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Endocrine-Disrupters and Thyroid Disorders : The next challenge ?

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.

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Endocrine-Disrupters and Thyroid Disorders : The next challenge ?

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  1. 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

  2. Human at the Top of the Food Pyramid

  3. Endocr Rev 2009;30:293-342

  4. 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

  5. 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

  6. 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 EDCs Exert Actions Diamanti-Kandarakis E et al. Endocrine Reviews, 2009, 30:293–342

  7. EDCs Group Molecules Natural Chemicals Synthetic 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)

  8. 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

  9. 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

  10. 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

  11. Impacts of EDCs on Endocrine Functions

  12. Impacts of EDCs on Female Reproduction TCDD, tetrachlorodibenzo-p-doxin

  13. Impacts of EDCs on Male Reproduction • Semen quality (phatalates, PCB, dioxin, pesticides) • Urogenital maltransformation/testicular germ cell cancer (TGCC) • Prostate cancer

  14. Neuroendocrine Targets of EDC

  15. EDCs may mimic or block some of these hormonal effects in the brain, thereby disrupting neuroendocrine processes Central Neurotransmitters Brain Pitultary Hormones EDCs Hypothalamus Hypothalamic Neuroendocrine Cells Thyroid Cardiovascular system Manmary Glands (female) pancreas Adipose Tissue Ovaries (female) Uterus (female) Anterior Pituitary Cells Prostat (female) Posterior Pituitary Testes (female) To Target Systems Schematic depiction of how hypothalamic neuroendocrine systems are targets of environmental endocrine disruptors. Hormones Gore AC. Hormones (Athens) 2010; 9: 16 -27 Diamanti-Kandarakis et al. Endocrine Rev 2009;30:293-342

  16. 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 Health2010,7, 2988-3005

  17. Impacts of EDCs onReproductive Neuroendocrine Systems • GnRH neurons • Sexually dimorphic brain regions and behaviour • HPA • Thyroid metabolism and growth

  18. The central neuroendocrine systems of the body serve as an interface between the brain and the endocrine systems in the rest of the body

  19. Endocrine Disruption of Reproductive Neuroendocrine Systems • GnRH neurons (PCB; organochlorine pesticides,stimulate GnRH response) • Sexually dimorphic brain regions and behavior (PCB; phytoestrogens; fungicides; pesticides; other xenobiotics) • Hypothalamic-pituitary-adrenal (HPA) (PCBs, dioxin, lindane and others) • Thyroid, metabolism, and growth (PBD; organochlorine) • Hormonal targets of neuroendocrine disruption

  20. 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

  21. EDCs and Obesity, Diabetes and CVD

  22. 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

  23. 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

  24. 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 60 50 40 30 20 10 0 Control DES * * * * * * * * Body Weight (g) Total Feed Consumed (g) * * P < 0.05 P<0.05 P<0.05 P<0.05 * * * 0 1 2 3 4 5 Control DES Time (months) Feed Consumption of Adult Mice Following Neonatal DES Exposure Body Weights of Mice Following Neonatal DES Exposure Newbold RR et al. Reprod Toxicol 2007; 23: 290-296

  25. 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

  26. 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

  27. CONCLUSIONSHigher urinaryconcentrations of BPA were associatedwith an increased prevalence ofcardiovascular disease, diabetes, andliver-enzyme abnormalities Lang IA et al. JAMA. 2008;300:1303-1310

  28. Thyroid Disruption

  29. 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

  30. 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

  31. 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

  32. 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.

  33. 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

  34. Thyroid DisruptionLigand Binding Study Rat Liver Nuclear Extract Binding of BPA to nuclearThyroid 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

  35. 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

  36. Thyroid Disruptors: Effect at Various Stages of Thyroid Metabolism Lyn Patrick, Alternative Medicine Review 2009

  37. Mechanisms and Effects of Thyroid Disruptors Lyn Patrick, Alternative Medicine Review 2009

  38. 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

  39. Thank you for your attention

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