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146 Cards in this Set

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What are the functional components of the nervous system?
-Sensation : vision, taste, hearing, smell, balance
-Movement : touch, control muscle movement, reflexes, coordination
-Interpretation: memory, symbol formation, cognition
-Emotion and Motivation
What are the functions of astrocytes?
1) Break glucose down to lactate before funneling it to neurons. 2)Store glycogen for when energy demand is high.
3) Provide materials needed to produce neurotransmitters.
4) Control the composition of fluid surround neurons by taking up or releasing compounds that must be kept at critical levels.
5) Provide physical support, wrapping around neuronal cell bodies and dendrites as well as blood vessels. ( Anchors neurons in place; Enables astrocytes to pass nutrients to neurons and remove
wastes; Isolates synapses and contains the movement of released neurotransmitters.)
What are the functions oligodendrocytes and schwann cells
1) Myelin forming cells that insulate neuronal axons.
2) Schwann cells in the periphery each wrap around a single distinct segment of an axon.
3) Oligodendrocytes, in the CNS, provide multiple
myelinated segments for multiple neurons.
What are the functions of microglials?
1) Protect the brain from microorganisms and remove debris and dead neurons.
2) Responsible for inflammation that occurs when brain damage or necrosis occurs
What are the ion concentration gradients of neurons that control resting membrane potential?
-Na+,K+-ATPase pumps Na+ out of the cell and K+ into the cell – requires ATP.
-Leakiness to K+ (100-fold greater than Na+) balances with K+ pumped in and attraction of negative charge to facilitate K+ balance.
-The net effects of the Na+,K+-ATPase pump and the leakiness of the membrane are gradients of the common ions in and around the neuron.
What is propagation of action potential along a plasma membrane of a neuron?
-Local currents produced at the site of the action potential will trigger another action potential at the polarized portion of adjacent membrane.
-The refractory state of the repolarizing portion of adjacent membrane will prevent backward propagation.
What is myelin of neurons?
-Myelin is an insulator.
-Membrane pumps need to reserve fewer ions and cells possess less ion channels.
-It is metabolically more cost-effective than unmyelinated axons.
-Myelin is formed by Schwann cells in PNS and Oligodendrocyte in CNS that wrap around the axon, acting as an insulator
-Voltage changes are detected from node to node, allowing the
AP to jump from node to node – Saltatory Conductance.
-Ion channels occur only at the Nodes of Ranvier
How does neuron-transmission communicate the action potential across synapses in neurons?
1. Ca+2 channels open with AP approach
2. Vesicles bind to pre-synaptic membrane
3. Neurotransmitter crosses synapse
4. Neurotransmitter binds ligand-gated ion channel – opened, allows ion flow
5. Transmitter is degraded or reabsorbed, terminating ion flow
What are toxicants in electrical conduction?
-tetrodotoxin
-saxitoxin
-batrachotoxin
-organochloride pesticides
What is axonal transport of the neuron?
1) The axon contains a large proportion of the volume and surface area of a neuron.
2) Axon and axon terminus do not have advanced cellular capacities such as organelle or protein synthesis / degradation.
3) Essential materials are produced, packaged and sent out into the axon from the cell body.
What are the internal structural components of the axon?
-Microtubules – Tubular shaped 25 nm in diameter, and 100um in length. Made up of α and β tubulins. Important for structure and transport.
-Microfilaments – Actin subunits intertwined to form 7 nm fibrils. Important in membrane and cellular cytoskeletons.
-Neurofilaments – Rope-like fibrils 8-12 nm in diameter, 10-100 um long, that make up the bulk of the axon’s structure (related to keratin in other tissues).
-Fast Transport: via microtubules, Anterograde: protein, tubulovesicular structures, neurotransmitters, neuropeptides and membrane lipids, 250-400 mm/day, mitochondria 50-100 mm/day.
Retrograde: Larger organelles, lysosome-bound materials and endogenous materials collected through endocytosis
-Slow Transport: 1-4 mm/day (move of cytoskeleton)
What are the vulnerabilities of the CNS?
1. The reliance of the CNS on aerobic respiration
2. A high metabolic rate
3. Membranes which are rapidly polarized and depolarized
4. The spatial extension of the neuron
5. The existence of a lipid-rich support system
6. The need to pass neurotransmitters across extracellular space.
7. The need for an extreme degree of organization in development.
8. Once the neuronal organization has been established, there is little guidance or support for effective repair of damaged regions.
What are the energy requirements of the CNS?
1.The brain is approximately 2% of body weight, but uses ~15% of cardiac output and accounts for 25% of oxygen consumption.
2. The CNS (and cardiac myoctyes) are dependent upon a continuous supply of energy due to constant maintenance of ionic gradients
3. The CNS completely dependent on aerobic metabolism. Brief Reduction in glucose supply or oxygen may impair functioning permanently.
-O2 or glucose are in low supply──>ATP levels are diminished ──> Na+,K+-ATPase does not functionin ──>Loss of function of excitable membranes ──> Cellular, mitochondrial and nuclear swelling due to excessive water accumulation from ion imbalance
What is hypoxia? ischemia? What neuronal damage can they cause?
-Hypoxia – Lack of O2 needed for function and survival
-Ischemia – Lack of blood flow (and associated O2 and glucose)
-Cause both focal and regional nerve damage, depending
on duration and areas affected
What are anoxic and ischemia related injuries and toxicants that cause them?
-Anoxic Anoxia: Inadequate oxygen with adequate blood flow.
Carbon Monoxide – CO poisons heme – no O2
-Ischemic Anoxia: Decreased blood pressure results in inability to supply brain with enough oxygenated blood
-Cytotoxic Anoxia: Refers to condition where proper cell metabolism is hindered. Oxygen and blood nutrient levels are adequate.
-Cyanide (-C≡N) is an inhibitor of the enzyme cytochrome C oxidase in the fourth complex of the eletron transport chain in the membrane of the mitochondria.
-3-Nitropropionic (3-NP), mycotoxin, irreversible inhibitor of succinate dehydrogenase-->ATPdepletion
What toxicants can inhibit electron transport?
