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