endocrine-disrupters and thyroid disorders : the next challenge ?
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Endocrine-Disrupters and Thyroid Disorders : The next challenge ?. Division of Diabetes and Endocrinology, Department of Medicine, Dr. Saiful Anwar Hospital, Medical Faculty, Brawijaya University, Malang. Djoko Wahono Soeatmadji. Human at the Top of the Food Pyramid. - PowerPoint PPT PresentationTRANSCRIPT
Endocrine-Disrupters and Thyroid Disorders : The next
challenge ?
Division of Diabetes and Endocrinology, Department of Medicine, Dr. Saiful Anwar Hospital,
Medical Faculty, Brawijaya University, Malang
Djoko Wahono Soeatmadji
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 respondto 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
Polychlorinated biphenyls (PCBs)
Polybrominated biphenyls (PBBs)
Plastics (BPA)
Plasticizers (phtalates)
Pestizides
Fungicides
Pharmaceutical agents (DES)
Natural Chemicals
Human / animal food
(phytoestrogens – ganistein, coumestrol)
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 hormones
Models of the Endocrine Systems Trageted by EDCs
Diamanti-Kandarakis E et 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 Clinical ImpactBPADES, DDE
DESTCDDBreast cancer
PCOSPremature ovarian failure Ovarian reserve Aneuploidy Granulosa steroidogenesisReproductive tract anomaliesEndometriosisBreast 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
Schematic depiction of how hypothalamic neuroendocrine systems are targets of
environmental endocrine disruptors.
EDCs may mimic or block some of these hormonal effects in the brain, thereby disrupting neuroendocrine processes
Gore AC. Hormones (Athens) 2010; 9: 16 -27Diamanti-Kandarakis et al. Endocrine Rev 2009;30:293-342
Brain
Hypothalamus
Pitultary
Thyroid
CardiovascularsystemManmary
Glands(female)
pancreas
Ovaries(female)
AdiposeTissue
Uterus(female)
Prostat(female)
Testes(female)
AnteriorPituitaryCells
PosteriorPituitary
To Target Systems
Hormones
HypothalamicNeuroendocrineCells
HormonesEDCs
CentralNeurotransmitters
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
Endocrine Disruptors and Obesity: An Examination of Selected Persistent Organic Pollutants in the NHANES 1999-2002 Data
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
• 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, 324–332Lovejoy JC & Sainsbury A. Obesity Review 2009;10: 154-167
Environmental Estrogen and Obesity
Wada et al. J Pharmacol Sci 2007; 105:133–137
Culture of 3T3-L1 Preadipocyte
Ganistein, Bisphenol A, nonylphenol
Accelerating maturation
Lipid accumulation
In vitro
Body Weights of Mice Following Neonatal DES ExposureFeed Consumption of Adult Mice Following Neonatal DES Exposure
Newbold RR et al. Reprod Toxicol 2007; 23: 290-296
P < 0.05P<0.05
Developmental ExposureCD-1 Mice-treated with DES
40.0
35.0
30.0
25.0
20.0
15.0
10.0
5.0
0.0
Control DES
P<0.05
Tota
l F
eed
Co
nsu
med
(g
)
P<0.05
0 1 2 3 4 5
60
50
40
30
20
10
0
Bo
dy
Wei
gh
t (g
)
ControlDES
Time (months)
*******
*
**
***
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 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*
Triglycerides (mg/ml) 116.9 + 1.7 106.8 + 1.5*
Incident Diabetes and pesticide Exposure among Licenced Pesticide Applicators: Agricultural Health Study, 1993 - 2003
Montgomery MP et al. Am J Epidemiol 2008; 167: 1235-1246
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.
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
Lang IA et al. JAMA. 2008;300:1303-1310
Results: Higher urinary concentrations of BPA were associated with an increased prevalence of cardiovascular disease, diabetes, and liver-enzyme abnormalities
CONCLUSIONSHigher urinary
concentrations of BPA were associatedwith an increased prevalence of
cardiovascular disease, diabetes, andliver-enzyme abnormalities
Lang IA et al. JAMA. 2008;300:1303-1310
Thyroid Disruption
HPT Axis - Thyroid Hormone Disrupters
• 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
A review of at least150 industrial chemicals summarizes the evidence in animal studies that
these chemicals can cause a reduction in thyroid-stimulating hormone (TSH) as well as thyroxine
Chemicals that affect thyroid metabolism, eitherthrough the hypothalamic-pituitary axis or directly
via nuclear receptors, are termed “thyroid disruptors” (TD)
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 chemically-induced 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
PCBsBPA
PBDA
Polychlorinated biphenyls (PCBs) Bisphenol A is a monomer of plastic material
Comparison of structures of BPA (A) and T3 (B)
Thyroid DisruptionLigand Binding Study
Binding of BPA to nuclear Thyroid Receptor (TR) in the presence or absence of BPA
Rat Liver Nuclear Extract
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 ofa 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