Quiz 1 Flashcards
Lectures 1-4
What is Toxicology?
A branch of science that studies the adverse effects of chemical, physical or biological agents on living systems and the ecosystem, including the prevention and the amelioration of such adverse effects
Toxicology is an Interdisciplinary field involving… (4)
biology, chemistry, pharmacology, and medicine
What is Descriptive Toxicology?
Focuses on testing of toxic substances
Typically using animals and then correlating findings to humans
Provides information for safety evaluation and regulation, such as dose-response information
Ex: Assessing the reproductive toxicity of BPA
What is Mechanistic toxicology?
Identifying and understanding the mechanisms that underlie the toxic effects of drugs or chemicals on living systems
Also identifies whether the effects are genotoxic, teratogenic, carcinogenic, neurotoxic, etc.
Ex: Study identifying targets of gymnodimines
What is Regulatory toxicology?
Assessing whether a drug or chemical poses a risk to human health
Uses information gathered from toxicity testing
Establishes standards and/or guidelines for safe exposure
Ex: guidance for the consumption of bitter apricot kernels
What is Forensic toxicology?
Concerned with the medicolegal aspects of the harmful effects of toxic substances, environmental chemicals or poisonous products on human and animals
Determines cause of death in a post-mortem investigation
Ex: Red tide in Florida linked to dolphin deaths
What is Clinical toxicology?
Concerned with disease states caused by or associated with toxic substances
Usually involves physicians or individuals specialized in emergency medicine and/or poison management
Ex: New study linked exposure to second-hand tobacco smoke can predict cardiac arrhythmia
What is Environmental toxicology?
Concerned with the impact of physical and chemical pollutants in the environment on biological organisms
Includes the effects on human health and non-human organisms (such as fish, birds, and terrestrial animals)
Ex: Microplastics in bottled water
What is Ecotoxicology?
Specialized are within environmental toxicology that is concerned with the impacts of toxic substances on population dynamics in an ecosystem
Also evaluates the transport, fate, and interactions of toxic substances in the environment
Ex: Studying the effects of glyphosate (herbicide) on honey bees
What did Paracelsus (16th Century) determine?
specific chemicals were responsible for the toxicity of a plant or an animal poison
“All substances are poisons; there is none which is not a poison. The right dose differentiates a poison and a remedy.”
Who is Orfila (19th Century) and what did he demonstrate?
Spanish physician considered the founder of toxicology
Demonstrated the effects of poisons on specific organs by analyzing autopsy materials for poisons and tissue damage associated with them
What is a toxin?
Peptides or proteins produced by living cells or organisms (i.e., natural toxins)
What is a toxicant?
Substances that are synthetic (man-made
What is a poison?
Any synthetic or natural substance that is harmful to health
Define Xenobiotic
Foreign substance taken into the body
May produce beneficial effects (i.e. pharmaceuticals) or produce toxic effects (i.e., heavy metals)
What is a toxic agent?
Anything that can produce an adverse biological effect
Can be chemical (cyanide), physical (radiation), or biological (snake venom)
What is a toxic substance?
Any material that has toxic properties
Can be a discrete toxic chemical (lead) or a mixture of chemicals (gasoline)
9 ways that toxins are classified
- Toxicity (extremely - slightly)
- Median Lethal Dose (LD50)
- Physical state (gas, solid, liquid)
- chemical composition
- intended use (pesticide, solvent, etc)
- source (natural/synthetic)
- mechanism of action
target organ - Special effect (carcinogen, mutagen, endocrine disruptor)
What is toxicity?
