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 diff stages neonatal dev’t 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 ?? 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 DDT DES Kepone Bisphenol A Nonylphenol 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

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 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

Estrogen receptor –Large protein –In target cells only –At least two (  ) –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 fold

Some physically combine –Form more estrogen-like molecule Some bind sites other than estrogen receptor –May 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, TFG  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 mg/kg during pregnancy Mother breast cancer 0.35 risk Daughter cerv. cancer 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, well- being? Nec for public health? Environmental health? Nec for wildlife propagation?