-Rotenone: broad spectrum insecticide, pisticide, and pesticide
-antimycin A: antibiotic and pisticide
What is the blood-brain barrier?
1. The Brain is protected from blood-borne toxicants by: tight junctions between endothelial cells in capillaries (rather than 4 nm gaps in the rest of the body)
2. Glial cells (astrocyte) surround capillaries, further isolating them from neurons
3. Selective transport processes for uptake of essential materials such as: amino acids, amines, inorganic ions, carboxylic acids and hexose sugars
4. Xenobiotic transporters that move chemicals out of the brain and back into the blood (Efflux: Multi-drug resistant protein)
5. Interstitial fluid protein concentrations are very low.
6. Lipophilic compounds enter brain quickly.
What are flaws in the blood-brain barrier?
-Not complete – Spinal and autonomic ganglia and the circumventricular organs of the brain do not have tight junctions. Overall, less protective of peripheral nerves
-Reduced or lacking in pituitary and hypothalamus
-Underdeveloped in the young, particularly so in premature infants.
-It can be damaged or modified by a variety of chemicals, physiological states or health conditions
-Chemicals that mimic essential materials can bypass the BBB
Ex. Methyl mercury-cystein via methionine transporter
-Lipophilic chemicals can traverse membrane
ex. morphine and heroine
What are is neuronal regeneration and recovery?
-Adult CNS neurons are non-dividing specialized cells
–not capable of cell division to replace lost neurons
–neuronal stem cells inactive in adult CNS
•Dead neurons replaced by glial cells (gliosis)
–recovery from serious brain or spinal cord injury is minimal
What is axonal or dendrite regeneration in the CNS?
-surviving neuronal cell bodies in spinal cord send out fresh neurite projections
-projections re-establish lost axonal (or dendritic) innervation to target tissues
-follows nerve pathways previously laid down by lost axons
-slow regeneration process takes months or years (depends on axon length)
What is functional recovery of neurons?
-occurs when structural damage cannot be adequately repaired
recruitment of alternate undamaged neurons to perform new functions
-CNS (stroke)
-PNS (polio recovery and post-polio syndrome)
What is nicotine as a neuronal toxicant?
-Cholinergic agonist: Bind to the nicotinic receptor and mimic the effect of acetylcholine
-Nicotinic receptor: sympathetic and parasympathetic systems-->mixed symptoms
-Acute overdose: Initial nausea, rapid heart rate, and perspiration followed shortly by marked slowing of heart rate with a fall in blood pressure. Somnolence and confusion followed by coma.
What is antropine as a neuronal toxicant?
-Muscarinic receptor antagonist
-Muscarinic receptor: G-proetin linked AchR
-Parasympathetic synapse of heart and glands
-Lead to imbalance of autonomic system-->in favor of the sympathetic division
-Tachycardia, dilation of the pupils, dilation of bronchioles, decrease in peristalsis, and decrease in secretions
What is organophosphate as a neuronal toxicant?
•Malathion, parathion, “nerve gases”
•Sarin is a fluorinated phosphonate
•Inhibits acetylcholinesterase (AChE) leading to continuous stimulation
•Neurobehavioral, cognitive, neuromuscular disturbances
•Death from respiratory distress
•OP modification is stable and only slowly reversible and dependent on the regeneration of acetylcholinesterase.
May be treated with antropine or other anticholinergics.
How do cocaine and amphetamien effect the CNS?
-Alternations in catecholaminergic neurotransmission by blocking dopamine reuptake transporter (DAT).
What are excitatory amino acids and how do they effect the CNS?
-Glutamate and Aspartate
-Glutamate: main excitatory neurotransmitter of the brain-->mediated by excitatory amino acid receptors (EAARs)
-Two subtypes: ligand-gated ion channel (ionotropic), G-protein coupled (metabotropic)
-Rodent Experiment: Regulated at BBB; Lead to neuronal swelling and neuronal cell death (dendrite and neuronal cell bodies)
-Human Condition-->Chinese Restaurant Syndrome-->burning sensation in face, neck and chest-->allergic or hypersensitive?
Kainic acid-->Glutamate analog (seaweed)-->kill neurons
What are inhibitory amino acids and how do they effect the CNS?
-Glycine: primarily in the brain stem and spinal cord
-Tetanus toxin (Clostridium tetani): binds to presynaptic membrane-->prevents release of Gly
-Strychnine (Strchnos nux vomica tree) : convulsant, binds and blocks postsynaptic Gly receptor
-Both toxicants: sustained muscle contraction
What are neuronopathies?
-Neuronal death is irreversible, including degradation of all cytoplasmic extensions (axons and dendrites) and associated myelin, either by necrosis or induced apoptosis.
What is methyl mercury as a neuronal toxicant?
•Mercury vapors from degassing in earth’s crust
•Methylated by microorganisms to CH3 Hg
–CH3 Hg is the most significant form of Hg in terms of toxicity from environmental exposure
–Bioconcentration in aquatic food chain
–90 to 95% absorption in GIT
–Crosses placenta, BBB (mimicking Met)
•Hg2+ binds strongly to sulfhydryl groups
•Impaired glycolysis, nucleic acid biosynthesis, aerobic respiration, and protein synthesis
•Neurotoxic effects lead to,
Paresthesia, Ataxia, Neurasthenia,Vision and hearing loss, and Coma and death
•Neurotoxic effects due to focal necrosis of neurons
•Poisoning therapy utilizes chelators such as cysteine, penicillamine, thiol resins
-Toxicity: Methyl Mercury or liberated mercuric ion??
What is trimethyltin as a neuronal toxicant?
-Organotins: plasticizers, antifungal agents, and pesticides
-Intoxication: Potentially irreversible limbic-cerebellar syndrome
-Access to the nervous system: unknown
-Neurons of Brain: Accumulation of cytoplasmic bodies composed of Golgi-like structures-->Cellular swelling and necrosis
-Hippocampus is particularly vulnerable: emotion (aggressive in animal)
What are the toxic effects of dopamine, 6-hydroxydopamine, and catecholamine on neurons?
