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NMS Labs Dinner Presentation by Dr. Andrea Gore 5-27-10

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Bisphenol A and other suspected estrogenic endocrine disruptors …

Bisphenol A and other suspected estrogenic endocrine disruptors

Andrea C. Gore Ph.D., University of Texas at Austin

Published in: Health & Medicine, Technology

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    • 1. Bisphenol A and other suspected estrogenic endocrine disruptors
      1
      Andrea C. Gore Ph.D., University of Texas at Austin
    • 2. 2
      Environmental Endocrine-Disrupting Chemicals (EDCs)
      Compounds in the environment that interfere with, block, or mimic effects of natural hormones.
      • Plastics (BPA), Plasticizers (phthalates)
      • 3. Industry (PCBs, dioxins)
      • 4. Pesticides, fungicides (DDT, methoxychlor, vinclozolin)
      • 5. Pharmaceuticals (DES, EE)
      • 6. Phytoestrogens (soy, alfalfa)
      • 7. Heavy metals
    • 3
      Estrogenic EDCs
      BPA
      PCBs
      Pesticides (methoxychlor)
      Phytoestrogens (?)
      Heavy metals
    • 8. 4
      Estrogenic EDCs
      Mechanisms of action:
      Nuclear hormone receptors – ERa, ERb
      Membrane receptors – GPER (GPR30)
      Steroidogenic enzymes (p450 aromatase)
      Steroid metabolizing enzymes – steroid sulfatase
      Neurotransmitter receptors
    • 9. EDCs –Brain & Behavior
      5
      Estrogenic EDCs
      Peripheral hormones,
      Reproductive function, Behaviors
      “Fetal/developmental basis
      of adult disease”
    • 10. 6
      Bisphenol A (BPA) – background
      • Monomer used to manufacture polycarbonate plastics, food liners, dental sealants.
      • 11. Used in high volume: >6 billion lbs annually.
      • 12. Heat causes hydrolysis and leaching.
      H3C
      C3H
      HO
      OH
      Richter et al., Reprod. Toxicol. 24: 199-224 (2007)
    • 13. 7
      Bisphenol A (BPA) – mechanisms of action
      • Estrogen receptor agonist/antagonist – up-regulation of Esr1, Esr2
      • 14. Androgen receptor antagonist
      • 15. Thyroid hormone receptor antagonist
      • 16. AhR, RARa, RXRa are up-regulated by BPA
      • 17. Enzyme activity
      • 18. Epigenetic modifications (DNA methylation)
      ER agonist effects are best-studied.
    • 19. 8
      Bisphenol A (BPA) – low doses
      • Generally used to refer to “environmentally” or “ecologically” relevant.
      • 20. LOAEL EPA reference dose = 50 mg/kg/day
      • 21. However: Is there really a LOAEL?
    • 9
      Bisphenol A (BPA) – humans
      • Measurable in serum, urine, amiotic fluid, placenta, umbilical cord blood, and human blood.
      • 22. Serum levels estimated from 0.2 to 20 ng/ml.
      • 23. Amniotic fluid levels measured at 8.3 ng/ml.
      • 24. Breast milk: mean 0.61 ng/ml.
      • 25. Urine: Numerous studies show detectable BPA.
      • 26. Assays include GC-MS, HPLC, ELISA, with sensitivity from 0.01 to 0.5 ng/ml.
      Vandenberg et al., Reprod. Toxicol. 24: 139-177 (2007)
    • 27. 10
      Bisphenol A (BPA) – other important considerations
      • Gestational/early postnatal exposures and long delay until the manifestation of a dysfunction.
      • 28. Multiple mechanisms make prediction of outcomes difficult.
      • 29. Likelihood of mixtures of EDC exposures.
      • 30. Individual differences in genes and factors regulating gene expression.
    • 11
      Bisphenol A (BPA) – the brain
      • Increased aggressive behavior
      • 31. Increased motor activity
      • 32. Increased pain sensitivity
      • 33. Impaired learning & memory
      • 34. Decreased maternal behavior
      • 35. Impairments in sexual behavior
      • 36. Impaired neural plasticity – rodents & non-human primates
      • 37. Hypothalamus and brain sexual differentiation are disrupted
    • 12
      Bisphenol A (BPA) – other endocrine targets
      • Mammary gland
      • 38. Prostate
      • 39. Ovary (oocytes)/ Testes (sperm)
      • 40. Uterus and vagina/ epididymis & seminal vesicles
      • 41. Adipocytes
      • 42. Thyroid
      • 43. Anti-androgen
      Newbold, Reprod. Toxicol. 23: 290-296 (2007)
    • 44. 13
      Polychlorinated Biphenyls (PCBs)
      • Estrogenic EDC
      • 45. Persist & bioaccumulate
      • 46. Adult exposure- contaminated food
      • 47. Developmental exposure- placental and lactational transfer
      • 48. Developmental PCB exposure- neurological/ reproductive deficits
      • 49. Aroclor 1221: PCB used in our lab
    • 14
      PCB effects on P1
      Treatment
      • Vehicle (DMSO)
      • 50. E2 (50 µg)
      • 51. A1221 (1 mg/kg)
      Birth
      E0
      E16
      E18
      P0




