NTP 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
Overall Goals of Workshop
 Evaluate the science associating exposure to certain chemicals or
chemical classes with development of diabetes or obesity in
humans
Arsenic
Persistent organic pollutants (POPs)
Bisphenol A (BPA)
Pesticides
Organotins
Phthalates
Maternal Smoking
Nicotine
 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
http://ntp.niehs.nih.gov/go/36433
• Plan to publish workshop reports in EHP
Charge to Participants

For 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”)
Points of General Agreement: Maternal Smoking

Maternal 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
Epidemiological data support an association between
maternal smoking and increased risk of obesity in offspring
+ association
+ association
+ association
+ association
+ association
overweight
obese
Points of General Agreement: Arsenic

Evidence 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
Epidemiological Studies of Arsenic and Diabetes in HAA Regions
Diabetes diagnosis based on death certificates
Points of General Agreement: Pesticides/POPs


Evidence from epidemiology studies is “sufficient” for an
association with diabetes for several organochlorines (transnonachlor, DDE, and dioxins/dioxin-like chemicals including
PCBs)
Data not sufficient to establish causality
cross-sectional
prospective
POPs: Vietnam Veterans and Diabetes
DDE and Diabetes
Trans-nonachlor and Diabetes
Organotins/Phthalates
Phthalates 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
Points of General Agreement: Organotins/Phthalates





Human 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
Points of General Agreement: Bisphenol A



Animal 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”
Body Weight Does May Not Capture Differences in Fat Mass
DXA/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)
High Throughput Screening Data: Top 15 Targets For
Biological Processes (DRAFT LIST)
Islet cell function
Insulin
sensitivity
Adipocyte differentiation
Feeding behavior
A. Holloway
M. White
M. White
B. Blumberg
J. Schlezinger
D. Clegg
(mammalian)
S. Srinivasan
(C. elegans)
Fentin
Milbemectin
HPTE
Mancozeb
(Z,E)-Fenpyroximate
Metiram-zinc
Metiram-zinc
Mancozeb
d-cis,trans-Allethrin
Fludioxonil
Prallethrin
d-cis,trans-Allethrin
Tebupirimfos
d-cis,trans-Allethrin
Cyazofamid
Maneb
Mancozeb
E. benzoate
E. benzoate
Metiram-zinc
Fentin
Chlorpyrifos oxon
Cinmethylin
Maneb
Fipronil
Spiroxamine
Prallethrin
Cyazofamid
Flusilazole
Prallethrin
Tebufenpyrad
Metiram-zinc
Bisphenol A
Milbemectin
PFOS
E. benzoate
Prochloraz
Flusilazole
Spiroxamine
Imazalil
Cyprodinil
Niclosamide
PFOS
Tebufenpyrad
Imazalil
Tebupirimfos
Bromoxynil
Flusilazole
Niclosamide
(Z,E)-Fenpyroximate
Milbemectin
Cyazofamid
Fentin
Mancozeb
Forchlorfenuron
Clorophene
Imazalil
d-cis,trans-Allethrin
Bromoxynil
Forchlorfenuron
Trichlorfon
Fluazinam
HPTE
Chlorethoxyfos
Bisphenol A
Naled
Lactofen
Abamectin
Clorophene
PFOS
Fludioxonil
Forchlorfenuron
Pyraclostrobin
Trichlorfon
Tetramethrin
Cyclanilide
Fentin
Lactofen
Flusilazole
Quinoxyfen
Diclofop-methyl
Fentin
Spiroxamine
Thidiazuron
Fluazinam
Phenoxyethanol
2-Phenylphenol
Pyrimethanil
Propargite
Isazofos
Fenarimol
Forchlorfenuron
Fenthion
HPTE
Niclosamide
PFOS
Chlorothalonil
Fenthion
Resmethrin
Flusilazole
Thidiazuron
Maneb
Fludioxonil
Carbaryl
Diuron
Conclusions

General support for:
–
–
–
–
Plausibility of “obesogen” hypothesis
Linkage 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