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  2. 2. In addition to genetic mutations that can affect development, numerous environmental factors can disrupt development Abnormalities caused by exogenous agents are called ‘disruptions’ Agents responsible for these disruptions are called ‘teratogens’.
  3. 3.  Rachel Carlson-1962-DDT- Destroying birds egg  Lenz-1962- Thalidomide- a sedative drug used to manage pregnancy- limb and ear abnormalities in fetus  Rubella infection– 20,000 fetuses- blind deaf or mentally retarded.
  4. 4. Human development is usually divided into two periods: 1) embryonic, 2) fetal
  5. 5. A teratogen is an agent that can produce a permanent alteration of structure or function in an organism exposed during embyronic or fetal life.
  6. 6. Many agents can produce a teratogenic effect under some circumstances.
  7. 7.  Nature of the agent Dose Route Frequency of exposure Duration of exposure
  8. 8.  Gestational timing Concurrent exposures Concurrent illness Genetic susceptibility – Mother – Fetus
  9. 9. Cell growth or proliferation Cell death Cell migration Cell and tissue interactions Disruptions
  10. 10. Principal mechanisms – Gene mutation – Chromosomal abnormalies Before or after conception Males and females both affected
  11. 11. Birth Defects Caused By Teratogenic Exposures Are Preventable.
  12. 12. Endocrine Disruptors
  13. 13. Any chemical agent in the environment that can alter normal endocrine system actions leading to deleterious effects on an organism or its progeny. Disruptors may act directly or indirectly. Direct acting disruptors are usually hormone agonists or antagonists that interfere with hormone actions on target cells. Indirect acting disruptors alter hormone dynamics in circulation, change hormone metabolism, or interfere with hormone regulation.
  14. 14. 1874 DDT synthesized 1881 PCB synthesized 1930-77 Widespread PCB use in transformers & as cutting oils 1938 DES synthesized 1942-72 Widespread DDT application in malaria control & agriculture 1941-54 FDA & USDA: DES approved for use in humans & animals 1959 DES produces cancer in experimental animals 1962 Publication of Silent Spring by Rachel Carson 1972 EPA bans DDT, FDA warnings on DES in pregnant women 1977 EPA bans PCBs 1979-95 Meetings & publications on estrogens in the environment 1995 EPA endocrine disruptor workshop; NAS/NRC panel meets 1996 Our Stolen Future, Colborn, Dumanoski & Myers, published; FQPA passed & Safe Drinking Water Act amended 1998 International Conference on Endocrine Disruptors, Kyoto 1999 NRC report, Hormonally Active Agents in the Environment
  15. 15. Known Hormonal Classes • Proteins & peptides chemcases.com/olestra/ images/insulin.jpg • Lipids (steroids, eicosanoids) • Amino acid derived (thyronines, neurotransmitters) chem.pdx.edu/~wamserc/ ChemWorkshops/ gifs/W25_1.gif • Gases (NO, CO) website.lineone.net/~dave.cushman/ epinephrine.gif
  16. 16. Hormone Receptors are cellular proteins that bind with high affinity to hormones & are altered in shape & function by binding; they exist in limited numbers. Binding to hormone is noncovalent & reversible. Hormone binding will alter binding to other cellular proteins & may activate any receptor protein enzyme actions.
  17. 17. Membrane Receptors Imbedded in target cell membrane; integral proteins/ glycoproteins; penetrate through membrane For protein & charged hormones (peptides or neurotransmitters) 3 major groups: Serpentine = 7 transmembrane domains, Growth factor/cytokine = 1 transmembrane domain, Ion channels Nuclear Receptors Nuclear proteins that usually act in pairs & bind to specific Hormone Recognition Elements (HREs) = sequences on the DNA in the promoter regions of target genes For small, hydrophobic molecules (steroids, thyroid hormones)
  18. 18. Known Classes of Endocrine Disruptors Estrogens DES, o,p’-DDT, DEHP, bisphenol A Anti-estrogens hexachloro-4-biphenylol, luteolin Anti-androgens p,p’-DDE, vinclozolin Progestogens norethindrone, norgestrel Adrenal toxins o,p’-DDD, glycyrrhizic acid Thyrotoxic agents PCBs, goitrin Aryl hydrocarbons [often anti-estrogens] TCDD, PAH Pancreatic toxins azoxyglycosides, streptozotocin Metals cadmium, nickel, aluminum Retinoids vitamin A analogs
  19. 19. Endocrine Disruptors Include Pesticides (herbicides, insecticides, …) Plasticizers Natural plant metabolites Pharmaceuticals (contraceptives, drugs,…) Detergents Chemicals from cooking & burning Antibiotics Metals
  20. 20. Results of Disruptions Inability to maintain homeostasis Altered growth & development Altered responses to external stimuli Altered behavior Suppressed gametogenesis Elevated gestational losses Induced neoplasiEmbryonic malformation a or carcinogenesis
  21. 21. Hormones & receptors co-evolve. It is common to have several hormone receptors demonstrate varying affinity for the same hormone. It is also common for one hormone to have some affinity for several different receptor types. Relative Affinities for Receptors of the Insulin Family to Family Members Receptor Relative Affinities Insulin Insulin >Proinsulin (10%) >IGF II >IGF I >>Relaxin(~0) IGF I IGF I > IGF II >Insulin ~ Proinsulin IGF II IGF II = IGF I >>Insulin ~ Proinsulin Relaxin Relaxin >NGF >Proinsulin > IGF >>Insulin (~0) NGF NGF (only) Promiscuity often occurs with opioids & steroids. Progestins can bind glucocorticoid receptors. Clomiphene binds estrogen receptors & demonstrates mixed anti-estrogenic & estrogenic actions. Cyproterone acetate is a progestin & anti-androgen. TCDD is an anti-estrogen & thyroid agonist.
