Download ENVIROMENTAL ENDOCRINOLOGY: The Endocrine

Endocrine-Disrupters and
Thyroid Disorders : The next
challenge ?
Djoko Wahono Soeatmadji
Division of Diabetes and Endocrinology,
Department of Medicine, Dr. Saiful Anwar Hospital,
Medical Faculty, Brawijaya University, Malang
Human at the Top of the Food Pyramid
Endocr Rev 2009;30:293-342
Endocrine-Disrupting Chemicals (EDCs):
“an exogenous agent that interferes with
synthesis, secretion, transport, metabolism,
binding action, or elimination of natural
blood-borne hormones that are present in
the body and are responsible for
homeostasis, reproduction, and
developmental process.”
U.S. Environmental Protection Agency (EPA). Diamanti-Kandarakis E et al.
Endocrine Reviews, June 2009, 30:293–342
EDCs - Physiological Perspective:
are compounds, either natural or
synthetic, which, through environmental or
inappropriate developmental exposures,
alters the hormonal and homeostatic
systems that enable the organism to
communicate with and respond
to its environment
Diamanti-Kandarakis E et al. Endocrine Reviews, June 2009, 30:293–342
EDCs Exert Actions
Nuclear Hormone
Receptors
•
•
•
•
•
Estrogen receptors
Androgen receptors
Progesterone receptors
Thyroid receptors
Retinoid receptors
Non-nuclear Steroid
Hormone Receptors
Non-steroid receptors
Orphan receptors
Enzymatic pathways
(steroid biosynthesis
and/or metabolism
Diamanti-Kandarakis E et al. Endocrine Reviews, 2009, 30:293–342
EDCs Group Molecules
Synthetic Chemicals
Natural Chemicals
Industrial Solvents/lubricatnts
Natural Chemicals
Polychlorinated biphenyls (PCBs)
Human / animal food
Polybrominated biphenyls (PBBs)
(phytoestrogens – ganistein,
coumestrol)
Plastics (BPA)
Plasticizers (phtalates)
Pestizides
Fungicides
Pharmaceutical agents (DES)
Models of the Endocrine Systems Trageted by EDCs
There is no endocrine system
that is immune to these
substances, because of the shared
properties of the chemicals and the
similarities of the receptors and
enzymes involved in the synthesis,
release, and degradation of
Diamanti-Kandarakis E et hormones
al. Endocrine Reviews, June 2009, 30:293–342
Clinical Aspects in Humans
- Each person has unique exposure
- Individual differences and variability
- Genetic polymorphysms
- Chronic exposure to a low amounts of
mixtures
- Latency
Diamanti-Kandarakis E et al. Endocrine Reviews, June 2009, 30:293–342
Important Issues
• Age at exposure
• Latency from exposure
• Importance of mixtures (additive or
synergistic ?)
• Nontraditional dose-response dynamiccs
• Transgenerational, epigenetic effects
Diamanti-Kandarakis E et al. Endocrine Reviews, June 2009, 30:293–342
Impacts of EDCs on Endocrine
Functions
Impacts of EDCs on Female
Reproduction
Substance
BPA
DES, DDE
DES
TCDD
Breast cancer
Clinical Impact
PCOS
Premature ovarian failure
 Ovarian reserve
Aneuploidy
Granulosa steroidogenesis
Reproductive tract anomalies
Endometriosis
Breast cancer
TCDD, tetrachlorodibenzo-p-doxin
Impacts of EDCs on Male Reproduction
• Semen quality (phatalates, PCB, dioxin, pesticides)
• Urogenital maltransformation/testicular germ cell cancer
(TGCC)
• Prostate cancer
Neuroendocrine Targets of EDC
EDCs may mimic or block some of these hormonal effects in the brain,
thereby disrupting neuroendocrine processes
Central
Neurotransmitters
Brain
Pitultary
Hormones
EDCs
Hypothalamus
Thyroid
Manmary
Glands
(female)
Hypothalamic
Neuroendocrine
Cells
Cardiovascular
system
pancreas
Adipose
Tissue
Ovaries
(female)
Uterus
(female)
Prostat
(female)
Testes
(female)
Schematic depiction of how hypothalamic
neuroendocrine systems are targets of
environmental endocrine disruptors.