Toxicity can be ________, __________, or ________
The degree to which a substance can harm humans or animals
Toxicity can be acute, subchronic or chronic
Toxicity can result from adverse… (3) changes
- Cellular changes
- ex: cell death (cytotoxins)
- Biochemical changes
- ex: elevated liver enzymes (hepatotoxins)
- Macromolecular changes
- ex: altered insulin signalling (diabetogens)
What is Acute Toxicity (4 points)
- Adverse effects occurring in an organism after a single exposure or short-term exposure (< 24 hours)
- Exposure to a large dose (weak toxin) or a small dose (potent toxin)
- Onset of symptoms is sudden and severe in nature
- Rapidly changing course of progress
What is Subchronic Toxicity? (2 points)
- Due to repeated exposure for several weeks or months
- The ability of a toxic substance to cause adverse effects for more than one year but less than the lifetime of the exposed organism
What is Chronic Toxicity? (3 points)
- The ability of a toxic substance to cause adverse effects over an extended period, usually upon repeated or continuous exposure, sometimes lasting for the entire life of the exposed organism
- Cumulative damage
- Damage becomes so severe that the organ can no longer function as normal
Two types of toxic responses: Exposure Effect
Local
- Effect at site of contact
- Ex: gastrointestinal tract, lungs
Systemic
- Effect distant from exposure site
- Ex: central nervous system, kidneys
Some both
2 Types of Toxic Responses: Target
Specific
- Affect only specific target organs
Widespread
- Can damage any cell or tissues that they come in contact with
Sometimes both
- Target organ may be affected after acute exposure whereas multiple organs affect after chronic exposure
- May depend on dosage and route of exposure
2 Types of Toxic Responses: Timing
Immediate
- Minutes to hours after a single exposure
- Ex: azaspiracids
Delayed
- Days to years after exposure
- Ex: BMAA (potentially linked to neurodegenerative diseases)
Some both
2 Types of Toxic Responses: Permanence
- 3 factors that influence permanence
Reversible
- Rapidly regenerating tissue
- Ex: liver, intestinal mucosa, blood cells
Irreversible
- CNS damage, carcinogenesis, mutagenesis, teratogenesis
Factors that influence if reversible or irreversible include:
- Tissue involved
- Length of exposure
- Magnitude of toxic insult
2 Types of Toxic Responses: Effect
Direct
- Substances or their metabolites themselves are toxic
Ex: phthalates (DEHP)
Indirect
- Some substances may be toxic by indirectly modifying an essential biochemical function, interfering with nutrition, or altering a physiological mechanism
Three Phases of Toxicology
Exposure phase
- How an organism comes in contact with a toxin
Toxicokinetic phase
- The study of the movement of the toxin within the body
- Absorption, distribution, metabolism, and excretion (ADME)
Toxicodynamic phase
- The study of what the toxin does to the body
- Physiological, biochemical, and/or molecular changes
Exposure Phase of Toxicology: 3 factors
- Sources (everyday items have hundreds of chemicals)
- Route (oral, dermal, inhalation, injection)
- Duration
Exposure Phase of Toxicology: Duration of exposure can be … (4)
Acute (< 24 hours)
Subacute (< 1 month)
Subchronic (1-3 months)
Chronic (> 3 months)
Exposure Phase of Toxicology:
An individuals exposure to a substance can be assessed based on the relationship between a person’s body weight and… (3)
- Concentration of the substance
- Amount of a substance taken into the body
- Duration and frequency of exposure
Exposure VS Dose
Exposure (outside)
- Any condition which provides an opportunity for an external environmental substance to enter the body
Dose (inside)
- The amount of an substance actually deposited within the body
- Dose can affected by route, duration, frequency, amount, concentration as well as body weight, sex, age, time etc.
What is an administered dose?
The quantity administered to an organism at one time
The entire dose may not necessarily be absorbed
What is an Internal/absorbed dose?
The amount of a toxin that stays in an organism’s body
What is a total dose?
Sum of all individuals doses
Total dose = Concentration X Amount X Frequency X Duration
What is a response/endpoint to a dose?
The biological response to a substance
Change in structure or function, morbidity, or mortality
Dose-response curve: Point at which toxicity first appears in known as the…
threshold dose level
What does NOAEL stand for
No Observed Adverse Effect Level (NOAEL)
Highest doses at which no toxic effects observed No
What does LOAEL stand for
Lowest Observed Adverse Effect Level (LOAEL)
Lowest dose at which toxic or adverse effects observed
What is Toxicokinetics
The study of the movement of the toxin within the body
Absorption, distribution, metabolism, and excretion (ADME)
Absorption: What is Passive Transfer
Consists of simple diffusion
No cellular energy or assistance is required
Most common way that toxins cross cell membranes
Two factors that determine the rate of passive transfer
Concentration gradient (high to low)
Movement through small pores in membrane or lipophilic interior of the membrane
3 Properties affecting a chemicals substance for passive transfer include:
Lipid solubility
Molecular size
Degree of ionization (positive/negative charge)
Absorption: What is Facilitated Diffusion
- Similar to simple diffusion: does not require energy and follows concentration gradient
- Requires special transport proteins embedded within the cell membrane to facilitate movement of molecules across the membrane
- Is faster and can move larger molecules than passive transport
Absorption: What is Active Transport
- Requires cellular energy (ATP)
- move through ion channels
Absorption: What is Endocytosis
Cell surrounds the substance within a section of its cell wall
What is distribution?
