Dinner Presentation From Dr. Gore Nms 5 27 10

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  • Dinner Presentation From Dr. Gore Nms 5 27 10

    1. 1. Bisphenol A and other suspected estrogenic endocrine disruptors<br />1<br />Andrea C. Gore Ph.D., University of Texas at Austin<br />
    2. 2. 2<br />Environmental Endocrine-Disrupting Chemicals (EDCs)<br />Compounds in the environment that interfere with, block, or mimic effects of natural hormones.<br /><ul><li>Plastics (BPA), Plasticizers (phthalates)
    3. 3. Industry (PCBs, dioxins)
    4. 4. Pesticides, fungicides (DDT, methoxychlor, vinclozolin)
    5. 5. Pharmaceuticals (DES, EE)
    6. 6. Phytoestrogens (soy, alfalfa)
    7. 7. Heavy metals</li></li></ul><li>3<br />Estrogenic EDCs<br />BPA<br />PCBs<br />Pesticides (methoxychlor)<br />Phytoestrogens (?)<br />Heavy metals<br />
    8. 8. 4<br />Estrogenic EDCs<br />Mechanisms of action:<br />Nuclear hormone receptors – ERa, ERb<br />Membrane receptors – GPER (GPR30)<br />Steroidogenic enzymes (p450 aromatase)<br />Steroid metabolizing enzymes – steroid sulfatase<br />Neurotransmitter receptors<br />
    9. 9. EDCs –Brain & Behavior<br />5<br />Estrogenic EDCs<br />Peripheral hormones,<br />Reproductive function, Behaviors<br />“Fetal/developmental basis<br />of adult disease”<br />
    10. 10. 6<br />Bisphenol A (BPA) – background<br /><ul><li>Monomer used to manufacture polycarbonate plastics, food liners, dental sealants.
    11. 11. Used in high volume: >6 billion lbs annually.
    12. 12. Heat causes hydrolysis and leaching.</li></ul>H3C<br />C3H<br />HO<br />OH<br />Richter et al., Reprod. Toxicol. 24: 199-224 (2007)<br />
    13. 13. 7<br />Bisphenol A (BPA) – mechanisms of action<br /><ul><li>Estrogen receptor agonist/antagonist – up-regulation of Esr1, Esr2
    14. 14. Androgen receptor antagonist
    15. 15. Thyroid hormone receptor antagonist
    16. 16. AhR, RARa, RXRa are up-regulated by BPA
    17. 17. Enzyme activity
    18. 18. Epigenetic modifications (DNA methylation)</li></ul>ER agonist effects are best-studied.<br />
    19. 19. 8<br />Bisphenol A (BPA) – low doses<br /><ul><li>Generally used to refer to “environmentally” or “ecologically” relevant.
    20. 20. LOAEL EPA reference dose = 50 mg/kg/day
    21. 21. However: Is there really a LOAEL?</li></li></ul><li>9<br />Bisphenol A (BPA) – humans<br /><ul><li>Measurable in serum, urine, amiotic fluid, placenta, umbilical cord blood, and human blood.
    22. 22. Serum levels estimated from 0.2 to 20 ng/ml.
    23. 23. Amniotic fluid levels measured at 8.3 ng/ml.
    24. 24. Breast milk: mean 0.61 ng/ml.
    25. 25. Urine: Numerous studies show detectable BPA.
    26. 26. Assays include GC-MS, HPLC, ELISA, with sensitivity from 0.01 to 0.5 ng/ml.</li></ul>Vandenberg et al., Reprod. Toxicol. 24: 139-177 (2007)<br />
    27. 27. 10<br />Bisphenol A (BPA) – other important considerations<br /><ul><li>Gestational/early postnatal exposures and long delay until the manifestation of a dysfunction.
    28. 28. Multiple mechanisms make prediction of outcomes difficult.
    29. 29. Likelihood of mixtures of EDC exposures.
    30. 30. Individual differences in genes and factors regulating gene expression.</li></li></ul><li>11<br />Bisphenol A (BPA) – the brain<br /><ul><li>Increased aggressive behavior
    31. 31. Increased motor activity
    32. 32. Increased pain sensitivity
    33. 33. Impaired learning & memory
    34. 34. Decreased maternal behavior
    35. 35. Impairments in sexual behavior
    36. 36. Impaired neural plasticity – rodents & non-human primates
    37. 37. Hypothalamus and brain sexual differentiation are disrupted</li></li></ul><li>12<br />Bisphenol A (BPA) – other endocrine targets<br /><ul><li>Mammary gland
    38. 38. Prostate
    39. 39. Ovary (oocytes)/ Testes (sperm)
    40. 40. Uterus and vagina/ epididymis & seminal vesicles
    41. 41. Adipocytes
    42. 42. Thyroid
    43. 43. Anti-androgen</li></ul>Newbold, Reprod. Toxicol. 23: 290-296 (2007) <br />