Anterior
Pituitary
Cells
Posterior
Pituitary
To Target Systems
Hormones
Diamanti-Kandarakis et al. Endocrine Rev 2009;30:293-342
Gore AC. Hormones (Athens) 2010; 9: 16 -27
Endocrine Disruptors and Obesity: An Examination
of Selected Persistent Organic Pollutants in the
NHANES 1999-2002 Data
BMI and WC are associated with persistant organic
pollutants (POPs, oxychlordane and DDT) levels, making
the chemicals plausible contributors to the obesity epidemic
Int. J. Environ. Res. Public Health 2010, 7, 2988-3005
Impacts of EDCs on Reproductive
Neuroendocrine Systems
• GnRH neurons
• Sexually dimorphic brain regions and
behaviour
• HPA
• Thyroid metabolism and growth
The central neuroendocrine
systems of the body serve as an
interface between the brain and
the endocrine systems in the rest
of the body
Endocrine Disruption of Reproductive
Neuroendocrine Systems
1. GnRH neurons (PCB; organochlorine
pesticides,stimulate GnRH response)
2. Sexually dimorphic brain regions and behavior
(PCB; phytoestrogens; fungicides; pesticides;
other xenobiotics)
3. Hypothalamic-pituitary-adrenal (HPA) (PCBs,
dioxin, lindane and others)
4. Thyroid, metabolism, and growth (PBD;
organochlorine)
5. Hormonal targets of neuroendocrine disruption
Important Area of Research
• The HPA axis is sensitive to HPG
hormones
• EDCs may act directlyupon the
glucocorticoid or mineralocorticoid
receptors or on steroidogenic pathways
• EDCs including PCBs, dioxin, lindane, and
others can affect synthesis of adrenal
steroids
EDCs and Obesity, Diabetes
and CVD
List of Chemicals as Possible
Obesogen
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Diethylstillbestrol (DES)
Bispgenol A (BPA)
Phthalates
Organotins
Polybrominated diphenyl ethers (PBR)
Polyfluoroalkyl chemicals
Organochlorine (OC)
Pesticides
Polychlorinated biphenyls (PCB)
Hatch EE et al. International Journal of Andrology 2010: 33, 324–332
Lovejoy JC & Sainsbury A. Obesity Review 2009;10: 154-167
Environmental Estrogen and
Obesity
In vitro
Ganistein, Bisphenol A,
nonylphenol
Accelerating maturation
Lipid accumulation
Culture of 3T3-L1
Preadipocyte
Wada et al. J Pharmacol Sci 2007; 105:133–137
Developmental Exposure
CD-1 Mice-treated with DES
40.0
60
Control
DES
50
* *
30.0
Body Weight (g)
Total Feed Consumed (g)
35.0
25.0
20.0
15.0
10.0
40
30
20
*
10
*
5.0
0
0.0
Control
P
< 0.05
P<0.05
**
0
DES
Feed Consumption of Adult Mice Following
Neonatal DES Exposure
* * *
*
*
P<0.05
P<0.05
* *
1
2
3
Time (months)
4
5
Body Weights of Mice Following Neonatal DES Exposure
Treatmenta
2 months
Control
DES
Leptin (ng/mL)
4.8 + 0.5
25.0 + 1.4*
Adiponectin (g/ml)
6.6 + 0.6
38.1 + 3.6*
IL-6 (pg/mL)
6.3 + 0.9
60.4 + 5.0*
Insulin (U/ml)
7.4 + 0.7
1.3 + 0.3*
Triglycerides (mg/ml)
97.6 + 3.2
122.9 + 3.5*
6 months
Newbold RR et al. Reprod Toxicol 2007; 23: 290-296
Control
DES
Leptin (ng/mL0
8.1 + 0.4
60.7 + 2.3*
Adiponectin (g/ml)
9.3 + 0.6
39.2 + 1.6*
IL-6 (pg/mL)
10.1 + 0.4
93.8 + 0.3*
Insulin (U/ml)
8.6 + 0.3
10.8 + 0.3*
116.9 + 1.7
106.8 + 1.5*
Triglycerides (mg/ml)
Incident Diabetes and pesticide Exposure
among Licenced Pesticide Applicators:
Agricultural Health Study, 1993 - 2003
Applicators who had used the organochlorine
insecticides (lipid soluble and accumulate in tissue)
aldrin, chlordane, and heptachlor more than 100
lifetime days had 51%, 63%, and 94% increased
odds of diabetes
Long-term exposure from handling certain
pesticides, in particular, organochlorine and
organophosphate insecticides, may be associated
with increased risk of diabetes.
