Download Environmental Endocrine Disruptors

Environmental Endocrine
Disruptors
1960’s
• Eagles
– Eggshells
– DDT affected
reproduction
• Mink – Lake
Michigan
– Repro failure
– Fed lake fish
– Those fed fish
from other
sources normal
1970’s
• Fish-eating birds –
Gulf Coast, Great
Lakes
– Abnormalities of
repro
structures/functions
– Malformed offspring
• Women
– DES daughters
– Repro cancers
• Rare cell changes – vagina, oviducts, uteri
– Repro organ dysfunction/disfigurement
– Estrogen replacement  repro effects
• (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
1980’s
• Male alligators
– DDT
– 1/2 testosterone
– Small penis size
– Repro
capacity??
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
– Fish
• Polluted water
• Vitellogenin
– Egg yolk protein
– Female fish-laying eggs
– Abs’d into ovaries
• Remains in tissue of males
• Also female fish masculinized
• Used as biomarker
• 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
– “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
• 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
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
Estradiol
DES
DDT
Nonylphenol
Kepone
Bisphenol A
Tributyl tin
(androgenic in
Invertebrates)
Characteristics of Endocrine
“Mimics”
• Persistence
• Bioaccumulation
• High potency
• Critical periods of vulnerability
• Absence of permanent exposure
markers
• Transgenerational effects
• Subtle biological outcomes
• “Natural” signal sent by “unnatural”
molecule
• Don’t alter genes
• Do change way genes expressed
How Natural Estrogens Work
• Target organs
– Breast
– Bone
– Liver
– Repro organs
– Cardiovascular
system
• Chemical
signals
• Steroid hormones
– Prod’d from cholesterol
– Synth’d from testosterone
– Secr’d from ovaries, testes when brain
hormone signals
– Transported att’d to transport proteins
• Fat soluble
– Pass directly into cells
– Receptors in cytoplasm, nucleus
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
• Estrogen receptor
– Large protein
– In target cells only
– At least two (a, b)
– Two binding sites
• Estrogen
• DNA
• 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
– Gene expr’n modulated for duration receptor
bound to ERE
– Examples of estrogenic genes
• Progesterone receptor gene
• Growth factor genes
• Growth factor receptor genes
Environmental Estrogen
Binding to Estrogen Receptor
• Receptor apparently not completely
specific
– Not all estrogenics “look like” estrogen
– Some atomic structures/distances impt
• Binding of mimics may 
– Estrogenic activity
– Inhib’n natural estrogen binding
(antiestrogenic)
• Most bind weakly BUT to strong effect
– Receptor binding strength not correlated
w/ estrogenicity
• 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 DES avail to enter cell
• Some must be act’d metabolically (ex:
PAH’s)
– Hydroxylation nec to mimic estrogen
– Enhances affinity for receptor
Estrogenics
• Synergism possible
– Ex: Study of dieldrin, endosulfan,
toxaphene, chlordane
– Weakly estrogenic alone
– In combination estrogenicty incr’d 1601600 fold
• 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)
• 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
• May alter synth pathways, metab of
natural hormones
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 transcr’n
• Estrogenics may affect growth factors
– Interaction w/ factors
– Binding of factor receptors
• Overall  change estrogenicity
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
• 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
• 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
• 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?
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
Large-Scale Clean-Up??
• Much $$$
• Nec for societal overall health, wellbeing?
• Nec for public health? Environmental
health?
• Nec for wildlife propagation?