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

Industrial Solvents/lubricatnts

Polychlorinated biphenyls (PCBs) Polybrominated biphenyls (PBBs) Plastics (BPA) Plasticizers (phtalates) Pestizides Fungicides Pharmaceutical agents (DES) Natural Chemicals

Natural Chemicals

Human / animal food (phytoestrogens – ganistein, coumestrol)

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 hormones 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 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 Brain Central Neurotransmitters Pitultary Hypothalamus Hormones EDCs Thyroid Hypothalamic Neuroendocrine Cells Manmary Glands (female) 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.

Diamanti-Kandarakis et al. Endocrine Rev 2009;30:293-342

Anterior Pituitary Cells Posterior Pituitary To Target Systems Hormones

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

• 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

Ganistein, Bisphenol A, nonylphenol

In vitro

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

35.0

30.0

25.0

20.0

15.0

10.0

5.0

0.0

Control DES Feed Consumption of Adult Mice Following Neonatal DES Exposure 60 50 40 30 Control DES * * * * * * * * 20 10 * * * * * 0 0 1 2 3 Time (months) 4 5 Body Weights of Mice Following Neonatal DES Exposure

Newbold RR et al. Reprod Toxicol 2007; 23: 290-296

2 months Leptin (ng/mL) Adiponectin (



g/ml) IL-6 (pg/mL) Insulin (



U/ml) Triglycerides (mg/ml) 6 months Leptin (ng/mL0 Adiponectin (



g/ml) IL-6 (pg/mL) Insulin (



U/ml) Triglycerides (mg/ml) Control 4.8 + 0.5

6.6 + 0.6

6.3 + 0.9

7.4 + 0.7

97.6 + 3.2

Control 8.1 + 0.4

9.3 + 0.6

10.1 + 0.4

8.6 + 0.3

116.9 + 1.7

Treatment

a

DES 25.0 + 1.4* 38.1 + 3.6* 60.4 + 5.0* 1.3 + 0.3* 122.9 + 3.5* DES 60.7 + 2.3* 39.2 + 1.6* 93.8 + 0.3* 10.8 + 0.3* 106.8 + 1.5*

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

• 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

thyroid stimulating 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 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

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