Exam 1 Flashcards
Endocrine disrupting chemicals
Study of ductless glands or tissues and their hormonal products
Endocrinology
Greek for ‘to arouse or excite’
Ernest Starling “..the chemical messengers which speeding from cell to cell along the blood stream, may coordinate the activities and growth of different parts of the body”
Hormone
William Bayliss, Ernest Starling demonstrated that substance released by lining of small intestine stimulated flow of pancreatic juice in dogs
Extract of small intestine injected into dogs caused response, indicating substance was blood-borne, not nervous
Crucial Experiment, 1902
In-vivo
Yolk: nutrient for ovum in all animals except placental mammals
Mixture of proteins, lipids
Vitellogenesis Induction
Binds estrogen (and other ligands) non-covalently with hydrogen bonds, hydrophobic interactions
Steroid Binding Domain
Formula for bound hormone, B?
[(Bmax)(F)]/(Kd+F)
Accidental exposure in Italy (1976)
Increased metabolic disease in women who were children in 1976
Lower sperm quality in men who were breastfed as infants just after explosion
Dose-related association between the serum and fertility problems in women
What EDC?
Dioxin
?? binds receptor specifically through numerous weak non-covalent bonds
Ligand
Binds to estrogen response element upstream of gene to be transcribed
DNA Binding Domain
1874: Invented in Germany
1939: Insecticidal properties realized
Post WWII: Widespread use in agriculture, public health, eradicated insect-borne diseases such as malaria and typhus
DDT
Contaminated with TCDD blamed for health problems among Vietnam veterans; sprayers at high risk for prostate cancer
Agent Orange
Whole, multicellular organism
in vivo
Attaches to something larger (hormones, EDCs)
Ligand
?? indicates potential to be agonist or antagonist
Displacement
?? receptors on cell surface
Hydrophilic
What major class of hormone? mostly hydrophilic; epinephrine, thyroxine
Amine
Estradiol agonist with very high affinity for receptor
Prescribed to pregnant women 1950s-1960s to reduce early labor, miscarriage
Daughters have more reproductive problems, risk of usually rare cervix, vagina cancers
Fewer indications on sons, model of potential damage from in utero exposure
DES (diethylstilbestrol)
Measure ability of living organisms, tissues, or cells to respond to estradiol agonist
Bioassays
?? binds endocrine receptor, is weakly estrogenic (~1:1000-10,000)
BPA
Very secondary sources of BPA (4)?
Plastics, dust, dental sealants, thermal paper
2 EDCs that aren’t estrogen agonists or antagonists?
Tributylin, Atrazine
Yeast expresses human ERs; human cDNA integrated into yeast genome
Yeast-Based Reporter Gene Assay
What are the 4 EDCs that are estrogenic agonists?
Octylphenols, BPA, Phthalates, DDT
in a test tube/petri dish
in vitro
In vitro
Responses to E2: proliferation, progesterone receptor up-regulation
Assesses proliferation in vitro by measuring DNA
MCF-7 Cell Line
Kd formula?
([H]{R})/[H*F]
Communication between cells
Cell Signaling
Signal cell, target cell connected by gap junctions; signal passed directly from one cell to another
Direct Cell Signaling
Organized by Theo Culburn; assessed EDC research in wildlife, humans; projected that EDCs had potential to impact wildlife populations, human fertility, human health
Wingspread Conference, 1991
Binds receptors, no response
Antagonist
Proposed that developmental alterations in wildlife due to chemicals that disrupted endocrine system of developing organisms. Implications that in utero exposure causes health issues not observed until later in life.
Introduced term “endocrine disruptor”
Wingspread Consensus Statement
Which major class of hormone? Hydrophobic; cortisol, testosterone, estradiol, progesterone
Steroids
Hormones transported by ?? system
circulatory
Signaling cell releases chemical messenger
Messenger carried in extracellular fluid
Nervous systems: Neurotransmitter released into adjacent synaptic cleft
Indirect Cell Signaling
Dose-response relationship in which curve changes direction, also called ‘low dose response’
Non-Monotonic Dose Response
Which major class of hormone? Hydrophilic; insulin, growth hormone, secretion
Peptides and Proteins
Profiled many facets of DDT, such as ability to accumulate in food chain
“Silent Spring” Rachel Carson, 1962
Sexually mature fish (adult) collected from ?? downriver sewage outfall, known for higher percentage of intersex fish
6 males, 3 females housed in spawning aquaria; males competed for females
Males intersex status compared to reproductive success
England River, UK
Radiolabeled substrate releases 3H20 when metabolized by enzyme
Aromatase Assay
What are the 4 receptor characteristics?
Specific binding, high affinity, saturation, signal transduction
Activates RNA polymerase
Transactivation Domain
Overproduction of estrogen in men leads to enlarged breasts, low libido, low sperm count, etc…
Had symptoms of estrogen excess but endogenous estrogen levels undetectable
Seldom wore gloves when applying ‘base cream’ to corpses
Mortician’s Base Cream
Battery of tests to determine if chemicals present risk to endocrine systems in humans, wildlife
Endocrine Disruptor Screening Program (EDSP)
?? usually inside cell
hydrophobic
What is the primary source of BPA?
Linings of metal food cans
Detected in 95% of samples from survey of US populations, reference/safe dose= 50 ug/kg-bw/day
BPA
Why are rodents good model for in utero effects?
Rodents at birth= human fetus in the second trimester
Progressive increase in the amount of a substance in an organisms which occurs because the rate of intake exceeds the organism’s ability to remove the substance from the body
Bioaccumulation
Anti-foulant in marine paint, may be an aromatase inhibitor
Tributyltin
Binds receptors, initiates a response
Agonist
Converts androgens into estrogens
Enzyme in many tissues including gonads, brain
Important factor in sexual development
Aromatase
Most widely used herbicide in US
Feminized amphibians
Suggested to induce aromatase
Atrazine
Does BPA free mean free of EDCs?
No, when it is removed it has to be replaced with another EDC
Binds estrogen receptor (ER), liganded ERs form dimers; is transcription factor for genes induced by this
Estradiol
If Kd is high, what is the affinity?
low
?? changes shape when ligand binds
Receptor
Consumed BPA excreted largely in ??
urine
What year?
EPA banned DDT; declining benefits, environmental, topological effects
DDT in environment, wildlife has decreased, but is persistent
Still used in Africa, India to control malaria
1972
Exogenous chemicals that can interfere with hormone actions
Endocrine Disrupting Chemicals
Cane toad feminization associated with degree of ??
agriculture
