1 Director, Office of Health Assessment & TranslationNTP Workshop: Role of Environmental Chemicals in the Development of Diabetes and Obesity January 11-13, 2011 Kris Thayer, Ph.D. Director, Office of Health Assessment & Translation NIEHS/NTP

2 Overall Goals of WorkshopEvaluate the science associating exposure to certain chemicals or chemical classes with development of diabetes or obesity in humans Provide input to NTP and NIEHS for development of a research agenda Bring together diverse expertise including toxicologists, epidemiologists, bio-informaticists, and experts in the pathobiology of disease Arsenic Persistent organic pollutants (POPs) Bisphenol A (BPA) Pesticides Organotins Phthalates Maternal Smoking Nicotine

3 Plan to publish workshop reports in EHP

4 Charge to ParticipantsFor the individual chemicals or chemical classes Evaluate strength/weaknesses, consistency, and biological plausibility of findings reported in humans and experimental animals Identify the most useful and relevant endpoints in experimental animals, in vitro models, and screening systems Identify data gaps and areas for future evaluation/research Consider relevant biological targets and pathways for assays for inclusion in the Toxicology in the 21st Century high throughput screening initiative (“Tox21”)

5 Points of General Agreement: Maternal SmokingMaternal smoking during pregnancy is associated with lower birth weight and later excess weight gains in children Provides support for plausibility of “obesogen” hypothesis Animal studies with nicotine reproduce “to a large extent” metabolic changes seen in the children of mothers who smoke

6 Epidemiological data support an association between maternal smoking and increased risk of obesity in offspring + association + association + association + association + association overweight obese

7 Points of General Agreement: ArsenicEvidence linking high arsenic exposure (> 150 ppb) with diabetes in humans is “limited to sufficient” Animal data is “inconclusive” but findings from recent studies support biological plausibility Mechanistic studies suggest several pathways: oxidative stress, glucose uptake and transport, gluconeogenesis, adipocyte differentiation, and Ca2+ signalling

8 Epidemiological Studies of Arsenic and Diabetes in HAA RegionsDiabetes diagnosis based on death certificates

9 Points of General Agreement: Pesticides/POPsEvidence from epidemiology studies is “sufficient” for an association with diabetes for several organochlorines (trans-nonachlor, DDE, and dioxins/dioxin-like chemicals including PCBs) Data not sufficient to establish causality

10 cross-sectional prospective

11 POPs: Vietnam Veterans and Diabetes

12 DDE and Diabetes

13 Trans-nonachlor and Diabetes

14 Organotins/PhthalatesPhthalates and organotins were grouped together because Both interact with the protein transcription factor PPARγ, which is intimately involved in the regulation of adipocyte differentation, metabolic syndrome, and insulin sensitivity Both have a common use as plasticizers in polyvinylchloride (PVC) plastics There are co-exposures to these two chemical classes

15 Points of General Agreement: Organotins/PhthalatesHuman studies are “insufficient” (phthalates) or nonexistent (organotins) for evaluating an association with diabetes or obesity Animal phthalate data are difficult to interpret because of PPARα contribution; relatively few studies on organotins Recent mechanistic studies show potent effects of organotins on adipogenesis of adipose-derived stem cells and PPARγ activation Phthalates activate PPARγ at 1000x lower potency than tins Mechanistic basis for recommending combination studies from co-occurrence in plastics

16 Points of General Agreement: Bisphenol AAnimal and mechanistic data provide support for an effect of BPA on glucose homeostasis/pancreatic β cell function/adipogenesis Human data too sparse to draw meaningful conclusions Studies of body weight difficult to use as a basis for evaluating “obesity”

17 Body Weight Does May Not Capture Differences in Fat MassDXA/image analysis of fat content in 4-month old males; areas with more than 50% fat are shown in white (Ohlsson et al. 2000) *No difference in body weight (wild-type = 33.0  1.1g; αERKO = 31.6  0.9g)

18 Adipocyte differentiation d-cis,trans-AllethrinHigh Throughput Screening Data: Top 15 Targets For Biological Processes (DRAFT LIST) Islet cell function Insulin sensitivity Adipocyte differentiation Feeding behavior A. Holloway M. White B. Blumberg J. Schlezinger D. Clegg (mammalian) S. Srinivasan (C. elegans) Fentin Mancozeb Metiram-zinc Fludioxonil Tebupirimfos Maneb E. benzoate Milbemectin (Z,E)-Fenpyroximate Prallethrin d-cis,trans-Allethrin HPTE Cyazofamid Chlorpyrifos oxon Spiroxamine Cinmethylin Fipronil Flusilazole Tebufenpyrad Bisphenol A PFOS Niclosamide Imazalil Prochloraz Forchlorfenuron Cyprodinil Bromoxynil Clorophene Trichlorfon Fluazinam Chlorethoxyfos Cyclanilide Pyrimethanil Propargite Thidiazuron Naled Lactofen Isazofos Pyraclostrobin Fenarimol Chlorothalonil Abamectin Quinoxyfen Phenoxyethanol Fenthion Carbaryl Tetramethrin Diclofop-methyl 2-Phenylphenol Resmethrin Diuron

19 Conclusions General support for: Plausibility of “obesogen” hypothesisLinkage of type 2 diabetes to certain chemical exposures Common mechanistic basis for certain chemical classes Tox 21 approaches identified a number of chemicals of potential interest