    44. 44. 13<br />Polychlorinated Biphenyls (PCBs)<br /><ul><li>Estrogenic EDC
    45. 45. Persist & bioaccumulate
    46. 46. Adult exposure- contaminated food
    47. 47. Developmental exposure- placental and lactational transfer
    48. 48. Developmental PCB exposure- neurological/ reproductive deficits
    49. 49. Aroclor 1221: PCB used in our lab </li></li></ul><li>14<br />PCB effects on P1<br />Treatment<br /><ul><li> Vehicle (DMSO)
    50. 50. E2 (50 µg)
    51. 51. A1221 (1 mg/kg)</li></ul>Birth<br />E0<br />E16<br />E18<br />P0<br />♂<br />♂<br />♀<br />♀<br />P1<br />P60<br />Puberty<br />Exposure during the critical period of brain sexual differentiation<br />
    52. 52. 15<br />ERα Expression in the mPOA (P1)<br />Female<br />DMSO<br />A1221<br />Male<br />DMSO<br />A1221<br />Sarah Dickerson, PhD dissertation (unpub.)<br />
    53. 53. 16<br />Apoptosis in the mPOA (P1)<br />DAPI<br />TUNEL<br />DAPI + TUNEL<br /><ul><li>Apoptosis is lower in females than males.
    54. 54. PCBs cause increased apoptosis in females – making them more “male-like.”</li></ul>Sarah Dickerson, PhD dissertation (unpub.)<br />
    55. 55. 17<br />PCB effects in adulthood<br />Injections<br /><ul><li> Vehicle (DMSO)
    56. 56. E2 (50 µg)
    57. 57. A1221 (1 mg/kg)</li></ul>Birth<br />E0<br />E16<br />E18<br />P0<br />♂<br />♂<br />♀<br />♀<br />P1<br />P60<br />Puberty<br />Postnatal development, Reproductive cycles,<br />Hypothalamic protein/gene expression, Behavior<br />
    58. 58. Developmental effects<br />Eye opening: Advanced in females (PCB).<br />Pubertal timing: Advanced in females (EB, PCB), delayed in males (EB, PCB).<br />Estrous cyclicity: Prolonged cycles in EB (46%), PCB (33%).<br />18<br />
    59. 59. 19<br />Hypothalamic control of reproduction<br />EDCs<br />
    60. 60. ERα cells in AVPV (P60)<br />Female<br />Male<br />DMSO<br />A1221<br />DMSO<br />A1221<br /><ul><li>ERa is greater in the AVPV of females than males.
    61. 61. PCBs cause ERa to decrease in the AVPV of females – making them more “male-like.”</li></ul>20<br />Sarah Dickerson, PhD dissertation (unpub.)<br />
    62. 62. 21<br />Kisspeptin in AVPV (P60)<br />Female<br />Male<br />DMSO<br />A1221<br />DMSO<br />A1221<br /><ul><li>Kisspeptin is greater in the AVPV of females than males.
    63. 63. PCBs cause kisspeptin to decrease in the AVPV of females – making them more “male-like.”</li></ul>Sarah Dickerson, PhD dissertation (unpub.)<br />
    64. 64. 22<br />GnRH-Fos co-expression (P60) in females<br />The co-expression of Fos in GnRH neurons is significantly suppressed in PCB females.<br />2X<br />20X<br />40X<br />100X<br />Sarah Dickerson, PhD dissertation (unpub.)<br />
    65. 65. 23<br />Paced mating behavior in females<br /><ul><li>Reproductive success is the ultimate biological outcome.
    66. 66. Reproductive success is enhanced when the female controls the pace of the mating.
    67. 67. A paced mating paradigm enables dissection of female-typical behaviors.</li></ul>RM Steinberg et al. (2007) Horm Behav 51: 364-372.<br />
    68. 68. Summary<br />Exposure to estrogenic EDCs during fetal development has long-term consequences on the molecular and cellular processes controlling reproduction.<br />EDCs are associated with the masculinization of the hypothalamus of females.<br />Puberty and reproductive physiology are perturbed, and reproductive behaviors are compromised.<br />24<br />
    69. 69. Implications<br />I propose that fetal exposures to EDCs reprogram the hypothalamus, and that this programming permanently compromises reproductive success.<br />I also believe that these effects may be transmitted to future generations through molecular epigenetic changes.<br />25<br />
    70. 70. 26<br />Acknowledgments<br />Funding:<br />NIH RC1 ES018139<br />NIH R21 ES12272<br />PhRMA<br />UT-Austin Fellowships<br />Sarah Dickerson<br />Deena Walker<br />

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