  22. 22. Synthetic enzyme inhibitor Agonist or antagonist binding to receptor Alteration of normal dose-response relationships www.pharmacist.com/images /estrogen_molecule.gif 17β-Estradiol www.ac-nantes.fr/peda/ disc/scphy/dochtml/3ieme/ch ouroug/images/molecule.gif Diethylstilbesterol
  23. 23. Biologically available (free) hormone levels vary due to: Changes in synthesis Changes in secretion Changes in degradation Changes in binding proteins Age Gender Developmental stage Reproductive status Stage of temporal rhythm so…, alterations at any process or stage changes free hormone levels.
  24. 24. Hormone Transport or Secretion Kinetics Enterohepatic Metabolism Feedback loops, Neural controls users.rcn.com/jkimball.ma.ultranet/Biolog www.fst.rdg.ac.uk/courses/ yPages/H/hypothalamic_feedback.gif fs916/lect5/l5b.gif www.nurse-prescriber.co.uk/
  25. 25. Modified from D.J. Liska, The Detoxification Enzyme Systems, www.thorne.com/altmedrev/ fulltext/detox3-3.html.
  26. 26. Human Sperm Suppression From the Study of Scottish Male Reproductive Health www.link.med.ed.ac.uk/ HEW/repro/default.htm
  27. 27. Disruption of Sex Determination Stages sensitive to hormonally active agents
  28. 28. Diethylstilbestrol *SAX TOXICITY EVALUATION: THR: Poison by intraperitoneal and subcutaneous routes. Moderately toxic by ingestion and other routes. A human carcinogen and teratogen by many routes. It causes skin, liver and lung tumors in exposed humans as well as uterine and other reproductive system tumors in the female offspring of exposed women. An experimental carcinogen, neoplastigen, tumorigen and teratogen by various routes. A transplacental carcinogen. Glandular system effects by skin contact. Human reproductive effects by ingestion. Implicated in male impotence and enlargement of male breasts. Other experimental reproductive effects. Mutagenic data. Bis (2-ethylhexyl) phthalate New Jersey Department of Health and Senior Services Cancer Hazard * Bis (2-Ethylhexyl) Phthalate may be a CARCINOGEN in humans. It has been shown to cause liver cancer in animals… Reproductive Hazard * Bis (2-Ethylhexyl) Phthalate may be a TERATOGEN in humans since it has been shown to be a teratogen in animals. * Bis (2-Ethylhexyl) Phthalate may damage the testes...
  29. 29. Impacts on Cancer Rates www.link.med.ed.ac.uk/ HEW/repro/default.htm Breast Cancer Risks. Reference group (R) vs quartiles of dieldrin exposure (adapted from Høyer et al. 1998 in Our Stolen Future Website: www.ourstolen future.org/ Images/graphs/breast%20 cancer%20dieldrin%20risk.jpg). Vertical bars = 95% confidence interval. Dose response is significant (p = 0.01).
  30. 30. Endocrine disruptors or hormonally active agents have been with us for millennia as elements of plants and cooking. The new abundance of synthetic compounds has unleashed a wave of new challenges to our physiology, including the endocrine system. The impacts are as pleiotropic as endocrine actions are. Not surprisingly they involve altered reproductive success, growth, and cancer risks because of endocrine controls or inputs in these processes. Due care will help minimize impacts, but some increased risks are here permanently.