-Monoamine oxidase-->H2O2 cytotoxicmetabolite
-Metal ion catalyzed auto oxidation results in catecholamine-derived quinones (strong eletrophile react with sulfhydryls) and superoxide anion
-·OH hydroxyl free radical from Fenton reaction
-React with proteins, lipids, and nucleic acids.
-H2O2 from dismutation
-Superoxide dismutase and glutathione peroxidase handle superoxide and hydrogen peroxide
-6-Hydroxydopamine, to induce Parkinsonism in laboratory animals
What is MPTP as a toxicant of neurons?
-A contaminant in “synthetic heroin”
-Parkinson’s Disease-like symptoms in drug addicts (1982)
-Loss of neurons in the substantia nigra which synthesize and secrete dopamine: tremor, slow movement, and rigidity
-MPTP
What are axonopathies?
● Due to chemical transection of the axon and separation from the cell body
● Repairable in the periphery, but not in the CNS where inhibitory factors from myelin cells and astrocytes prevent axonal regrowth.
● Long sensory and motor neurons and longer spinal cord tracts are most sensitive.
● Often due to disruption of axonal transport processes
What is the molecular delivery system of the axon? major components?
-anterograde -- transports supplies forward toward distal axon
-retrograde -- returns to cell body to pick up new load and dispose degradable materials
-microtubules (tubulin) -- ‘delivery tracks’
-neurofilaments (NF protein) -- ‘conveyor belt’
-ATPase - ‘electrical generator’
-kinesin and cytoplasmic -dynein -- molecular motors
-Fast axoplasmic transport is inhibited by distal axonopathy agents
How do Gamma-Diketones cause axonopathy?
Hexane: Constituents of gasoline and glues used for shoes, leather products, and roofing
-Industry switching away from n-hexane in favor n-heptane of where possible
-Distal axonopathy
What is carbon-disulfide as a toxicant for axonopathy?
-Vulcan rubber and viscose rayon industries
-Protein Crosslinking:
-Dithiocarbamate ester: reversible
-Thiourea: irreversible
-Distal axonopathy
-May accelerate the process of atherosclerosis
What is IDPN as a toxicant for axonopathy?
-Bifunctional nitrile
-causes “waltzing syndrome”
-Nitrile groups undergo bioactivation to form bifunctional crosslinking reagents
-Degeneration of the vestibular sensory hair cells
-Massive neurofilament swelling of the proximal axon
What is acrylamide as a toxicant for axonopathy?
-Vinyl monomer used in paper products, water treatment, soil-stabilizing, waterproofing , and PAGE gel in lab research
-Toxic distal axonopathy begins with the denegation of the nerve terminal
-Both anterograde and retrograde fast axonal transports are affected
-Recent studies have shown it to be present in carbohydrates cooked at high temperatures
How does paclitaxel cause microtubule-associated neurotoxicity?
-Microtubules aggregate to create arrays of microtubules
How does colchicine cause microtubule-associated neurotoxicity?
-Fewer microtubules within the axons
What is organophosphate-induced delayed neuropathy?
●A variety of OPs cause a progressive neuropathy that is delayed in onset from 7 to 10 days
● Associated with the inhibition of “Neuropathy Target Esterase” activity, rather than acetylcholinesterase
● Neuropathy target esterase (NTE) is an integral membrane protein present in all neurons and in some non-neural-cell types of vertebrates. (neuron and glial cell signal )
● Repairable in the periphery, but not in the long central tracts.
● Initial human occurrence in 1930 – adulterated ginger extract drink for its 70% alcohol content (during alcohol prohibition)
● Contained tri-ortho-cresyl phosphate
● Poisoned ~50,000, some recovered
● Generally resulted in a high-stepping, foot slapping walk known as the Jake Walk
What is myelinopothy?
•Varies in chemical composition and configuration for different cells, but performs the same insulating function.
•Composed of about 80% lipid (glycolipid as galactocerebroside) and about 20% protein (Myelin basic proteins, Myelin oligodendrocyte glycoprotein, proteolipid protein.
•Forming by the progressive wrapping of their cytoplasmic progresses around the axon in successive loops (20-200 sheets).
What is intramyelinic edema of myelinopothy?
-separation of the myelin lamellae (alternations of transcription of MBP mRNA)
What is demyelination of myelinopathy?
-the loss of myelin with the preservation of axons
What is remyelination of myelinopothy?
-Schwann cells are capable of capable of remyelination-->shorter distance between adjacent nodes
How is the immune system involved in myelinopothy?
-up regulation of tumor necrosis factor (TNF)-->overproduction of cytokines
How is hexachlorophene a toxicant for myelinopathy?
•Antibacterial agent, was at one time wildly used
•Newborn infants, particularly premature infants, were bathed with the compound to avoid staphylococcal skin infection
•Hydrophobic-->intramyelinicedema-->formation of vacuoles
•Possible routes: loss of ion gradients or uncoupling of mitochondrial oxidative phosphorylation
•Reversible in the early stages
What is tellurium as a toxicant for myelinopathy?
•Demonstrated in animals
•Decreased synthesis of cholesterol, cerebroside, lipid rich in myelin, mRNA of myelin proteins
•Possible target: Squalene epoxidase, a microsomal monooxygenase that utilizes NAPDH cytochrome P450 reductase.
What is lead as a toxicant for myelinopathy?
•Ubiquitous toxic metal
•Primary route of exposure is by ingestion
•Source is from lead-based paint, contaminated drinking water, lead- glazed pottery
•Encephalopathy occurs at blood lead levels of 80-100 μg/L
•Symptoms of encephalopathy include lethargy, vomiting, irritability, loss of appetite, and dizziness
•Progression of symptoms lead to ataxia, reduced level of consciousness, which may progress to coma and death
•Recovery is often associated with life-long epilepsy, mental retardation, optic neuropathy, blindness
•Chronic toxicity affects PNS: Schwann cell degeneration
•Mechanisms of toxicity include: Impairment of cell-cell connections, Alterations in neurotransmitter levels, Disrupts calcium metabolism
What are functional manifestations of neurotoxicity?
