Tox 502 Test 3
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Tox 502 Test 3
Tox Toxicology 502 test ccraigr
502 Exam 3 Lecture 21: developmental toxicants
Describe the relationship of an oxidizing or reducing cellular environment to specific cellular outcomes (The answer is a graph).
In what cellular environment would the formation of cancer cells be optomized?
A highly reducing environment (because of the optomization for cellular proliferation).
In what cellular environment would a pathologic outcome be optomized?
What are these pathologic outcomes?
A highly oxidizing environment.
1st apoptosis, then as it becomes more oxidizing, necrosis.
What type of cellular E
environment would optomize cells for differentiation?
that is not highly reducing nor highly oxidizing (middle of the road, leaning toward reducing) is perfect for cellular differentiation.
What is the effect of GSH transferase on E
and cellular outcome?
High GSH would indicate a highly reducing environment. This would optomize a proliferative outcome.
What would be the effects of a low level of GSH transferase on E
and cellular outcome?
Low GSH would decrease the reducing environment. (But it wouldn't increase the oxidizing environment, a separate stimulus is needed for that like p450).
This would lead to a more neutral E
and cellular differentiation.
(So its not reducing nor oxidizing:middle of the road).
How does Thalidomide act? (give the normal & then the pathological state)
B normally needs reduced thiols to do 2 things: 1 cross into the nucleus from the cytosol; 2 bind to DNA target and activate transcription of angiogenic growth factors
: Thalidomide causes an oxidative environment where ROS oxidizes the critical thiols: this stops NF-
B from acting on its targets=no angiogenic growth factors.
What is the result of a loss in angiogenesis?
No angiogenesis=No tissue development.
How would we classify something as a developmental toxicant?
If it interferes with:
2 Normal Growth
What is the timing for key developmental events in humans?
What are somites? When do they develop in humans?
Blocks of Mesoderm.
They become the vertebral collumn, ribs, skeletal muscles, cartilege, tendons, & dermis.
Formed 20-21 days in utero.
When would we see a threshold dose?
When wouldn't we see a threshold dose?
Use the graph from the book.
Why is the embryo so vulnerable?
1. Because the embryo is largely undifferentiated cells, it does not have a lot of repair/detoxification ability.
(think about GSH "buffering" capacity)
2. Its immunosuppressive system may be missing or underdeveloped.
3. Complecated coctail of cellular products are needed for proper differentiation. Decrease or loss of 1 single product may be enough.
When is the Embryo/Fetus most sensitive to teratogenic effect?
During Organogenesis primarily. Histogenesis to a lesser extent.
say something about cell cycle changes and development
What are some Key Points about Retinoic Acid Structures?
Metabolized in the body to Retinoic Acid (RA).
RA acts on RXR and RAR.
Bound RA-RXR/RAR induces transcription of developmental genes.
This is a normal process, but overactivation is pathological.
Give specifics about Isotrentinon:
metabolized to RA.
Leads to craniofacial abnormalities in utero.
Rx'd as Acutane for acne. (pregnant mothers with acne?).
Give the MOA for diethylstilbesterol (DES)
is a synthetic estrogen
: so p450 activation to DES-semiquinone then changes to DES-quinone.
Leads to Vaginal Clear Cell Adenocarcinoma in young women (when exposed in Utero).
Epididimal cysts and hypotrophic testis in male.
Endocrine disruptor (but that's such a broad term).
Antineoplastic cancer therapy.
Causes ssDNA breaks, & DNA-protein cross linking. =poor cell rep leading to apoptosis(possibly by p53 activation).
Hydrocephaly (Neural tube)
Cleft Pallate (Neural tube)
micrognathia (Neural tube)
AKA mustard gas
Bioactivated by p450 and then spontanious 2 step degradation to toxic metabolite.
Degradation is antagonized by ADH (1st degrade) and ALDH (2nd Degrade).
Describe Valproic Acid
Epidemical to Spina Bifida in france.
normally an anticonvulsant (seizures,
Possibility of a
Etiology uncertain. But study showed loss of TH+neurons after VA exposure(2005)
Describe the effects of Ethanol in Fetal Alcohol Syndrome:
Acts during neural tube closure resulting in craniofacial dysmorphism.
psychomotor and intelectual development retardation.
Low birth weight due to growth retardation.
ROS via alcohol pathway.
Toxic Syndromes: Sympathomimetic
: slight inc.
: Hyperalert, inc. reflexes.
