Environmental Endocrine Disruptors

1. Environmental Endocrine Disruptors

2. 1960’s • Eagles • Eggshells • DDT affected reproduction

3. Mink – Lake Michigan • Repro failure • Fed lake fish • Those fed fish from other sources normal

4. 1970’s • Fish-eating birds – Gulf Coast, Great Lakes • Abnormalities of repro structures/functions • Malformed offspring

5. Women • DES daughters • Repro cancers • Rare cell changes – vagina, oviducts, uteri • Repro organ dysfunction/disfigurement • Estrogen replacement  repro effects

6. (DES • Potent estrogenic • Growth stimulant in cattle • Miscarriage prevention in women) • Men • DES sons • Abnormalities of genitalia, sperm • Testicular cancer • Undescended testicles • Kepone spill • Low sperm count

7. 1980’s • Male alligators • DDT • 1/2 testosterone • Small penis size • Repro capacity??

8. 1990’s • Male wildlife • Various cmpds in water • Sea gulls • Eggs exposed to DDT  female • Turtles • Eggs exposed to PCB’s  female • Male-producing temps • Same as estrogen exposure

9. Fish • Polluted water • Vitellogenin • Egg yolk protein • Female fish-laying eggs • Also female fish masculinized

11. Laboratory Animal Studies • Drugs/toxins @ diff stages neonatal dev’t • Sensitive @ spec times of dev’t • Irreversibility • Too much/too little may be harmful • Too little testosterone  testicular feminization

12. “Behavior sex” of brain • If no androgens  phentypic female • Estrogen masculinizes brain • Brief exposure ONLY • Affects repro ability later in life • Detox  low doses tolerable • BUT higher doses overwhelm metab

13. Human sperm count depleted?? • 50% drop 1938-1990?? • Incr’d human prostate, testicular cancers reported • Poss female repro dysfunctions • Incr’d human breast, ovarian cancer rates • Incr’d PolyCystic Ovarian Disease • Related to neonatal androgenization (rodents) •  early onset estrus acyclicity

14. What Are Endocrine Disruptors? • EPA • “Exogenous substance that changes endocrine function and causes adverse effects at the level of the organism, its progeny and/or (sub)populations of organisms” • May act like endogenous hormones • OR metabolites can act like hormones • OR can block effects of opp sex hormones, growth factors, other hormones

15. Estradiol DDT Kepone DES Bisphenol A

16. Characteristics of Endocrine “Mimics” • Persistence • Bioaccumulation • High potency • Critical periods of vulnerability • Absence of permanent exposure markers

17. Transgenerational effects • Subtle biological outcomes • “Natural” signal sent by “unnatural” molecule • Don’t alter genes • Do change way genes expressed

18. How Natural Estrogens Work • Target organs • Breast • Bone • Liver • Repro organs • Cardiovascular system • Chemical signals

19. Steroid hormones • Prod’d from cholesterol • Synth’d from testosterone • Secr’d from ovaries, testes on brain hormone signals • Transported att’d to transport proteins • Fat soluble • Pass directly into cells • Receptors in cytoplasm, nucleus

22. Progesterone: a progestin, produced directly from pregnenolone and secreted from the corpus luteum, responsible for changes associated with luteral phase of the menstral cycle, differentiation factor for mammary glands Testosterone: an androgen, male sex hormone synthesized in the testes, responsible for secondary male sex characteristics, produced from progesterone  Estradiol: an estrogen, principal female sex hormone, produced in the ovary, responsible for secondary female sex characteristics 

23. Estrogen receptor • Large protein • In target cells only • At least two (a, b) • Two binding sites • Estrogen • DNA

25. Estrogen+receptor complex  nucleus • Binds regulatory regions of specific genes • At DNA regulatory site • “Estrogen Response Element” • Gene promoter near ERE • Activates, represses expression • Through proteins bound to promoter • Effects transcription of gene

29. Gene expr’n modulated for duration receptor bound to ERE • Examples of estrogenic genes • Progesterone receptor gene • Growth factor genes • Growth factor receptor genes

31. Environmental Estrogen Binding to Estrogen Receptor • Receptor apparently not completely specific • Not all estrogenics “look like” estrogen • Some atomic structures/distances impt

32. Binding of mimics may  • Estrogenic activity • Inhib’n natural estrogen binding (antiestrogenic) • Most bind weakly BUT strong effect • Receptor binding strength no correlated w/ estrogenicity

34. Binding extracell prot’s may be impt (ex: DES) • Binds estrogen receptor weakly • BUT binds serum binding prot less tightly than nat’l estrogen • More avail to enter cell • Some must be act’d metabolically (ex:PAH’s) • Hydroxylation nec to mimic estrogen • Enhances affinity for receptor

35. Estrogenics • Synergism possible • Ex: dieldrin, endosulfan, toxaphene, chlordane • Weakly estrogenic alone • In combination estrogenicty incr’d 160-1600 fold

36. Some physically combine • Form more estrogen-like molecule • Some bind sites other than estrogen receptor • May be @ site other than estrogen binding site • Probably interactive • Stronger response when both occupied (perhaps one w/ endogenous estrogen)

37. Some may bind subunits of receptor together •  more strongly functioning unit • Dimer may bind ERE • May affect synthesis natural estrogen • May affect release of nat’l estrogen into circulation

38. Growth Factors Affect Estrogen Activity • Estrogens act through EGF, IGF, TFGa • Cell membr receptors bind factors • Get series intracell biochem rxns • One endpoint signal cascades transcr’n estrogen receptor

40. Estrogenics may affect growth factors • Interaction w/ factors • Binding of factor receptors • Overall  change estrogenicity

41. Is There a Problem? • Public opinion against regulation/study • Wildlife effects “esoteric” • Not enough scientific evidence • Too alarmist • Public opinion for regulation/study • Effects are clear • Human-wildlife link believable • Cancers, birth defects, red’d sperm ct frightening

42. Risks to humans/wildlife/environment • Need 5x amt DES to equal estradiol • Admin DES @250-350 mg/kg during pregnancy • Mother breast cancer 0.35 risk • Daughter cerv. cancer 0.001 risk • Daughter birth defect 0.3 risk

43. Not only isolated chem’s at work in wildlife • Evidence mostly relates to persistent substances (DDT, kepone) • No longer legal • Removal not related to hormonal effects • Effects mostly related to specific sites • Difficult to prove one chem. effect

44. Wildlife studies isolated • Magnitude of doses • Synergism? • Fish studies showed vitellogenesis in vitro, not in field tests • Lab animals good models? • Tissue culture samples valid?

45. EPA Task Force • Food Quality Protection Act, Safe Drinking Water Act • Best models • Best cmpds to test • Validity analytical techniques • End points assigned • Risk vs. cost

46. Large-Scale Clean-Up?? • Much $$$ • Nec for societal overall health, well-being? • Nec for public health? Environmental health? • Nec for wildlife propagation?