(1) Assessment of signs of autonomic function
(i) lacrimation and salivation
(ii) piloerection and exophthalmus.
(iii) urination and defecation, including polyuria and diarrhea.
(iv) Pupillary function
(v) Degree of palpebral closure, e.g., ptosis.
(2) Convulsions, tremors, abnormal motor movements
(3) Reactivity to general stimuli such as removal from the cage or handling,
(4) Level of activity during observations
(5) Posture and gait abnormalities
(6) Ranking of gait abnormalities
7) Forelimb and hindlimb grip strength
(8) Quantitative measure of landing foot splay;
(9) Sensorimotor responses to different stimuli, Pain perception (tailpinch,
tail-flick, or hot-plate) Sudden sound,
(10) Body weight.
(11) Unusual or abnormal behaviors, excessive or repetitive actions (stereotypies), emaciation, dehydration, hypotonia or hypertonia, altered fur appearance, red or crusty deposits around the eyes, nose, or mouth.
(12) Additional measures. Such as:
(a) Count of rearing activity on the open field.
(b) Ranking of righting ability.
(c) Body temperature.
(d) Excessive or spontaneous vocalizations.
(e) Alterations in rate and ease of respiration, e.g., rales or dyspnea.
(f) Sensorimotor responses to visual or proprioceptive stimuli.
How do you assess for neurotoxicity and their descriptions?
Voltage clamp: use external energy source to maintain membrane potential at a desired value (ion channel) (Biochemical and cellular level)
Eletroencephalogram (EEG): electrical activity of the brain by measuring the potential difference between electrodes (Physiology)
Computerized tomography (CT): measure the degree of X-ray absorbed and reconstitute an imagine of brain slice
Positron emission tomography (PET): through radioactively labeled molecules to map the location of these molecules in brain
How is the botulinum toxin a toxicant for neurons?
●Botulinum toxin: a group of at least seven different toxi proteins produced by seven different serotypes of Clostridium botulinum.
● Botulism from food poisoning. Clostridium botulinum is a strict anaerobe and heat resistance.
● Infant infection through GI tract (Honey with Clostridium spore)
● Botulinum toxin is among the most toxic substances known: LD50 1 ng/kg.
● Inactive polypeptide of 150 kDa cleaved by a protease to form two subunits linked by a disulfide bond
● Enter into cholinergic neuron through high affinity receptor binding and endocytosis
●Toxin A and E cleave SNAP-25 to block the release of acetylcholine
●Interruption of the impulse transmission: muscle weakness and paralysis, blurred vision etc.
What are theraputic actions of botulinum toxin?
-Muscle spasms
-Migraine Headache
-Excessive Sweating
-BOTOX
•Paralyze facial muscles responsible for wrinkles
•Minimum amount, direct injection, last 3 months
•Up to 20% of patients treated clinically developed immunity
How was botulinum toxin used as a biological weopan?
-Developed during WWII by Japan and Germany
-Loaded into weapon by Iraq in 1990s
-Tried but failed in downtown Tokyo to disperse Clostridium botulinum.
-Main concern: inhalational delivery
What toxicants cause neuronopathy?
-Methyl mercury
-Trimethyltin
-Catecholamine
-MPTP
What toxicants cause myelinopathy?
-Hexachlorophene
-Tellurium,
-Lead
-Inflammation
What toxicants cause axonopathy?
-n-HEXANE
-CS2
-IDPN
-Acrylamide
-Paclitaxel
-Colchicine
-OP (NTE)
What are neurotransmission related toxicants?
-acetylcholine:
Nicotine, Atropine, OP
BOTOX
-Dopamine:
Cocaine, Amphetamine
-amino acids: Glutamate
Gly (Tetanus toxin)
What are the seminiferous tubules of the reproductive system?
-Contain spermatogonia Stem cells: involved in spermatogenesis
-Contain sustentacular cells:
Sustain and promote development of sperm
What are the sertoli cells of the reproductive system?
-Form blood-testis barrier
-Secrete several proteins essential to spermatogenesis) (BTB,
-1) chemical permeability
-2) luminal fluid )
What are leydig cells of the reproductive system?
-synthesize testosterone
What is spermatogenesis?
● 2 types of spermatogonia
1)produces other spermatogonia (diploid) (some mitosis occurs in the embryo)
2)produces sperm (haploid)
● beginning at puberty, millions formed each day
● Testes produce mature spermatozoa
● Sperm – smallest human cell
● Animals generally produce many more sperm/day than human
● About 7 million/day/gm in young man; after 50 yrs drops to about ½
● Sperm enter epididymus, duct deference
-Elongated tubule with head, body and tail regions
-Monitors and adjusts fluid in seminiferous tubules
-Stores and protects spermatozoa
-Facilitates functional maturation of spermatozoa
–damaged sperm can be rapidly replace with “fresh” sperm (4-6 weeks)
What is ovarian function?
-Oogenesis--> maturation of oocyte--> expulsions of the mature oocyte--> secretion of female hormone
•Between 300,000 and 400,000/ovary at birth
•Continuously die (atresia)
•Reduced to appr ½ by puberty
•Appr 25,000 by 30 yrs
•Remain in primary follicle stage until puberty
•Depletion in the pool can lead to infertility
•About 400 primary follicles yield mature ova
What is oogenesis?
-The fetal oogonia cease dividing at the 7th month after conception
-Meiotic arrest at primary oocyte till puberty
-Primary oocyte undergoes 2 meiotic divisions, one just before ovulation and the other after sperm fuses with egg
-Ovum production
Occurs monthly in ovarian follicles
What is the uterine cycle?
•Repeating series of changes in the endometrium
•Continues from menarche to menopause
–Menses
•Degeneration of the endometrium
•Menstruation
–Proliferative phase
•Restoration of the endometrium
–Secretory phase
•Endometrial glands enlarge and accelerate their rates of secretion
What are the general functions of the hormones of the reproductive system?
•Control the reproductive cycle
•Coordinate the ovarian and uterine cycles
What are the key hormones of the reproductive system and their functions?
