Environmental Endocrine Disruptors

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Environmental Endocrine Disruptors
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1960s

• Eagles
• Eggshells
• DDT affected reproduction

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

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1970s

• Fish-eating birds Gulf Coast, Great Lakes
• Abnormalities of repro structures/functions
• Malformed offspring

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

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• (DES
• Potent estrogenic
• Growth stimulant in cattle
• Miscarriage prevention in women)

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• Men
• DES sons
• Abnormalities of genitalia, sperm
• Testicular cancer
• Undescended testicles
• Kepone spill
• Low sperm count

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1980s

• Male alligators
• DDT
• 1/2 testosterone
• Small penis size
• Repro capacity??

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1990s

• Male wildlife
• Various cmpds in water
• Sea gulls
• Eggs exposed to DDT ? female
• Turtles
• Eggs exposed to PCBs ? female
• Male-producing temps
• Same as estrogen exposure

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• Fish
• Polluted water
• Vitellogenin
• Egg yolk protein
• Female fish-laying eggs
• Absd into ovaries
• Remains in tissue of males
• Also female fish masculinized
• Used as biomarker

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• Laboratory Animal Studies
• Drugs/toxins _at_ diff stages neonatal devt
• Sensitive _at_ spec times of devt
• Irreversibility
• Too much/too little may be harmful
• Too little testosterone ? testicular feminization

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• Behavior sex of brain
• If no androgens ? phenotypic female
• Estrogen masculinizes brain
• Brief exposure ONLY
• Affects repro ability later in life
• Detox ? low doses tolerable
• BUT higher doses overwhelm metab

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

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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

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Nonylphenol
Estradiol
DDT
Kepone
DES
Tributyl tin (androgenic in Invertebrates)
Bisphenol A
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Characteristics of Endocrine Mimics

• Persistence
• Bioaccumulation
• High potency
• Critical periods of vulnerability
• Absence of permanent exposure markers

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• Transgenerational effects
• Subtle biological outcomes
• Natural signal sent by unnatural molecule
• Dont alter genes
• Do change way genes expressed

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How Natural Estrogens Work

• Target organs
• Breast
• Bone
• Liver
• Repro organs
• Cardiovascular system
• Chemical signals

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• Steroid hormones
• Prodd from cholesterol
• Synthd from testosterone
• Secrd from ovaries, testes when brain hormone
  signals
• Transported attd to transport proteins
• Fat soluble
• Pass directly into cells
• Receptors in cytoplasm, nucleus

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Progesterone a progestin, produced directly from
pregnenolone and secreted from the corpus luteum,
responsible for changes associated with luteal
phase of the menstrual 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 precursor 
Estradiol an estrogen, principal female sex
hormone, produced in the ovary, responsible for
secondary female sex characteristics 
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• Estrogen receptor
• Large protein
• In target cells only
• At least two (a, b)
• Two binding sites
• Estrogen
• DNA

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• Estrogenreceptor 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

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• Gene exprn modulated for duration receptor bound
  to ERE
• Examples of estrogenic genes
• Progesterone receptor gene
• Growth factor genes
• Growth factor receptor genes

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Environmental Estrogen Binding to Estrogen
Receptor

• Receptor apparently not completely specific
• Not all estrogenics look like estrogen
• Some atomic structures/distances impt

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• Binding of mimics may ?
• Estrogenic activity
• Inhibn natural estrogen binding (antiestrogenic)
• Most bind weakly BUT to strong effect
• Receptor binding strength not correlated w/
  estrogenicity

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• Binding extracell prots may be impt (ex DES)
• Binds estrogen receptor weakly
• BUT binds serum binding prot less tightly than
  natl estrogen
• More DES avail to enter cell
• Some must be actd metabolically (ex PAHs)
• Hydroxylation nec to mimic estrogen
• Enhances affinity for receptor

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Estrogenics

• Synergism possible
• Ex Study of dieldrin, endosulfan, toxaphene,
  chlordane
• Weakly estrogenic alone
• In combination estrogenicty incrd 160-1600 fold

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

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• Some may bind subunits of receptor together
• ? more strongly functioning unit
• Dimer may bind ERE
• May affect synthesis natural estrogen
• May affect release of natl estrogen into
  circulation
• May alter synth pathways, metab of natural
  hormones

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Growth Factors Affect Estrogen Activity

• Estrogens act through EGF, IGF, TFGa
• Cell membr receptors bind factors
• Get series intracell biochem rxns
• One endpoint of signal cascades is estrogen
  receptor transcrn

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

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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, redd sperm ct frightening

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• Risks to humans/wildlife/environment
• Need 5x amt DES to equal estradiol
• Admin DES _at_250-350 mg/kg during pregnancy
• Mother breast cancer 0.35 risk
• Daughter cerv. cancer 0.001 risk
• Daughter birth defect 0.3 risk

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• Not only isolated chems 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

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• 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?

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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

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Large-Scale Clean-Up??

• Much
• Nec for societal overall health, well-being?
• Nec for public health? Environmental health?
• Nec for wildlife propagation?