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Environmental pollutants as endocrine disruptors

Date post:28-Nov-2014
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Endocrine system is disrupted by Environmental disruptors...how?
  • 1. Any unwanted and undesired substances which contaminate or deteriorate the quality of air, water and soil. These may directly interact with environment after their indirect production in various ways. These may be present in gaseous,liquid as well as solid state.
  • 2. The endocrine system is a complex network of glands and hormones that regulates many of the body's functions, including growth, development and maturation, as well as the way various organs operate. including the pituitary, thyroid, adrenal, thymus, pancreas, ovaries, and testes release carefully-measured amounts of hormones into the bloodstream that act as natural chemical messengers, traveling to different parts of the body in order to control and adjust many life functions.
  • 3. An endocrine-disrupting substance is a compound, 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. The number of substances believed to act as endocrine disruptors is wide and varied, including both natural and synthetic materials. Concern arises because potential endocrine disruptors may be present in the environment at very low levels but still may be able to cause effects.
  • 4. Endocrine disruptors are found also in synthetic chemicals used as industrial solvents, lubricants, and their byproducts. These include polychlorinated biphenyls (PCBs), polybrominated biphenyls (PBBs), and dixons. bisphenol A (BPA) from plastics dichlorodiphenyltrichloroethane (DDT) from pesticides vinclozolin from fungizides diethylstilbestrol (DES) from pharmaceutical agents. Certain metals such as cadmium, mercury, arsenic, lead, manganese, and zinc also disrupt endocrine systems.s
  • 5. They can mimic a natural hormone and lock onto a receptor with in the cell. The disruptor may give a signal stronger than the natural hormone, or a signal that occurs at the "wrong" time. They can bind to a receptor within a cell and thus prevent the correct hormone from binding. The normal signal then fails to occur and the body fails to respond properly. The disruptors can interfere or block the way natural hormones and receptors are made or controlled. This interference or blockage may occur only if relatively large doses of the substance are present.
  • 6. A direct evidence of human susceptibility was found. In the 1950s and 1960s pregnant women were prescribed diethylstilbestrol (DES), a synthetic estrogen, to prevent miscarriages Not only did DES fail to prevent miscarriages, but it also caused health problems for many of these women's children. In 1971, doctors began reporting high rates of unusual vaginal cancers in teenage girls. Investigations of the girls' environmental exposures traced the problem to their mothers' use of DES. The girls also suffered birth defects of the uterus and ovaries, and immune system suppression.
  • 7. During normal conditions, a carrier protein transports hormones to the cell wall; there, it binds to a receptor, and the hormone and receptor together bind to a specific region of a cell's DNA to activate particular genes.
  • 8. EDCs interfere with this normal hormonal activity in number of ways. They can amplify the effect of normal hormones by: 1. Mimicking a hormone by binding to its receptor. 2. By stimulating the production of more hormone receptors. They can weaker the normal hormone functions by binding to its receptor.
  • 9. They can prevent hormonal action simply by occupying the appropriate hormone's site on the receptor. They can bind to carrier proteins and reduce the availability of these proteins to transport hormones . They can alter the level of endogenous hormones by accelerating their breakdown and elimination.
  • 10. Several possible modes of actions have been cleared up in recent years, most important of them are mentioned here.
  • 11. An exogenous agonist is a ligand that can bind to a receptor like the natural substrate and turn it on. The potency of an exogenous agonist depends on: Its affinity to the receptor Its ability to turn the receptor on Concentration of the ligand
  • 12. Well-known examples are: Diethylstilbestrol (DES) Ethinylestradiol Xenoestrogens PCBs metabolites An antagonist is a ligand that blocks or diminishes responses provoked by hormones because the receptor cannot be activated as usual.
  • 13. The inhibition of the receptor can be: Competitive that can lead to total deactivation of the receptor. Noncompetitive that can result in reduced reactions performed by the receptor. Well known examples are: linuron vinclozolin pharmaceutical tamoxifen
  • 14. Change in conc. of hormones indirectly i.e. by inhibiting or influencing the specific enzymes. Examples: Biosynthesis of estrogens include the conversion of testosterone to an estrogen catalyzed by the enzyme aromatase. EDCs can inhibit this enzyme, leading to higher testosterone concentrations and to lower estrogen concentrations.
  • 15. Hormone metabolism can also be influenced by induction of hormone- metabolizing enzymes like the cytochrome P450-group in the liver. In receptor-mediated processes, both components, endogenous ligand and hormone receptor, own a key function.