–FSH
•Stimulates follicular development
–LH
•Maintains structure and secretory function of corpus luteum
–Estrogens
•Multiple functions
–Progesterones
•Stimulate endometrial growth and secretion
How do granulosa cells conduct hormonal regulation of ovarian activity?
1.Nourish Oocyte
2.Chemical messengers: oocyte and theca cells
3.Antral Fluid
4.Early and middle follicular phases: Estrogen and FSH action sites
5.Covert androgen (aromatase) from theca cells
6.Inhibin-->inhibits FSH
7.LH action site for ovulation and formation of corpus luteum
How do barriers of the reproductive system influence toxicity?
a. blood testes barrier
ability to penetrate depends on MW, lipophilicity, degree of ionization, etc.
b.no equivalent structure in ovary
C. Placenta-mostly sieve
How does gametogenesis influence reproductive toxicity?
a. males- sperm produced continuously
b.females- finite number of oocytes available
How does biotransformatio and metabolism of the reproductive system influence toxicity?
a.testes- spec. act.< liver
b.ovary-not as well studied; complex hormonal involvement; cytochrome systems and mixed function oxidases
What are potential mechanisms/sites for reproductive toxicity?
1.DNA damage
2.Cytotoxicity (gametes or gonads) (Direct or Biotransformation)
3.Interference with hormonal control (Endocrine disruptors)
4.Altered fluid composition
5. Interference with gamete function
6. Nerve transmission
How does DNA damage of the reproductive system occur?
1. Alkylating Agents (damage DNA) and antimetabolites (inhibit nucleotide biosynthesis) can directly inhibit sperm production.
2. X-ray and other ionizing radiation cause decrease in spermatogenesis.
3. Potentially interfere with oogenesis
4. Lead toxicity induces a variety of chromatid and chromosome breaks.
What is cyclophosphamide as a toxicant of the reproductive system? symptoms?
-DNA damage
-nitrogen-mustard derived alkylating agent
-pink/bloody urine,
-unusual decrease in the amount of urine,
-mouth sores,
-unusual tiredness or weakness,
-joint pain,
-easy bruising/bleeding,
-stopping of menstrual periods,
-infertility
-existing wounds that are slow healing
What is the age-dependent sensitivity of cyclophosphamide toxicity of the reproductive system?
–Young females more sensitive to oocyte destruction than older females.
–Young males more resistant to toxicity than older males.
–Rate of spermatogenesis in prepubertal testis is low.
What is cytotoxicity of the reproductive system?
N-hexane-->microsomalozidation-->2,5-hexanedione ( γ-diketone)
-->testicular atrophy
Alternations in Sertoli cell microtubules via pyrrole- dependent cross-linking
Slow onset-->protein trafficking-->Sertoli-germ cell contacts
-Carbon Disulfide
What are glycol ethers as toxicants for the reproductive system?
●industrial compounds with little or no mutagenic activity
● apparently metabolized to active metabolite but no evidence for genetic or hormonal mechanism of action.
-Sertoli cells are primary targets
- Decreased RNA synthesis in spermatocyte
-Interfering with signal transduction pathways within either Sertoli cells or germ cells
What is DBCP (Dibromochloropropane, 1,2-Dibromo-3-chloropropane) as a toxicant of the reproductive system?
-Fungicide
-Banned in 1979 by EPA
-Continuing presence as contaminants in ground water
-No preferable uptake by testes
-Gonadotoxicity is male specific
-Inhibition of spermatogenesis
-Causing sterility through the Sertoli cells
-Inhibition of oxidative phosphorylation (NADH dehydrogenase)
How are DNB (Dinitrobenzene) , DNT (Dinitrotoluene) as toxicants of the reproductive system?
-May effect energy metabolism in testes
-Cause vacuolization on the Sertoli cells and the detachment of germ cells
How are esters of o-phthalic acid (Phthalate esters or PAEs)?
-Plasticizers and used in medical devices
-Different PAE-->varying degree of testicular toxicity
-Diethyl hexyl phthalate (DEHP) and its metabolite monoethyhexyl phthalate (MEHP)
-->early sloughing of spermatidsand spermatocytes, and severe vaculizationof sertolicell cytoplasm
-->MEHP interfere with FSH binding and pathways
-->DEHP suppress preovulatory follicle granulosa cell estradiol production
What are the female cytotoxic substances and mechanism of action?
●Antineoplastic agents, heavy metals, polycyclic aromatic hydrocarbons, or radiation
●Oocytes damage: stage dependent
●Mature secondary oocytes-->temporary infertility
●Partial destruction of primary oocytes-->may not lead to immediate infertility -->early onset of menopause
●Total destruction of oocytes-->infertility and premature menopause
How are polycyclic aromatic compounds a toxicant of the reproduction system?
● Consist of fused aromatic rings and do not contain heteroatoms or carry substituents
● Formed in automobile exhaust, smoke emissions,0 cigarette smoke.
● Several PAHs destroy oocytes in weanling and mature rats and mice
● PAH metabolites (ovarian P450) destroy primary oocytes
● Cigarette smoke and nicotine suggested to impair reproduction and fetal development in experimental animals and humans. Not known whether from PAHs, nicotine, CO or other components of cigarette smoke
What are toxicant areas to interfere with hormonal control?
-CNS
-Inhibition of Steroidogenesis
-Endocrine Disruptors
How is the CNS a target of toxicants that interfere with hormonal control of the reproductive system?
● Targets: hypothalamus and anterior pituitary etc.
● Alternation of hypothalamic-releasing hormones and/or gonadotropins
What is steroidogenesis?
-Steroid Biosynthesis from cholesterol
-Endocrine organs: Adrenal cortex, ovary, and testes
Other peripheral tissues and the CNS
-precursor-->pregnenolone
-Ovaries-->estrogens (granulosacells) and progesterone (theca cells)
-Testes-->androgen (testosterone and dihydrotestosteron) (Leydigcells or the interstitial cells)
How do endocrine disruptors (environmental estrogens) interfere with hormonal control of the reproductive system?
