An Introduction to the Endocrine System through a Study of Endocrine Disruptors

1. An Introduction to the Endocrine System through a Study of Endocrine Disruptors

2. Nervous and Endocrine Systems • Act together to coordinate functions of all body systems • Nervous system • Nerve impulses/ Neurotransmitters • Faster responses, briefer effects, acts on specific target • Endocrine system • Hormone – mediator molecule released in one part of the body but regulates activity of cells in other parts • Slower responses, effects last longer, broader influence

3. Endocrine Glands • 2 kinds of glands • Exocrine – ducted • Endocrine – ductless • Secrete products into interstitial fluid, diffuse into blood • Endocrine glands include • Pituitary, thyroid, parathyroid, adrenal and pineal glands • Hypothalamus, thymus, pancreas, ovaries, testes, kidneys, stomach, liver, small intestine, skin, heart, adipose tissue, and placenta not exclusively endocrine glands

5. Hormone Activity • Hormones affect only specific target tissues with specific receptors • Receptors constantly synthesized and broken down

6. Chemical classes of hormones • Lipid-soluble – use transport proteins • Steroid • Thyroid • Nitric oxide (NO) • Water-soluble – circulate in “free” form • Amine • Peptide/ protein • Eicosanoid

7. Mechanisms of Hormone Action • Response depends on both hormone and target cell • Lipid-soluble hormones bind to receptors inside target cells • Water-soluble hormones bind to receptors on the plasma membrane • Activates second messenger system • Amplification of original small signal • Responsiveness of target cell depends on • Hormone’s concentration • Abundance of target cell receptors • Influence exerted by other hormones • Permissive, synergistic and antagonistic effects

8. Control of Hormone Secretion • Regulated by • Signals from nervous system • Chemical changes in the blood • Other hormones • Most hormonal regulation by negative feedback • Few examples of positive feedback

9. What are endocrine-disrupting substances (EDCs)? • Exposure to EDCs can be environmental or developmental. • Natural or synthetic compounds that alter the hormonal and homeostatic systems that enable an organism to communicate with and respond to its environment.

10. Key issues to understanding the consequences of exposure • Dose/response • Long-term latent effects • Age at exposure • Latency from exposure • Mixture of chemicals

11. All endocrine systems are susceptible The endocrine disruptors have shared properties. There are similarities in the receptors and enzymes involved in the synthesis, release, and degradation of hormones.

12. Effects may be inherited Can be transmitted to future generations through epigenetic modifications or continued exposure of offspring to the compounds.

13. What does the evidence show? There is strong evidence of adverse reproductive outcomes: Infertility Cancers Malformations

14. What does the evidence show? There is growing evidence for effects on other endocrine systems: Thyroid Neuroendocrine Obesity and metabolism Insulin and glucose homeostasis

15. Where are EDCs? Environment Food Consumer products

16. What do EDCs do? EDCs interfere with hormone biosynthesis, metabolism, or action. Such interference results in a deviation from normal homeostatic control or reproduction.

17. The Scientific Statement of the Endocrine Society (2009) Presents evidence that EDCs have effects on male and female reproduction, breast development and cancer, prostate cancer, neuroendocrinology, thyroid, metabolism and obesity, and cardiovascular endocrinology

18. EDCs represent a public health concern Based on results from animal models human clinical observations epidemiological studies

19. Mechanisms of EDC action are diverse Some pathways include: Estrogenic Antiandrogenic Thyroid Neurotransmitter receptors and systems

20. EDCs represent a broad class of molecules Organochlorinated pesticides and industrial chemicals Plastics and plasticizers Fuels Others present in the environment or in widespread use

21. Endocrine Disruptors industrial solvents/lubricants: Polychlorinated biphenols (PCBs) Polybrominatedbiphenols (PBBs) Dioxins Plastics: bisphenol A (BPA) Plasticizers: phthalates Pesticides: methoxychlor, chloropyrifos, DDT Fungicides: vinclozolin Pharmaceuticals: DES

22. Endocrine Disruptors Natural chemicals in food and feed: Phytoestrogens – genistein and coumestrol - widely consumed and in infant formula (soy- based)

23. PCBs and Dioxin

24. Dioxin and PCBs

25. Bisphenol A (BPA)

26. National Toxicology Program review (2009)

27. Chloropyrifos and methoxychlor

28. Phytoestrogens

29. DES – synthetic estrogen (teratogen) human use and animal feed additive (increase size)

30. Steroids

31. What do you notice about the structure of EDCs as compared to steroids?

32. What do you notice about the structure of EDCs as compared to steroids? • It is the phenolic structure:

33. Mode of action? • They are thought to mimic natural steroid hormone and enable EDCs to interact with steroid hormone receptors as analogs or antagonists. • Several classes of EDCs act as antiandrogens and as thyroid hormone receptor agonists or antagonists. • Androgenic EDCs have been identified.