      P1
      P60
      Puberty
      Exposure during the critical period of brain sexual differentiation
    • 52. 15
      ERα Expression in the mPOA (P1)
      Female
      DMSO
      A1221
      Male
      DMSO
      A1221
      Sarah Dickerson, PhD dissertation (unpub.)
    • 53. 16
      Apoptosis in the mPOA (P1)
      DAPI
      TUNEL
      DAPI + TUNEL
      • Apoptosis is lower in females than males.
      • 54. PCBs cause increased apoptosis in females – making them more “male-like.”
      Sarah Dickerson, PhD dissertation (unpub.)
    • 55. 17
      PCB effects in adulthood
      Injections
      • Vehicle (DMSO)
      • 56. E2 (50 µg)
      • 57. A1221 (1 mg/kg)
      Birth
      E0
      E16
      E18
      P0




      P1
      P60
      Puberty
      Postnatal development, Reproductive cycles,
      Hypothalamic protein/gene expression, Behavior
    • 58. Developmental effects
      Eye opening: Advanced in females (PCB).
      Pubertal timing: Advanced in females (EB, PCB), delayed in males (EB, PCB).
      Estrous cyclicity: Prolonged cycles in EB (46%), PCB (33%).
      18
    • 59. 19
      Hypothalamic control of reproduction
      EDCs
    • 60. ERα cells in AVPV (P60)
      Female
      Male
      DMSO
      A1221
      DMSO
      A1221
      • ERa is greater in the AVPV of females than males.
      • 61. PCBs cause ERa to decrease in the AVPV of females – making them more “male-like.”
      20
      Sarah Dickerson, PhD dissertation (unpub.)
    • 62. 21
      Kisspeptin in AVPV (P60)
      Female
      Male
      DMSO
      A1221
      DMSO
      A1221
      • Kisspeptin is greater in the AVPV of females than males.
      • 63. PCBs cause kisspeptin to decrease in the AVPV of females – making them more “male-like.”
      Sarah Dickerson, PhD dissertation (unpub.)
    • 64. 22
      GnRH-Fos co-expression (P60) in females
      The co-expression of Fos in GnRH neurons is significantly suppressed in PCB females.
      2X
      20X
      40X
      100X
      Sarah Dickerson, PhD dissertation (unpub.)
    • 65. 23
      Paced mating behavior in females
      • Reproductive success is the ultimate biological outcome.
      • 66. Reproductive success is enhanced when the female controls the pace of the mating.
      • 67. A paced mating paradigm enables dissection of female-typical behaviors.
      RM Steinberg et al. (2007) Horm Behav 51: 364-372.
    • 68. Summary
      Exposure to estrogenic EDCs during fetal development has long-term consequences on the molecular and cellular processes controlling reproduction.
      EDCs are associated with the masculinization of the hypothalamus of females.
      Puberty and reproductive physiology are perturbed, and reproductive behaviors are compromised.
      24
    • 69. Implications
      I propose that fetal exposures to EDCs reprogram the hypothalamus, and that this programming permanently compromises reproductive success.
      I also believe that these effects may be transmitted to future generations through molecular epigenetic changes.
      25
    • 70. 26
      Acknowledgments
      Funding:
      NIH RC1 ES018139
      NIH R21 ES12272
      PhRMA
      UT-Austin Fellowships
      Sarah Dickerson
      Deena Walker