● Chemicals that have the potential to disrupt the endocrine system of humans and animals
•mimic natural hormones
•block action of natural hormones
•interact with hormones
•disruption of synthesis
•alteration of hormone receptor levels
• reproduction dysfunction in wildlife
● Non-heavy metal
● Lipophilic and accumulation in fatty tissues
● Persistent organic pollutants accumulated in animals
What are synthetic/ anabolic steroids as endocrine disruptors?
● Synthetic steroids (19-nortestosterones,Nandrolone ) -->suppressing gonadotropinsecretion and hence blocking ovulation
● Anabolic steroid-->try to separate anabolic effects and androgenic effects-->lower testosterone levels and suppress spermatogenesis
How is DTT (Dichloro-Diphenyl-Trichloroethane) and other organochloride pesticides as an endocrine disruptor?
-Early puberty in girls and dysplasia in boys
How are PCB (polychlorinated biphenyls) endocrine disruptors?
-Dielectric fluids in transformers and capacitors, coolant etc.
-PCB production was banned in the 1970s
What are Nonylphenols (polyethoxylates) as endocrine disruptors?
-Estriol induction of vitellogenesis (yolk deposition) in male fish
-Industrial surfactant in manufacture of wool and metal
What is TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin, dioxins) as an endocrine disruptor?
-Dioxins occur as by-products in the manufacture of organochlorides
-Alteration of germ cells at all stages
-Activity of the estrogen receptors and other receptors
What is cimetidine (tagamet) as an endocrine disruptor?
− a histamine H2-receptor antagonist that inhibits the production of acid in the stomach
− Used for treatment of peptic ulcers
− Competes with dihydrotestosterone for
receptors in the testis and accessory sex glands
− Leads to low sperm count, gynecomastia (development of abnormally large mammary glands in males)
What is the putative link between endocrine disruptor exposure and decreased male fertitlity?
-One study (1992) indicated a significant worldwide decline in sperm count
-Another study(1994) has not detected any decline
-Sperm count-->variable-->location and time etc.-->not a good indicator of male reproductive health
-Other concerns: reproductive abnormalities and cancers
-New hypothesis:
-Due to increased estrogen exposure in uterus
-Possible exposure to estrogen mimics Diethylstilbestrol (DES) and DDT, naturally occurring phytoestrogens (coumestan (coumarin derivative) isoflavonoids), and botanically derived substances (soy proteins)
How does Epichlorohydrin interfere with the fucntion fo the gamete?
-Inhibition of sperm motility
-Paper reinforcement and water purification
How does Procarbazine interfere with the function of the gamete?
-Damage to sperm head
-Antineoplastic chemotherapy drug for the treatment of Hodgkin’s lymphoma and certain brain cancers, alkylating agents
What human assessment can be done for testing for reproductive toxicity?
Male:
1)Reproductive history
2)Semen characteristics – sperm count, motility, semen volume, and morphology.
3)Serum hormone level

Female:
1)Reproductive history
2)Serum hormone level
3)X-rays of the uterus and fallopian tubes (structural abnormalities)
4)Body temperature
How do you conduct animal testing for reproductive toxicity?
1)Choice of species (developmental pathways and xenobiotic metabolism) (hamster, mice and rat-->short gestation times) (rabbits)
2)Route of administration for a toxicant (similar to human exposure: injection, intubation, inhalation, or food/water)
3) Fertility evaluation
Male: a) Semen characteristic; b) Sperm penetrating and fertilizing an egg; c) histological evaluation of the testes, epididymis, prostate and other glands; d) hormone level and in vivo and in vitro binding test; e) mating of toxicant-exposed males with normal females
What are some problems with testing for animal reproductive toxicity?
1) Rodent reproductive / developmental processes not always equivalent to humans (Thalidomide)
2) Doses may be excessively high -- unrealistic compared to human exposures
3) Route of exposure often unrealistic (oral dosing)
How do you conduct in vitro testing of reproductive toxicity?
1)Cultured embryos from rat and mouse-->exposing to toxicant-->changes in normal developments
2)Cultured cells or group of cells from organs removed from organogenesis
3)Cells derived from Drosophila eggs and Xenopus embryos
What is teratology?
•Teratology is the science that studies the causes, mechanisms, and patterns of abnormal development.
•Developmental disorders present at birth are called congenital anomalies, birth defect or congenital malformation.
•Congenital anomalies are of four clinically significant types: malformation, deformation, disruption and dysplasia.
What are birth defects?
•3% of all live-born infants have an major anomaly
•Additional anomalies are detected during postnatal live – about 6% at 2 year-olds, 8% in 5year-olds, other 2% later
•Single minor anomalies are present in about 14% of newborns
•Major anomalies are more common in early embryos (up to 15%) than they are in newborns (3%). Most severely malformed embryos are spontaneously aborted during first 6 to 8 weeks.
What are possible classes of teratogens?
•Drugs ( warfarin, valproic acid, phenytoin, vitamin A, thalidomide, cyclophosphamide, lithium carbonate)
•Chemicals (PCBs, methylmercury, alcohols)
•Infections (rubella, cytomegalovirus, herpes, toxoplasma, syphilis)
•Ionizing radiation
•Maternal factors (diabetes mellitus, hyperthermia, phenylketonuria, hyper-/hypo-thyrosis)
What are the outcomes of pre-implantation exposure of teratology? Implantation to time of organogenesis? fetal to neonatal exposure?
-embryonic lethality
-morphological defects
-functional disorders, growth retardation, carcinogenesis
How is exposure to rubella virus depended on the stage of pregnancy for teratology?
-<8 weeks of pregnancy-->defects of the visual and cardiovascular systems
-8-12 weeks-->hearing impairment
What is fetal alcohol syndrome?
●Most common preventable cause of adverse CNS development
● 4,000-12,000 infants per year in US
● Characteristics: Growth retardation; Facial malformations; Small head; Greatly reduced intelligence
What is fetal alcohol effects?
● Milder form of FAS
● 7,000-36,000 infants per year in US
●Characteristics: Growth deficiency; Learning dysfunction;
Nervous systems disabilities
What are possible teratopathies from ethanol?