Montgomery MP et al. Am J Epidemiol 2008; 167: 1235-1246
Association of Urinary Bisphenol A
Concentration With Medical Disorders
and Laboratory Abnormalities in Adults
Context: Bisphenol A (BPA) is widely used in epoxy
resins lining food and beverage containers. Evidence of
effects in animals has generated concern over low-level
chronic exposures in humans
Results: Higher urinary concentrations of BPA were
associated with an increased prevalence of
cardiovascular disease, diabetes, and liver-enzyme
abnormalities
Lang IA et al. JAMA. 2008;300:1303-1310
CONCLUSIONS
Higher urinary
concentrations of BPA were associated
with an increased prevalence of
cardiovascular disease, diabetes, and
liver-enzyme abnormalities
Lang IA et al. JAMA. 2008;300:1303-1310
Thyroid Disruption
HPT Axis - Thyroid Hormone Disrupters
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Polychlorinated Bisphenyls (PCBs)
Polybrominated Diphenyl Ethers (PBDEs)
Perchlorate
Bisphenol-A
Pesticides (?)
Diamanti-Kandarakis E et al. Endocrine Rev 2009; 30: 293 – 342
Zoehler TR. , 2009
Chemicals that affect thyroid metabolism, either
through the hypothalamic-pituitary axis or directly
via nuclear receptors, are termed “thyroid
disruptors” (TD)
A review of at least150 industrial chemicals
summarizes the evidence in animal studies that
these chemicals can cause a reduction in thyroidstimulating hormone (TSH) as well as thyroxine
Possible linking of PCBs and specific organochlorines with enlarged thyroid
glands of fish in the Great Lakes
Leatherland JF, 1999
In men and women from a PCB-polluted area in Slovakia, those with highest
blood PCB levels compared with the lowest blood PCB levels (5th quintile
compared to the 1st quintile) had significantly higher TPOAb. Twenty-eight
percent of male workers in the highest quintile of blood PCB levels had
TPOAb as opposed to only 20 percent of those in the lowest quintile.
Langer P, 1998
PCB, dioxin, and heavy metal exposures have been associated with
increased levels of both TPOAb and TgAb
Osius N et al, 1998
• Animal studies assessing the role of TSH in
activating growth and differentiation of follicular
cells have shown that a prolonged disruption of
the HPT-axis is linked to thyroid neoplasia
• Two mechanisms involved are chemicallyinduced blocking of thyroid peroxidase and
inhibition of T4 deiodinases, which are known to
occur with thyroid disrupters (TD) exposure
Santini F et al. J Endocrinol Invest 2003:26:950-955.
Environmental chemicals impacting
thyroid hormone transport,
metabolism, and clearance
PCBs
BPA
PBDA
Comparison of structures of BPA (A) and T3 (B)
Polychlorinated biphenyls (PCBs)
Bisphenol A is a monomer of plastic material
Thyroid Disruption
Ligand Binding Study
Rat Liver Nuclear Extract
Binding of BPA to nuclear Thyroid Receptor (TR) in the presence or absence of BPA
BPA is a weak ligand for TR
Moriyama K et al. J Clin Endocrinol Metab 2002; 87: 5185 - 5190
The inhibitory effects of BPA on the gene
transcription mediated by the TR-LBD
BPA suppresses TR-mediated transcription in the presence of
a physiological range of T3
Moriyama K et al. J Clin Endocrinol Metab 2002; 87: 5185 - 5190
Thyroid Disruptors: Effect at Various
Stages of Thyroid Metabolism
Lyn Patrick, Alternative Medicine Review 2009
Mechanisms and Effects of Thyroid Disruptors
Lyn Patrick, Alternative Medicine Review 2009
Conclusions
• The possible role of EDCs in the etiology of
complex disease
• The potential role of EDCs directly or indirectly in
the pathogenesis of ATD and thyroid cancer
• The scientific community should not ignore the
wide spectrum of industrial chemicals to which
an average consumer might be exposed
• Further research is required