- _______, ________, and _______ can distribute chemicals.
Distribution is the process in which an absorbed chemical moves away from the site of absorption to other areas of the body
Blood, lymph, and CSF can distribute chemicals
4 storage sites for chemicals in the body
adipose tissue
liver
kidney
bone
Distribution: 3 Barriers that stop chemicals
Blood-Brain Barrier (BBB)
Blood-CSF Barrier
Placental Barrier
What is metabolism
Also known as biotransformation
Conversion of a chemical from one form to another by a biological organism
Two phases of metabolism:
Phase I reactions
- modify the chemical by adding a functional structure
Phase II reactions
- conjugate the modified substance with another substance
Phase I Metabolism
Detoxification
- Chemical substance is converted to a less toxic form
- Generally speaking lipid-soluble compounds are converted to polar compounds
Phase II Metabolism
Bioactivation
- Chemical substance is converted to more reactive or toxic forms
Excretion: where does it occur
Kidney is primary excretory organ
- Other sites of excretion include the GI tract, lungs, sweat, tears, and breast milk
What is toxicodynamics
The study of what the toxin does to the body
- Physiological, biochemical, behavioural, and/or molecular changes
- Toxic chemical effects critical target, causes modification to target, causes overt biological response or effect
Factors Influencing Toxicity: Factors Related to the Substance (5)
- Form of a substance (chemical makeup)
- Innate chemical activity of a substance
- Dosage
- Exposure Route
- Level of absorption
Factors Influencing Toxicity: Factors Related to the Organism (7)
- Species
- Life stage
- sex
- Metabolism
- Distribution within the body
- Health and Nutritional status
- Circadian rhythms
Factors Influencing Toxicity: Other Factors (1)
- interactions with other present chemicals
-
Factors Influencing Toxicity: The combined effects of two or more chemicals can be… (4)
- additive
- synergistic (may occur due to both chemicals using similar metabolism pathways or one of the chemicals can inhibit the metabolism pathway of the other)
- Potentiation Effects ( Occurs when one chemical that does not normally have a toxic effect is added to another chemical, making the second chemical more toxic)
- Antagonistic effects (Effects of two or more chemicals interfere with each other’s action)
Factors Influencing Toxicity: 4 types of antagonism
Physiological antagonism
- Severe drop in blood pressure due to a barbiturate overdose reversed by administration of vasopressor
Chemical antagonism
- Mercury toxicity can be reduced by chelating the mercury ions with dimercaprol
Dispositional antagonism
- Swallowed poison is absorbed by introducing charcoal into the stomach reducing duration of chemical at target organ
Receptor antagonism
- Carbon monoxide poisoning is treated with oxygen to displace the carbon monoxide from the hemoglobin receptors
What is a hazard VS a risk?
Hazard
- The potential of a substance to cause damage
- i.e., the inherent toxicity of a substance
Risk
- A measure of the probability that harm will occur under defined conditions of exposure to a substance
Substances which pose only a small hazard but there is frequent or excessive exposure may pose as much risk as substances which have a high degree of hazard but only limited exposure
What is a monotonic dose-response curve?
The higher the dose, the greater the response (effect)
“S” shaped curves
linear
What is a non-monotonic dose-response curve?
- The shape of the dose response curve reverses as the dose increases
- “U” or “J” shaped curves with high responses at low and high doses
- Inverted “U” shaped curves with high responses at the intermediate doses
- when the dose is high enough, the response stops increasing and starts to decrease
Why do we get non-monotonic responses:
What is Hormesis?