-fetal alcohol syndrome
-fetal alcohol effects
How is cocaine teratogenic?
•Neurological and developmental defects
•Potentate the effect of norepinephrine (sympathetic nerves of autonomic nervous division)
•May have direct effects on the developing brain
•Stimulate blood vessels to contract-->decrease blood flow to fetus -->hypoxia
•Stimulate contraction of uterine smooth muscle -->tendency to premature labor
How is Diethylstilbestrol (DES) cause teratogenic?
• A synthetic estrogen used from 1940-1970 for pregnancy maintenance (ineffective)
•Effects were not seen in offspring until they reached puberty:
Females: vaginal neoplasia (tumors), vaginal adenosis, cervical erosion
Males: Hypotrophic testes, poor semen, volume and quality
•Interference with reproductive tract development (6-16 weeks) (transplacental carcinogenesis)
How are retinoids teratogenic?
-Vitamin A –like compounds
-Skin disorder such as sever cystic acne (isotretinoin) and psoriasis (etretinate)
-Act via retinoic acid receptor (RAR) (expressed in embryonic tissues)
-Brain damage, aberrations in neural crest cell derivatives (a small and asymmetric face), cardiac defects etc.
-Effective in dermatologic treatment and extremely terotogenic
How are anti-epiletic drugs teratogenic?
-include: valproic acid, phenytoin, phenobartital and carbamazepine
~50,000 women in Europe and North American need epilepsy treatment during pregnancy
-Valproic acid: histone deacetylase inhibitor, neural dysfunction
-phenytoin, phenobarbital and carbamazepine: potassium channel inhibitors , growth retardation, minor defect related to growth retardation, cardiovascular malformation
How is warfarin teratogenic?
-Anticoagulant. (initially marketed as a pesticide)
-Vitamin k antagonist -->vitamin K reductase-->carboxylationof several blood coagulation proteins (factor VII and prothrombin)
-Often in women with artificial heart valves
-Short nose and brachygnathia (abnormal shortness of the lower jaw), distal digital hypoplasia etc.
How is thalidomide teratogenic?
•Introduced in 1956 in Germany, 1958 in Canada and England as sedative (sleeping pill) and to reduce nausea and vomiting during pregnancy
•Very low acute toxicity
•Discovered to be a human teratogen causing shortening (phocomelia) and absence of limbs (amelia) or limb malformations in newborns
•Withdrawn in 1961 from European market and 1962 from Canadian market
•Sold worldwide 30 countries
•Affected children 6,000-10,000
•Not approved in the US due to inadequate data (FDA employee Frances Kelsey repeatedly rejected the application )
What are the general in vivo effects and in vitro mechanisms of bisphenol A?
-Selective Estrogen Receptor Modulator (SERM) (?)
-BPA ≈ E2 and BPA ≠ E2 (√ )
-->androgen receptor -->androgen antagonist(?)
-->anti-thyroid hormone (??)
-->Metabolism in various tissues
biochemical activity ≠ biological activity
Rodent ≠ Human
What are the in vitro mechanisms of bisphenol A?
a. BPA can act as an estrogen. Its effects are, however, cell type specific.
b. Timing (developmental stage) of exposure and exposure dose/concentration are critical.
c. When BPA binds to classic nuclear estrogen receptors and induce specific ERE binding, BPA is usually less potent than estradiol.
d. When BPA action is mediated by estrogen receptors outside the nucleus, its potency is as high as that of estradiol, ranging within the pico- and nano-molar concentrations.
e. Because of cell-type specific expression patterns and the role of varied specific co-regulatory factors, the effects of BPA might be different in individual cell types and these effects can vary depending on intrinsic and extrinsic influences.
f. BPA is not simply a SERM (selective estrogen receptor modulator).
g. BPA exerts pleiotropic cellular and tissue-type specific effects and non-monotonic dose–response at the cellular and intracellular levels at low physiologically relevant concentrations.
What is inflammation? What is the response?
-Is a beneficial host response to foreign challenge or tissue injury – -facilitates the restoration of tissue structure and function
-Response requires innate immunity and (in some cases) an adaptive immune response
-Acts as the first line of defense against noxious material
-Adaptive response relies on the innate immune system to provide the necessary effectors, such as phagocytes and granulocytes
-However, prolonged inflammation can cease to be a beneficial event as it contributes to the pathology of many diseases.
What is the patho-physiology of inflammation?
-Inflammation begins with the recognition of INJURY, followed by AMPLIFICATION phase involving SOLUBLE MEDIATORS and CELLULAR inflammatory systems.

-Inflammatory responses are terminated by SPECIFIC INHIBITORS of the mediators, and APOPTOSIS of the inflammatory cells
What is acute inflammation?
-short duration (minutes to 1-2 days)
-The hallmarks include accumulation of fluid and plasma components in the affected tissue
-Intravascular stimulation of platelets and the presence of PMN(neutrophils)
What is chronic inflammation?
-longer duration,
-The characteristic cells are MACROPHAGES, LYMPHOCYTES and PLASMA CELLS.
What are the results of inflammation?
1. Tissue injury is eliminated and normal tissue architecture and physiological function restored
2. The injured area is walled off by the collection of inflammatory cells, resulting in the destruction of the tissue --- ABCESS. A scar may form
3. if the pathogenic insult is not removed, chronic inflammation expends, leading to FIBROSIS and SCAR formation
What is starling's law? Types of pressure?
-Normal fluid balance is maintained by opposing sets of forces:
-Interstitial tissue osmotic pressure and intravascular hydrostatic pressure cause fluid to move out of circulation.
-Plasma protein osmotic pressure and tissue hydrostatic pressure cause fluid to move in to circulation
What leukocytes activities are induced during inflammation?
-margination (selectins),
-adherence (ICAM, integrins)
-Trans-endothelial emigration (PECAM).
What is effusion edema as a type of inflammatory response?
-excess fluid in the CAVITIES of the body
What is transudate edema as a type of inflammatory response?
-edema fluid with low protein content (sp.gr. <1.0)
What is exudate edema as a type of inflammatory response?