  • 16. Example Down-regulation of steroid hormones TCDD is an exogenous agonist for the arylhydrocarbon (Ah)-receptor. Its activation can have different influences on the endocrine system by: (1) An increased degradation rate of estrogen receptors (2) Induction of estradiol metabolizing enzymes (3) Inhibition of gene expression controlled by estradiol or growth promoters.
  • 17. Importance of Thyroid Harmones Thyroid hormones are essential for: Normal brain development in fetus. For the control of metabolism, For normal adult physiology.
  • 18. Environmental pollutants Interfere with the normal functioning of thyroid hormone and produce hazaderous effects on: development metabolism adult physiology Disturbed Thyroid Harmone signalling pathways.
  • 19. Structural Similarity with THs: Several Thyroid Disruptors have high degree of structural resemblance to the thyroxine (T4) and triiodothyronine (T3) due to which they get attach to receptor sites instead of THs. Interference with regulation: Many industrial chemicals and pollutants can interfere with thyroid function by acting on different points of regulation of thyroid hormone synthesis, release, transport through the blood, metabolism of thyroid hormone.
  • 20. Perchlorate It block uptake of Iodide(form of iodine) in thyroid cells.As a result T3 and T4 synthesis decreased.Higher in smoker Women. PCBs These are lipophilic in nature and accumulate in fatty tissues.PCBs inhibit TSH receptors and decrease production of T3 and T4. It reduce T4 circulation in blood. Acetochlor(Herbicide) It enhance hepatic(liver) metabolism results in increase metabolism of T3 and T4 unneccesarily
  • 21. Pentachlorophenol T4 transport to target tissues via serum transport proteins e.g Transthyretin(TTR) but if pentachlorophenol competitively binds to serum transport proteins then T4 would not be transported to target tissue. Bisphenol A(BPA) At high temprature BPA leach out of plastics into food.
  • 22. In Human embryonic kidney cell and hepatoblastoma cells BPA inhibit T3 binding to TR . Isoflavones, especially those found in soy protein (e.g., genistein, coumesterol) cause goiter in Human infants.
  • 23. Neurodevelopmental toxicity Goiter and thyroid diseases are associated with TH disruption. Hypothyroidism It results in impaired intellectual development in childrens or permanent cognitive deficiencies.
  • 24. Perchlorate is a known competitive inhibitor of the sodium-iodide in humans and can inhibit iodide uptake, leading to the suppression of T3 and T4. Effects It has been related to lower levels of iodine in breast milk.As a result of iodine deficiency neurodevelopmental disorders occur in utero.
  • 25. In an environment with perchlorate exposure may have a significant effect on thyroid hormone production particularly in the environment of dietary iodine insufficiency
  • 26. The concept that PCBs can exert a neurotoxic effect on the developing brain by causing a state of relative hypothyroidism. Polychlorinated biphenyls belong to the class of organochlorine compounds classified as persistent organohalogenated pollutants (POPs) Disruption Mechanisms: (1)It reducing the ability of thyroid hormones to bind to transport proteins in the bloodstream
  • 27. (2)It enhance hepatic metabolism by up- regulating the sulfotransferases that break down thyroid hormones in the liver (3)It inhibit the production of deiodinases that allow T4 to be converted to T3 (4)it act as either an agonist or antagonist at the site of the cellular thyroid receptor.