- Biphasic response to increasing amounts of a substance
- Low doses show beneficial effects whereas high doses show detrimental effects
Why do we get non-monotonic responses: what is the low-dose hypothesis
Responses that may occur at doses well below those levels previously tested and determined to be safe
Why do we get non-monotonic responses: Toxins can also be _____________ _____________
Need small amounts of these substances to maintain good health
High doses of these substances can be toxic
What is neurotoxicity?
The capacity of chemical, biological, or physical agents to cause adverse functional or structural changes in the nervous system at any time in the life cycle
functional changes: Neurochemical, neurophysiological, or behavioural changes
structural changes: Neuroanatomical changes (macroscopic and microscopic)
What are adverse neurotoxic effects?
- Persistent structural changes or persistent functional changes in behavioural, neurochemistry, neurophysiology
- Reversible effects occurring at doses that could endanger performance in the workplace
- Reversible effects occurring at doses that are associated with a known neurotoxicological mechanism of action
Neurotoxic Effects may have…. (2)
both structural and functional effects
localized or far-reaching effects
Manifestations of neurotoxicity can be: (3)
immediate
progressive
delayed
What is the Blood Brain Barrier (BBB)
- Physical barrier between the lumen of the cerebral blood vessels and the brain parenchyma
- Specialized microvascular endothelial cells form luminal tight junctions which occlude or severely attenuate movement through the intercellular spaces
- Outside of the endothelial cells is a basement membrane which is surrounded by pericytes
- Around these structures are the astrocytic endfeet from nearby astrocytes
Blood-Brain Barrier: what are endothelial cells? ECs
- Form the walls of blood vessels
- The diameter of large arteries and veins can be made up of dozens of ECs
Blood-Brain Barrier: Specifications of CNS endothelial cells
- extremely _______
- held together by tight _____________
- lack ___________ (pores)
- express extremely low levels of ______________ ____________ molecules
- undergo extremely low rates of ________________
- higher amounts of ________________
- differential ___________ ______________ altering the physical properties of molecules
thin junctions fenestrae leukocyte adhesion transcytosis mitochondria vascular metabolism
Blood-Brain Barrier: What is the basement membrane?
- Attach layers of tissue in the body (connecting ECs to neural tissue)
- Provide an anchor for many signalling processes at the vasculature
- Provide an additional barrier for molecules to cross before reaching neural tissue
Blood-Brain Barrier: What are pericytes?
- Embedded in the BM and do not touch the endothelium
- Are contractile proteins, and have the ability to contract to control the diameter of the capillary
BBB: Pericytes have an important role in… (5)
- Regulating angiogenesis,
- Wound healing,
- Regulating immune cell infiltration,
- Regulation of blood flow in response to neural activity
- Regulating the formation of the BBB during development
BBB: CNS Pericyte specifications (2)
- derived from the neural crest rather than the mesoderm
- CNS microvasculatures have the highest CNS PCs coverage of any tissue
Blood-Brain Barrier: what are Astrocytes
Astrocytes provide a cellular link between neuronal circuitry and blood vessels
- This allows astrocytes to relay signals that regulate blood flow in response to neuronal activity
- Includes contraction and dilation of vascular smooth muscle cells as well as PCs
The endfeet of the basal process of astrocytes almost completely surrounds the vascular tube
Blood-Brain Barrier: Tight Junctions, importance
- CNS ECs are held together by tight junctions
- This creates a highly resistant paracellular barrier to molecules and ions
- Have a size elective permeability to uncharged molecules up to 4 nanometers (nm)
Two main categories of transporters in CNS endothelial cells
Efflux Transporters
- Transport a wide variety of small lipophilic molecules into the blood that could otherwise passively diffuse across the EC membrane to the CNS
Nutrient Transporters
- Transport specific nutrients across the BBB into the CNS
- Facilitates the removal of specific waste products from the CNS into the blood
Development of BBB
- begins with __________________
- endothelial ______________ cells innervate the embryonic __________________
- neural ____________ cells secrete factors that guide sprouting ______________ cells
- Innervation of ______________ cells by ____________ and ____________
- ____________ of interendothelial ________ ______________ by ____________
angiogenesis
progenitor. .. neuroectoderm
progenitor. .. endothelial
endothelial. .. astrocytes… pericytes
sealing. .. tight junctions… astrocytes
