aryl hydrocarbon receptor (AhR) 101 ban on use catechols 100, 101 chemical structures 120 commercial baby food levels 19, 23 cytochrome P450-dependent monooxygenases (CYPs) 102 dairy products 204 dietary exposure 200 dioxin-like 15–16, 101 enantiomers 102 estrogen receptor (ER) binding 100–1, 102 231 fetal exposure 99 glucocorticoid receptor (GR) 102 herring infant formula 19, 23 infants exposure 16, 18, 21, 22 marine levels 16 metabolism 99–102 reproductive effects 7, 100 seafood 204, 206 sources 15–16, 119, 123 steroidogenesis 102 sulfotransferases (SULTs) 101 thyroid hormone (TH) 101, 145 toxic equivalent factors (TEFs) 122 uses 99 uterus 100 vegetable oil 203 Xenopus laevis (African clawed frog) 145 polychlorinated dibenzo-p-dioxins (PCDDs) accidental human exposure 124 chemical structures 120 commercial baby food levels 19, 23 dairy products 204 historical perspective 120 human levels 120 infant formula 19, 23 infants daily exposure 18, 21–2 sources 15, 34, 119, 123 toxic equivalent factors (TEFs) 122 polychlorinated dibenzofurans (PCDFs) accidental human exposure 124 chemical structures 120 commercial baby food levels 19, 23 dairy products 204 infant formula 19, 23 infants daily exposure 18, 21–2 sources 15, 119, 123 toxic equivalent factors (TEFs) 122 View Online -Zurich on 12 February 2012 Published on 28 October 2011 on http://pubs.rsc.org | doi:10.1039/9781849732970-00216 232 polycyclic aromatic hydrocarbons (PAHs) 115, 116, 118 POPs see persistent organic pollutants postmenopausal health effects 71–8, 86–7 poultry 124 PPAR-alpha see peroxisome proliferator activated receptor alpha predictive power 179 pregnancy exposure 7, 23 diethylstilbestrol (DES) 8, 35 dioxins 16 phthalates 32 pregnane X receptor (PXR) 94 prenylflavonoids 83–6 8-prenylgenistein 85 6-prenylnaringenin (6PN) 83, 84, 85 8-prenylnaringenin (8PN) 36, 83, 84, 85–6 prepubertal growth period diet 56 Principal Component Analysis (PCA) 176 procymidone 30–1, 37 proestrogens 96 progesterone receptor (PR) 30 Promensil 76, 77, 78 propylthiouracil (PTU) 144 prostaglandin E synthase 95 prostate 86 protein expression profiles 155 protein restriction 52 Provisional Monthly Tolerable Intake (PMTI) 22 prunetin 72 pseudobaptigenin 72 PXR see pregnane X receptor pyruvate dehydrogenase kinase (Pdk4) 192, 193 QSAR (quantitative structure-activity relationship) method 172–7, 181 combined with virtual docking 179–80 quercitin 125, 126–7, 206 Subject Index REACH (Registration, Evaluation and Authorization of Chemicals) 171, 173 reactive oxygen species (ROS) 119, 208 read-across 172 red clover 71–8 see also comuestrol extracts 71, 74–8, 86–7 5a-reductase (5aR) 27, 28, 30, 33 reelin gene promoter 52 Registration, Evaluation and Authorization of Chemicals (REACH) 171 regulation 9, 10, 12, 15 reporter animals 154–68 reproduction bisphenol A (BPA) effects DES effects polychlorinated biphenyls (PCBs) 100 reproductive development androgen receptor (AR) antagonists 29 DDE effect 32 dioxins 34–5 disruption 26 endocrine disrupter chemicals (EDCs) 37–9 genistein (GEN) 79, 87 phthalates 38 soy infant formula 78–9 vinclozolin 104 reproductive health 6, reproductive tract development 26, 27–8, 35, 53 residence time 95 respiratory problems 128 resveratrol 36, 37, 125, 127–8 retinoic acid 59–62, 128–9, 207–8 retinoids 128–9 ribosomal RNA gene 52 rice 202–3 rice oil 124 rigid docking 178 Rimostil 76, 77, 78 risk assessment 9, 10–11, 15, 155, 210 View Online Subject Index -Zurich on 12 February 2012 Published on 28 October 2011 on http://pubs.rsc.org | doi:10.1039/9781849732970-00216 RNA interference (RNAi) system 140–1 RSort program 188 SAH (S-adenosylhomocysteine) 57, 58 salmon 16, 124, 205 SAM (S-adenosylmethionine) 46, 52, 57, 58 SAR (structure–activity relationship) 172, 174 schizophrenia 52 screening methods high-throughput 136, 138–9 robotized 139 in silico research 170–82 sea trout 16 seafood 204, 205, 206 see also fish seals second messengers see signal transducing molecules selective estrogen receptor modulators (SERMs) 160 semi-flexible docking 178 semicarbazide 200 serine 49 Sertoli cells 27 Seveso, Italy 15, 121, 123–4 sex hormone binding globulin (SHBG) 98 sex ratios sheep clover disease 71 signal transducing molecules Silent Spring small model organisms (SMOs) 138–50 smooth endoplasmic reticulum 34 sodium perchlorate 144 soil trace elements 203 sorghum 209–10 soy 35, 96–7, 202, 206 see also genistein soy infant formula 6, 22, 36, 78–83, 87, 201 soy milk 162–3, 164 sperm count 8, 29, 35, 54, 121 spermatogenesis 38 233 vinclozolin 53, 55–6 zinc 208 steroid hormone receptors 63 steroidogenesis bisphenol A (BPA) effect 36 cadmium 209 dioxins effect 34 fetal Leydig cells (FLC) 26, 28, 31, 32–3, 37 genestein effect 36 methoxychlor 107 phthalates effect 32–4, 38 phytoestrogens effect 36 polybromodiphenyl ethers (PBDEs) 103 polychlorinated biphenyls (PCBs) 102 species-dependent differences 37 zinc 209 Stockholm Convention 15 stress 52–3 structural keys 173 structure–activity relationship (SAR) 172, 174 suicide victims 52 sulfate conjugation 94–5, 100, 139 sulfotransferases (SULTs) 95, 96 flavonoids 127, 203 isoflavones 97 polybromodiphenyl ethers (PBDEs) 102, 103 polychlorinated biphenyls (PCBs) 100, 101 Swedish National Food Administration 16 T3 see triiodothyronine Taiwan 124 tamoxifen 62 tannins 208, 209–10 tarragon 189 TBBPA see tetrabromobisphenol A TCDD see tetrachlorodibenzo-pdioxin tea 127 teleost fish 137, 142 View Online -Zurich on 12 February 2012 Published on 28 October 2011 on http://pubs.rsc.org | doi:10.1039/9781849732970-00216 234 TEQ (toxic equivalent) 15, 23 testicular dysgenesis syndrome (TDS) 8, 26–7 DDT derivatives 32 dioxins 34 linuron effect 31 phthalates effect 33 procymidone effect 31 vinclozolin effect 30 testicular function 36 testosterone adult Leydig cells production 38 binding 98 bisphenol A (BPA) effects 36 dioxins effect 34–5 equol effect 98 fetal Leydig cell production 28 linuron effect 31 methoxychlor effect 32, 107 phthalates effect 33, 34 procymidone effect 31 reproductive development 27 soy infant formula effect 36 vinclozolin effect 30 tetrabromobisphenol A (TBBPA) 139, 146 tetrachlorodibenzo-p-dioxin (TCDD) accidental human exposure 124 aryl hydrocarbon receptor (AhR) 117, 118 carcinogen 115–16 chemical structure 120 epigenome effect 60 gene expression 54 growth factors activity 121 growth patterns 121 liver cancer 15 lutein 128 metabolic resistance 119 placenta development 54 reproductive development 34–5 sources 34 toxic equivalent factors (TEFs) 122 vitamin A 128 thiocyanates 203 Subject Index Threshold of Toxicological Concern (TTC) 172 threshold values 10 thyroid gland iodine 201 perchlorate 206 phthalates 206 phytoestrogens 202 vertebrate conservation 137 thyroid hormone (TH) bisphenol A (BPA) 146 copper 209 flavonoids 203 genistein (GEN) 206 perfluorooctanoic acid (PFOA) 146–7 perflurooctanesulfonate (PFOS) 146–7 phytoestrogens 206 polybromodiphenyl ethers (PBDEs) 208 polychlorinated biphenyls (PCBs) 101, 145 signalling 142–4 tetrabromobisphenol A (TBBPA) 146 zinc 209 thyroid hormone (TR) receptors bisphenol A (BPA) 146 model organisms 137–8 perchlorate 144–5 zebrafish (Danio rerio) 142 