-edema fluid with high protein content (sp.gr. >1.0) also may have high lipid content and cellular debris
What is serous edema as a type of inflammatory response?
-absence of a prominent cellular response in exudate or transudate
What is serosanguineous edema as a type of inflammatory response?
-When red cells are present
What is fibrous exudate edema as a type of inflammatory response?
-When coagulation process occur and fibrin deposited
What is purulent edema as a type of inflammatory response?
-exudate or effusion that contains prominent cellular components, e.g. PMN frequently identified with pyrogenic bacterial infection
-Pus is purulent exudate
What are sources of vasoactive mediators of inflammation?
-Primary sources are cells and plasma.
-Important cellular source of vasoactive mediators:
-endothelial cells (nitric oxide or EDRF)
-circulating platelets
-tissue plasma cells
-basophils
What are the cellular sources of chemical mediators of inflammation?
-Preformed mediators in secretory granules,e.g.
-Histamine: mast cells, basophils, platelets
-Serotonin: platelets
-Lysosomal enzymes: PMNs and macrophages
-Newly synthesized , e.g.
-Arachidonic acid metabolites: -Protaglandins and Leukotrienes
-Platelet activating factor
-Activated oxygen species
-Nitric oxide
-Cytokines
What are factors from plasma that mediate inflammation?
-Factor XII (Hageman factor) activation: Kinin system (bradykinin)
-Coagulation / fibrinolysis system
-Complement activation: -Anaphylatoxins, (C3a, C5a)
-Opsonins (C3b)
-Membrane attack complex
What are anaphylatoxins of inflammation?
-C3a, C4a and C5a have potent effects on smooth muscle and vasculature, e.g.
-Enhancement of smooth muscle contraction and increasing vascular permeability
-C3a and C5a also induce mast cell and basophil degranulation
-Also they enhance arachidonic acid metabolism
-C5a is also a potent chemotactic factor
-C3b binds to bacterial surface to cause opsonization
What is arachidonic acid formation of inflammation?
1. Phospholipase A2 action on phospholipid e.g. phosphotidylcholine

2. Phospholipase C acting on phosphotidylinositol to yield diacylglycerol, then diacylglycerol lipase cleaves to form arachidonic acid
What is arachidonic acid metabolism of inflammation?
1. Cyclooxygenase to yield prostaglandins and thromboxanes
2. Lipoxygenase to yield monohydroxyeicosatetranoic (HETEs) and dihydroxyeicosatetranoic acids (diHETEs), and leukotrienes
What are the functions of prostaglandin and thromboxane in inflammation?
-PGI2 and PGE2 are vasodilatory, therefore enhance vascular permeability
-Thromboxane A2 is a potent vasoconstrictor and mediate in the "second wave" of platelet aggregation
What are monohydroxyeicosatetranoic (HETEs)
of inflammation?
-are metabolized to various leukotrienes
-e.g.Leukotriene B4 is a potent chemotactic agent for PMNs, monocytes and macrophages
-LTC4, LTD4 and LTE4 are called slow reacting substances of anaphlaxis( SRS-As), they stimulate contraction of smooth muscle, and enhance vascular permeability
What are cytokines of inflammation?
-Produced by non-lymphoid cells -Glycosylated Polypeptides that stimulate other cells
-lymphocytes --- lymphokines
-monocytes --- monokines
-as a class, these are called interleukins
What is interleukin-1 (IL-1) as a pro-inflammatory cytokine? Effects on endothelium?
-produced by all cell types, stimulated by endotoxin, immune complexes, toxins, physical injury and a variety of inflammatory processes.
1. Induction and synthesis of surface adhesion molecules
2. Induction of synthesis and release of PGI2
3. Stimulation of PAF synthesis
4. Rendering endothelial cell surface more thrombogenic
What is tumor necrosis factor (TNF-a) as a pro-inflammatory cytokine?
-originally discovered as a product of stimulated macrophages that causes lysis of tumor cells in-vitro, and hemorrhagic tumor necrosis in-vivo.
-IL-1 and TNF are very similar molecules and have the same spectrum of biologic effects.
What is tissue growth factor as an anti-inflammatory cytokine?
-family of polypeptide growth factors that control the development and homeostasis of most tissues in metazoan. It plays a central role in tissue repair.
-Binds to transmembrane receptors that are serine/threonine kinases to affect intracellular signal transduction pathways such as the Smad and then NF-κB nuclear transcription.
What is the mechanism of action of tissue injury produced by phagomononucleocytes (PMNs)?
-Phagocytosis: engulfment and internalization of foreign agents or injured cell material by phagocytic cells e.g.PMN
-Phagocytosis activates NADPH oxidase, to produce peroxide, then through myeloperoxidase, PMNs produce HOCl (kills bacteria)
-reactive oxygen species HOCl cause tissue damage
What is chronic inflammation after phagocytic damage by PMNs?
-Following acute injury of tissue, PMNs are replaced over several days by lymphocytes, mononuclear phagocytic cells and plasma cells.
This "subacute inflammatory response" represent the early stages of resolution leading to the formation of GRANULATION TISSUE: proliferation of endothelial cells and fibroblasts, angiogenesis and increased connective tissue matrix.
What is granulomatous inflammation?
-If the acute inflammatory response is unable to remove the causative agents, for example, material that cannot be digested by the neutrophils, the lesion develops into a persistent and destructive acute inflammation
-The principal cells are macrophages and lymphocytes and “epitheloid cells”-- Granuloma
What are the various increases in specific circulatory cell types? How?
-Neutrophilia -- bacterial infection and infarction of tissue
-Lymphocytosis -- viral infection
-e.g. mononucleosis (can appear very similar to leukemia)
-Eosinophilia e.g. in parasitic infection and allergic reaction
What are defects in leukocyte function?
1. numbers: e.g. neutropenia
2. cell adherence: decrease or mutation in adhesion proteins
3. cell migration and chemotaxis: e.g. defective chemotactic factor, inhibition of leukocyte locomotion
4. phagocytosis: e.g. actin dysfunction, decreased opsonization
5. microbiocidal activity: defective enzyme system in producing ROS and HOCl