In humans, the BBB is fully established prenatally at approximately ___________ weeks of gestation
23-32
What is the Blood-CSF Barrier
A barrier between the blood and the cerebrospinal fluid (CSF) along the lateral, third, and fourth ventricles
CSF-Brain Barrier in embryos/ development (2)
Gap differences in fetuses/adults (2)
- Only significant barrier in the embryo
- Created by the separation of the ventricular system from the extracellular fluid of the brain
- In embryos and fetuses, strap junctions (tight, nothing can get through) between neuroependymal cells
- In adults, gap junctions (free exchange) between ependymal cells
What is the Meningeal Barrier
Blood-brain interface over the outer surface of the brain within the pia-arachnoid
- Arachnoid membrane and blood vessels in the arachnoid and pial surface have tight junctions
Junctions in the meningeal barrier in adults vs fetuses
In adults, cells lining these regions are linked by gap junctions
In early brain development, cells lining these regions are linked by strap junctions
Neurotoxic agents can be classified by (3)
cellular target sites, neuropathological effects, or mode of action
7 types of Neurotoxic agents
- neuronopathies
- axonopathies
- myelinopathies
- Neurotransmission-associated anomalies
- Toxins affecting astrocytes and vascular integrity
- developmental neurotoxins
- neurocarcinogens
NEUROTOXIC AGENTS: What are Neuronopathies (3)
- The neuron cell body is the target site for toxic agents
- Irreversible loss
- Damage to the neuron progresses through various stages resulting in apoptosis or necrosis which can lead to axonal and dendritic degeneration
NEUROTOXIC AGENTS: What are axonopathies (5)
- The axon is the target site for toxic agents
- The disruption of axonal transport appears to be the toxic mechanisms for most axonotoxic chemicals
- Damage to the axon will result in secondary myelin degeneration, but the neuron cell body will remain intact
- Irreversible in the CNS
- Longer axons as affected first
NEUROTOXIC AGENTS: What are myelinopathies (3)
- Myelin is the primary target of the toxic agent
- Exposure to the toxin may lead to direct myelin damage or by damage to myelin-producing cells
- Remyelination in the CNS may occur to a very limited extent
NEUROTOXIC AGENTS: What are Neurotransmission-associated anomalies (1)
Different aspects of neurotransmission that may be affected (4)
- Primary target of toxic agent is neurotransmission
- Different aspects of neurotransmission may be affected depending on the toxic agent:
1. Interruption of impulse transmission
2. Blockage of transsynaptic communication
3. Inhibition of neurotransmitter uptake
4. Interference with second-messenger systems
NEUROTOXIC AGENTS: What are Toxins affecting astrocytes and vascular integrity (3)
- Toxins which disrupt vascular permeability
- Can lead to increase permeability of the BBB, neuronal cell death, and edema
- Recent evidence suggests that astrocytes may be the primary target at the BBB
NEUROTOXIC AGENTS: What are Developmental Neurotoxins (4)
- Toxic agents that produce functional deficits at…
1. Doses at which other indications of developmental neurotoxicity are evidence and
2. Doses with minimal toxicity to adults - Some effects may be transient or reversible while others may be permanent
NEUROTOXIC AGENTS: What are neurocarcinogens (2)
- Toxic agents that induce cancer by either genotoxic (mutagenic) or nongenotoxic mechanisms
- Granular cell tumors and malignant reticuloses originating from the cerebral or cerebellar meninges have been linked with chemical exposure
Factors that make the nervous system especially vulnerable to toxins and toxicants:
- Complexity of ____________ and _____________ Integration
- Limitations on ________
- Accessibility to _______-________ toxins/toxicants
- Dependence on __________
- ________ transport
- ___________ transmission
- ______ Channels
Structural... functional repair lipid-soluble glucose Axonal Synaptic Ion
3 Types of Axonal transport
Fast anterograde (forward) Slow anterograde (forward) Fast retrograde (backwards)
Types of disruptions to synaptic transmission:
- Increase the ________ of effects of ___________________, which can lead to _______________
- Mimic the _______ of a ________________ by interaction with its ___________ __________
- ________ a neurotransmitter’s __________ to it’s ____________ __________
- Interfere with the ____________ of a _________________ or prevent the _________ of a neurotransmitter from an _________
- Can be _____________ by neuronal ___________ and produce ___________ _____________
length… neurotransmitter… overstimulation
action… neurotransmitter,,, receptor molecule
Block… access… receptor module
synthesis… neurotransmitter… release… axon
metabolized… enzymes… damaging metabolites
How are ion channels vulnerable to toxic insults?