Toxic Syndromes: Anticholinergic
: Slight inc, or NC
: decreased bowell sounds
: alt mental status.
Toxic Syndromes: Cholinergic
: Slight DC or NC
: Inc bronchial sounds
: Inc bowell sounds
: alt mental status
Toxic syndromes: Opiod
: NC or late stage Rales
: Decreased Bowell Sounds
: DC conciousness
: vasoconstriction, mydriasis, Coronary Artary Dialation, DC bowell motility, bladder contraction
: smooth muscle dialation, gluconeogenesis, insulin release, Broncho dialation, vasodialation, DC bowell, bladder relaxation. miosis.
: agonist. (epi analogue)
watch out for tachycardia to the max. Any arrythmias will be enhanced.
Anticholinergic Poisoning mneumonic
Red as a beet
Dry as a bone
mad as a hatter
hot as a stone
Bowell and Bladder lose their tone
heart runs alone
Cholinergic Poisoning mneumonic
Anticholinergic poisoning treatment vs cholinergic poisoning treatment
Physotigmine vs Atropine +pralodoxamine.
The Autonomic nervous system (figure)
How to help increase elimination of a toxin?
if toxin pka is low, increase pH.
if toxin pka is high, decrease pH.
(helps ionise, increasing filtration and excretion via kidney)
Opiods are metabolized by what type of enzyme?
GU is common.
Opiod agonist. (Naloxone)
start low and SLOWLY increase dose.
curarae vs ...
black widow toxin, tobacco, insecticides.
Tachycardia, hypertension, weakness, paralysis, muscle fasciculations.
Cramps, Diarrhea, (possible, low fever and bloody D) 3 or so days
How STEC works?
Cleaves RNA, inhibiting protein synthesis=cellular death.
STEC vs EHEC vs ETEC
Symmetric Descending Paralysis
Must regengerate new presynapse. (recovery weeks to months)
Fusion complex (snare proteins). (Ach release)
Botulism V. Tetanus
Toxin is very similar, varies type of target.
: PNS, Stimulatory Motor Neurons
: CNS, Inhibitory Motor Neurons
: Flaccid P. (b/c no ach is being released)
: Rigid P. (b/c no inhibitor is being released)
Sudden Flu Like Symptoms
Sudden Fever (over 102)
Staph aureus. (TSS toxin)
Watch out for sceptic shock and organ failure.
Toxic Shock/Scalded Skin
*Non-specific t lymphocyte proliferation
leading to sustained cytokine release.
Which exogenous toxins are pyrogenic?
But you would also see Anticholinergics!!
Describe toxic shock syndrome
Systemic bacterial infection.
diffuse cytokine release.
2. Lethal Factor (Zn metaloprotinase)
3. Protective antigen.
LPS Sceptic Shock
G neg bacteria. Cell envelope toxin.
Endothelial cell damage.
disseminated intervascular coagulation
multiple organ failure.
Similar to Anthrax.
Peripheral paralysis and muscle weakness
Gait ataxia, breathing dificulty.
similar to AcH poisoning.
improves upon removal.
inhibits AcH release.
oral and peripheral numbness,
Difficulty swallowing, throat constriction, speech incoherent.
PSP from saxitoxin.
Closes Na channels.
12 hour to beginning of recovery
Saxitoxin V Brevitoxin
Both are dinoflagellate.
PSP v red tide.
: more mild than S.
reversal of hot/cold.
Metalic Hg. (Hg 0)
: Pulm, CNS, fetal
: Lipid solluble.
Inorganic Hg (+1 Mercuric, +2 Mercurous
: Renal, GI, Fetal
: Accumulation via active transport of conjugates.
: Ingestion of contaminated food.
Organic (methyl Hg etc.)
: Renal, CNS, PNS, Fetal.
: Major accumulation.
: inorganic bacterial converted to organic. bioaccumulation.
accumulation leads to depletion of MT enzyme levels. then ROS production, edema, and cellular death.
Hg can inhibit AcHE and resemble AcH poisoning. Mad as a Hatter sound familiar?
Cd (+2 only state)
T:Lungs (smokers) kidney, bone.
: MT conjugation, deposition, ROS production
: Mining, food/water, tobacco.
20-30 year half life!!
: CNS, BONE, Nephron.
: Heme synth interuption. Synaptic poisoning.
: Drinking water, Paint, industrial, folk remedies
Tell me a little about MT
Metals induce transcription.
cystein residues chelate metals.
binds a dozen or so metal atoms/molecule.