  • 28. PCBs BPA(4,4 isopropylidenediphenol) PBDEs (polybrominated diphenylethers)
  • 29. The role of TSH in activating growth and differentiation of follicular cells have shown that a prolonged disruption of the pituitary-thyroid axis is linked to thyroid neoplasia. Two mechanisms involved in the disruption of the pituitary thyroid axis are chemically-induced blocking of thyroid peroxidase and inhibition of T4 deiodinases, which are known to occur with TD exposure
  • 30. Humans are exposed to thousands of chemicals used in several anthropogenic processes. Environmental factors that are under the focus of the scientific community include organic and chemical solvents, pesticides, heavy metals, polychlorinated biphenyls (PCBs) and other persistent organic pollutants (POPs). Among environmental pollutants, special concerns have been raised by endocrine disrupting chemicals (EDCs), which are hormonally active, synthetic or natural compounds that can interfere with the normal activity of endocrine system/tissue, most notably the reproductive endocrine axis. Human Reproductive Hormone Disruptors Introduction
  • 31. 1. Adverse reproductive effects have been observed in male populations, wildlife, and laboratory animals as a consequence of exposure to hormonally active chemicals. 2. Chemicals could play a role in a number of reproductive abnormalities in females. 3. Endocrine disrupting chemicals could be contributing to a population-wide decline in fertility. 4. Exposure to dioxins, toxic byproducts of incineration and industrial processes, may be associated with fewer male births. The hazardous effects
  • 32. 5. Prenatal exposure to some chemicals is associated with deficits in IQ and memory, neurobehavioral effects, and delayed neuromuscular development in children. Examples: A. Diethylstilbosterol (DES). B. Polychlorinated biphenyls (PCBs). C. Polybrominated biphenyls (PBB). D. Chloroform. E. Dioxins and furans. F. Pesticides
  • 33. Diethylstilbosterol (DES): Consider one of the most famous endocrine disruptors. A synthetic estrogen prescribed to pregnant women in the 1950s and 1960s to prevent miscarriage. Ultimately, more than 300 cases of CCA(clear cell endocarcinoma) have been documented in women exposed in utero to DES. Polychlorinated biphenyls (PCBs): Uses: paints. Lubricants Plastic water and baby bottles, food and beverage can linings and dental sealants ate the most commonly encountered uses of this chemical.
  • 34. 1. The children born to these prenatally exposed mothers have the following more than unexposed ones: 1. Sperm with abnormal morphology, reduced motility, and reduced strength. 2. Intrauterine growth retardation (IUGR). 3. Abnormal skin pigmentation. 4. Delayed, developmental milestones. 5. Lower (IQs). 2. Women who had eaten PCB-contaminated fish before and during pregnancy documented dose- related delays in development and reductions in intellect in their infants in the absence of any overt symptoms.
  • 35. PESTICIDES: Reproductive effects: Effects on the reproductive system or on the ability to produce healthy offspring. Teratogenic: Causes birth defects if used it during their pregnancy. The aberrant production of ovarian steroid hormones (progesterone, estradiol, and androgens) can disrupt normal folliculogenesis. It follows that environmental agents and pathogens that mimic the actions of ovarian steroids via the activation of steroid hormone receptors, could disrupt follicle development and/or ovulation. Anti-androgenic endocrine disruptors: Vinclozolin. DDE.
  • 36. Hazardous effects: Clear cell adenocarcinoma (CCA) of the vagina and cervix . Irregular uterine bleeding. Recurrent abortion. Intrauterine growth retardation. Abnormalities within the reproductive, cardiovascular, neuroendocrine, and immune systems. Effects on the ovary and female reproductive function:
  • 37. BREAST CANCER A review of known risk factors includes the possible influence of exogenous estrogens and several that are related to levels of the naturally synthesized estrogen estradiol. Early onset of menstruation, late menopause, never having given birth and never having breastfed contribute to the risk by elevating a woman's lifetime exposure to estradiol. Another risk factor, being older than 50, probably reflects older women's long-term exposure to this hormone. Additionally, the increased odds of the disease that have been found among women with diets high in animal fat and with high levels of alcohol consumption may be explained by the fact that fat tissue can manufacture estrogen, and alcohol can increase the hormone's production. These are not the only risk factors for the disease (high-dose exposure to X rays also plays an important role). Researchers hypothesize that if an excess of natural estrogen can be harmful, prolonged exposure to man- made estrogens might pose similar threats.
  • 38. Eat lower on the food chain. Eat deep-water fish (avoid sword fish, tuna and shark and all farm raised fish) In general, substitute natural products for synthetic products whenever possible. Eat fresh organic products as meat and milk free from rBGH (Recombinant Bovine Growth Hormone). Buy products at your local Farmers' Market or join a buying club. Use fewer processed, prepackaged foods whenever possible. Do not give young children soft plastic toys, since these leach potential endocrine disrupting chemicals. Measures to lower the exposure to endocrine disruptors
  • 39. Avoid smoke. Avoid use chemicals or any pesticides. Avoid use makeup, hair sprays & coloring products or nail polish. Avoid use strong chemicals, glues, paints, nail polish remover, floor & carpet cleaners. Avoid heat food or eat hot food in plastic containers, even the ones frozen dinners now come in. Avoid products with hydrogenated, partially hydrogenated fats. Avoid stay in places that smell of chemicals.

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