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Uterine Muscle as a Target of Polychlorinated Biphenyls

Uterine Muscle as a Target of Polychlorinated Biphenyls. Rita Loch Caruso, Ph.D. Toxicology Program School of Public Health University of Michigan. B- 1. Childbirth. B- 2. Parturition. Preterm Birth (11.6%). Prolonged Labor (0.8%). Complications. Postmaturity (7.2%).

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Uterine Muscle as a Target of Polychlorinated Biphenyls

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  1. Uterine Muscle as a Target of Polychlorinated Biphenyls Rita Loch Caruso, Ph.D. Toxicology Program School of Public Health University of Michigan B-1

  2. Childbirth B-2

  3. Parturition Preterm Birth (11.6%) Prolonged Labor (0.8%) Complications Postmaturity (7.2%) Dysfunctional Labor (2.8%) B-3

  4. Human Pregnancy Myometrium Drawing by M. Brodel, from Williams, Am. J. Obstet. Gynecol, 13:1, 1927

  5. Toxicants Parturition Fetal / Maternal Signal(s) Coordinated, Forceful & Sustained Myometrial Oscillatory Contractions Parturition B-5

  6. A Mechanistic-based Approach for Assessing Potential Chemical Hazards to Parturition B-6

  7. Contraction-Promoting Signals estrogen Cell Relaxation oxytocin prostaglandins Cell Contraction stretch

  8. PCBs and Parturition • Exposure to PCBs is associated with decreased gestation length in humans • The PCB mixture Aroclor 1248 induces spontaneous abortion in monkeys • Several PCB mixtures and congeners exhibit estrogen-like activity

  9. PCB Residues in Tissues Sampled From Women During Parturition Data are expressed as ppm of extracted lipids. From Polishuk et al., Environ. Res. 13:278, 1977.

  10. Uterine Anatomy Human Rat Endometrium Myometrium

  11. Recording Pen Uterine Contractility Measurement Isometric Force Transducer Uterine Segment Polygraph Organ Bath B-11

  12. Aroclor 1242 Stimulates Uterine Contraction Bae, J. et al. Environ. Health Perspect. 109:275, 2001

  13. Aroclor 1242 Stimulates Uterine Contraction

  14. Microbial Dechlorination of Aroclor 1242 Auto1242 (control) HR1242 (incubated with microbes) 2,4-CB/2,5-CB 2,2'-CB/2,6-CB Difference between Auto1242 and HR1242

  15. Microbial Dechlorination Increases Uterotonicity of Aroclor 1242 Bae, J. et al. Environ. Health Perspect. 109:275, 2001

  16. Microbial Dechlorination of Aroclor 1254 Auto1242 (control) 2,2',4-CB HR1242 (incubated with microbes) 2,2',4,4'-CB Difference between Auto1242 and HR1242

  17. Microbial Dechlorination Increases Uterotonicity of Aroclor 1254 Bae, J. et al. Environ. Health Perspect. 109:275, 2001

  18. Structure Abbreviation PCB Cl Cl 3,3',4,4'-CB 3,4-TCB Cl Cl Cl Cl 3,4-PCB 3,3',4,4',5'-CB Cl Cl Cl Cl Cl 2,4-TCB 2,2',4,4'-CB Cl Cl Cl Cl HCB 2,2',4,4',5,5'-CB Cl Cl Cl Cl Cl 2,4,6-CB 2,4,6-TCB Cl Cl Cl 4-OH-TCB 4-OH-2',4',6'-CB OH Cl Cl

  19. PCB Congener Uterotonicity Tsai, Webb, and Loch-Caruso. Reprod. Toxicol. 10:21-28, 1996.

  20. Ortho- and Para-Substituted PCB Congeners DMSO 2-MCB 2,2'-DCB 2,4-DCB 2,4'-DCB Pretreatment 30 uM 60 uM 100 uM Tsuneto et al., unpublished

  21. Intracellular Calcium Increases Stimulate Uterine Muscle Cell Contraction Calcium Calmodulin Calcium-Calmodulin Myosin Light Chain Kinase Actin + Myosin Actomyosin-P Myosin Light Chain Phosphatase Cell Relaxation Cell Contraction B-21

  22. Mechanisms of Intracellular Calcium Increase PIP2 IP3 RR Ca2+ SR VOCC Thapsigargin Ryanodine Nifedipine

  23. Aroclor 1242 Does Not Increase Inositol Phosphate Release

  24. Aroclor 1242 Increases Intracellular Calcium Bae et al. Toxicol. Appl. Pharmacol. 155:261, 1999

  25. Aroclor 1242 Requires Calcium for Uterotonicity Aroclor 1242 (A1242) Carbachol (CCH)

  26. Inhibition of Voltage-Operated Calcium Channels Prevents Aroclor 1242 Stimulation Aroclor 1242 (A1242) Carbachol (CCH)

  27. Aroclor 1242 stimulation is not inhibited by thapsigargin or ryanodine pretreatment

  28. Prostaglandins Stimulate Uterine Contraction Phospholipids Phospholipase Arachidonic Acid Cyclooxygenase Eicosanoids (Prostaglandins F2 & E2)

  29. Aroclor 1242 releases large amounts of arachidonic acid that is not significantly metabolized • Aroclor 1242 inhibits prostaglandin synthesis

  30. PLA2 Inhibitors Prevent Aroclor 1242 Uterotonicity

  31. Aroclor 1242 Mechanism Ca2+ Ca2+ VOCC Arachidonic acid ? PLA2 Aroclor 1242 VOCC: Voltage operated Ca2+ channels PLA2: Phospholipase A2

  32. Cl Cl Cl OH Hypothesis: Long-term exposure to estrogenic PCBs promotes uterine contraction by an estrogen receptor-mediated mechanism.

  33. 4-Hydroxy-2',4',6'-Trichlorobiphenyl Increases Oxytocin-induced Contraction Frequency 10 1 M 4-OH-TCB 1 M 4-OH-TCB + Tamoxifen Tamoxifen Frequency (cycles/min) 5 Control 0 Tsai et al. Biol Reprod. 56:341, 1997 0 0.1 1 100 1000 Oxytocin (nM) B-33

  34. 17-Estradiol Increases Oxytocin-induced Contraction Frequency 10 nM estradiol 10 10 nM estradiol + tamoxifen Tamoxifen Frequency (cycles/min) 5 Control 0 Tsai et al. Biol Reprod. 56:341, 1997 0 0.1 1 100 1000 Oxytocin (nM)

  35. ER 4-OH-2',4',6'-TCB Mechanism OT OTR 4-OH-TCB Ca2+ 4-OH-TCB: 4-hydroxy-2',4',6'-trichlorobiphenyl ER: Estrogen receptor OT: Oxytocin OTR: Oxytocin Receptor B-35

  36. B-36

  37. Superfund Basic Research Program University of Michigan Acknowledgments Dr. R. Clinton Webb Dr. Ed Stuenkel Dr. Marc Peters-Golden Dr. Mei-Ling Tsai Dr. Jeehyeon Bae Taeko Tsuneta B-37

  38. Thank You After viewing the links to additional resources, please complete our online feedback form. Thank You Links to Additional Resources

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