34. How can we be exposed? • EDCs enter the food chain and can bioaccumulate (due to low water solubility and high lipid solubility. • Contaminated drinking water • Breathing contaminated air and contacting contaminated soil • Occupational exposure to pesticides and industrial chemicals

35. Clinical Challenges to Diagnosis • Challenges to discerning EDC involvement in a particular disorder • Each person’s unique exposure to a variety of known and unknown EDCs • Individual differences in metabolism, body composition, and genetic traits • Human disorders usually result from long term chronic exposure to low levels of mixtures of EDCs • Latency between exposure to EDCs and occurrence of clinical disorder makes causal connection difficult (may be years or decades)

36. Mechanisms of Endocrine Disruption • EDCs act by more than one mechanism. • An EDC may have mixed steroidal properties: it may be both estrogenic and antiandrogenic. • An EDC may be metabolized into different subproducts with different properties. • Balance between estrogenic and androgenic properties of EDCs may be significant because reproduction in both sexes involves an interplay of androgens and estrogens.

37. Mechanisms of Endocrine Disruption • Many organs are targeted by sex steroids and vulnerable to endocrine disruption. • Hypothalamic-pituitary-gonadal system • Breast • Uterus • Cervix • Vagina • Brain • Bone, muscle and skin In addition, reproductive dysfunction can result from thyroid disruption

38. Clinical Impacts on Female reproduction • Interference with development and function of the female reproductive tract can predispose women to: • Infertility • Ectopic gestation • Poor pregnancy outcomes • Endometriosis • Uterine fibroids • Altered anatomy and functionality

39. EDCs linked to cancer? • Hypothesized that the significant increase of breast cancer in the industrialized world in the last 50 years may be due to exposure to hormonally active chemicals. • Similar increase in incidence of testicular cancer, male genital tract abnormalities, and decrease in sperm quantity/quality suggest a link to the introduction of these chemicals into the environment.

40. Neuroendocrine System • Interface between Nervous and Endocrine systems • Controls diverse functions, such as reproduction, stress, growth, lactation, metabolism and energy balance, osmoregulation, other homeostatic regulators • Mediates ability of organism to respond to environment through rapid (neuronal) and more sustained (endocrine) responses

41. Neuroendocrine System • Neuroendocrine cells in brain have both neuronal and endocrine properties • As a result, EDCs can have neurobiological and neurotoxic effects along with endocrine effects • Several levels of organization: the brain (hypothalamus), the pituitary gland, and a target organ • The reproductive Hypothalamus-Pituitary-Gonad (HPG) connection is the best studied in the area of endocrine disruption

42. Endocrine disruption of reproductive neuroendocrine systems • Gonadotropin-releasing hormone (GnRH) (also called Luteinizing hormone) is produced in the hypothalamus and drives reproduction throughout the life cycle. It is the primary stimulus to the pituitary and the gonads.

43. What GnRH does in the Body • GnRH release stimulates gonadotropin release from anterior pituitary • Gonadotropin release activates steroidogenesis and gametogenesis in the ovary and testes • Steroid hormones produced by the gonad act on target tissues that release estrogen, progestin and/or androgen receptors (AR) • Many EDCs interfere with steroid hormone actions

44. Sex steroids control GnRH neurons • But GnRH neurons do not have steroid receptors • This means that other cells in the brain that do have steroid receptors and that regulate GnRH cells through afferent neural inputs are targets for EDCs • Neuronal cells with steroid receptors include those that make neurotransmitters (such as serotonin and dopamine) and can regulate GnRH neurons • EDCs have been shown to cause neurotoxicity to these neurons • This is evidence of convergence of effects of EDCs on the link between neural and endocrine systems