thyroid neuroendocrine system tolerable daily intake (TDI) 184 toxic equivalency (TEQ) 15, 23, 122 toxic equivalent factors (TEFs) 121–2 toxicity 93–4 effect of prolonged exposure 155, 163, 165 methodologies 168, 184 peer review panels 155 in silico research 172, 174, 181 toxicogenomics 155, 184–97 trace elements 208 trade globalisation View Online 235 -Zurich on 12 February 2012 Published on 28 October 2011 on http://pubs.rsc.org | doi:10.1039/9781849732970-00216 Subject Index transcription factors 59–62 transgenerational effects 9, 55–6, 58–9, 201 transsulfuration pathway 57, 58 transthyretin 103 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) 123–4 triiodothyronine (T3) 137, 144 TTC (Threshold of Toxicological Concern) 172 Turkey infants daily exposure 22 turmeric 128 tyrosine aminotransferase (Tat) 62 tyrosine kinase inhibitors 119 uridine-diphosphate glucuronic acid (UDPGA) 94 uridine-diphosphate glucuronosyl transferase (UGT) 94, 95, 96, 97, 100 uterine leiomyometra 79 uterus genistein (GEN) 79 polychlorinated biphenyls (PCBs) 100 prenylflavonoids effect 85–6 red clover extracts 74–5, 77 vagina early life soy intake effect 79 estrogenic compounds exposure 159, 160, 161 prenylflavonoids 86 red clover extracts 74 vegetable oil 5, 203 vegetables 125, 203–4, 209 vegetarianism 202 vehicle pollution 55 vinclozolin 30 androgen receptor (AR) 53, 105 bioactivation 104–5 DNA methylation 53 epigenome effect 60 estrogen receptor (ER) 105 fetal exposure 104 gene expression 58 hypospadia 207 metabolism 103–5 reproductive development 37, 55–6, 58, 104 virtual docking 177–9, 181–2 combined with 3D-QSAR 179–80 vitamin A 128, 129, 207–8 vitamin B12 54–5 vitamin C 208 vitamin D receptor 59 vitamin E 208 vitellogenin 149 water perchlorate levels 145 WHO (World Health Organization) 15 wildlife exposure 7, Wingfield statement 2, Wolffian duct 27, 33 World Health Organization (WHO) 15 World Wildlife Fund X-ray crystallography 177, 178 xanthohumol (XN) 83, 84, 85 xenobiotic metabolism pathway 94 xenoestrogens 148 Xenopus embryonic thyroiddisruption assay (XETA) 143, 144 Xenopus laevis (African clawed frog) 138 bisphenol A (BPA) 139, 140, 146 gene knock-down 141 glucuronidation 139 polychlorinated biphenyls (PCBs) 145 sulfation 139 tetrabromobisphenol A (TBBPA) 139, 146 THbZIP-GFP 144, 146, 147 thyroid hormone (TH) 143–4 xenosensors 118–19 XETA (Xenopus embryonic thyroiddisruption assay) 143, 144 View Online 236 -Zurich on 12 February 2012 Published on 28 October 2011 on http://pubs.rsc.org | doi:10.1039/9781849732970-00216 Yucheng disease 124 Yusho disease 124 zearalenone 200, 202, 205 zebrafish (Danio rerio) 138, 139 bisphenol A (BPA) 140, 142 endocrine disrupter chemicals (EDCs) 139–40 estrogen receptor (ER) 142 estrogen signalling 148–50 Subject Index gene knock-down 141 heavy metal pollution 150 luciferase 148–9 thyroid hormone (TR) receptors 142 vitellogenin 149 zinc-finger nuclease (ZFN) 141–2 zinc 208, 209 zinc-finger nuclease (ZFN) 141–2 zygote 55 ... of these chemicals is required This book ‘? ?Hormone- disruptive Chemical Contaminants in Food ’’ serves, in my view, as a base for communicating the importance of this message of EDCs in food and... they were initially utilized.14 Typical synthetic contaminants found in the food chain are industrial chemicals, like combustion by-products including PCBs and dioxins, the polybrominated flame-retardants... discovery regarding potential health hazards and legislative implementation Issues in Toxicology No 11 Hormone- Disruptive Chemical Contaminants in Food Edited by Ingemar Pongratz and Linda Vikstroăm