Substances that inhibit metabolic enzymes may cause sodium to accumulate and potassium to be lost resulting in membrane depolarization and then the loss of excitability
How is the Accessibility of lipid-soluble toxins dangerous for the CNS?
Many classes of toxins and toxicants dissolve readily in lipids
Can accumulate and reach high local concentrations
Are relatively protected from enzyme degradation and do not enter general circulation
How is the CNS vulnerable to toxins due to it’s dependence on glucose?
Toxins that inhibit enzymes that metabolize glucose are particularly damaging
How does axonal transport make the CNS vulnerable to toxins?
Intracellular transport down the axon is highly vulnerable to interruption by toxic chemicals
Functional integrity of the neuronal cell body often depends on a reciprocal supply of trophic factors from cells that it innervates
Exposure of the infant in utero to toxins can occur through….
- Placental transfer
- Lactation (via breast milk)
Differences in toxicokinetics (TKs) between developing and developed organisms
- Developing organisms may not have the systems in place to metabolize or excrete certain substances
- May be differences in metabolizing enzyme, rates of excretion, binding affinity to target proteins
Two approaches to disease prevention
- Primary prevention: Identifying potential neurotoxic hazards before humans are exposed
- Secondary prevention : Early detection of a disease or dysfunction in exposed persons or populations followed by prevention of additional exposure
Tests of Nervous System Function: Behaviour
3 Pros
1 Con
PROS: 1. Behaviour is through to be a relatively sensitive indicator of exposure
- Behavioural endpoints tend to be non-invasive and can be used to repeated assess participants/animals
- Common behavioural endpoints include, acoustic startle, motor activity, learning and memory
CON: 1. Behavioural tests often lack specificity for the nervous system
Tests of Nervous System Function: Neurochemistry
1 Pro
1 Con
PRO: Neurochemical endpoints are particularly useful in understanding neurotoxic mechanisms of action
CON: Neurochemical changes are not necessarily indicative of a neurotoxic effects, unless they induce neurophysiological, neuropathological, and/or neurobehavioural effects
Tests of Nervous System Function: Morphology
2 Pros
2 Cons
PROS: 1. Neuroanatomical changes resulting from exposure to toxic substances are always regarded as adverse
2. Most structural changes tend to be detectable only at the light microscopic levels
CONS: 1. Sometimes need to know what you are looking for in order to find it
2. Hard to determine if there are compensatory mechanism in place to adapt to potential CNS damage
Tests of Nervous System Function: Neurophysiology
1 Pro
2 Cons
PRO: Can produce reliable indicators of the functional status of affected portions of neuronal networks
CONS: 1. Are usually post hoc studies
2. Results sometimes reflect varied and often unknown exposures
Tests of Nervous System Function: In Vitro Systems
2 Pros
2 Cons
PROS: 1. In vitro models can be less complicated
2. Information can be easily collected and quantified
CONS: 1. Generalizability of in vitro models can be limited
2. CNS complexity can complicate the interpretation of in vivo studies
5 Different tests of Nervous System Function
Behaviour Neurochemistry Morphology Neurophysiology In Vitro Systems
How Did MPTP Lead to Parkinsonogenic Effects? (“The Frozen Addicts”)
WHAT IS THE METABOLIC PROCESS
MPTP itself is not toxic!
- MPTP is lipophilic and can easily pass into the brain
- Once in the brain, it is converted from MPTP into MPDP+ by monoamine oxidase B and then converted into active toxic compound MPP+
- MPP+ is then released in extracellular space by unknown mechanism
How Did MPTP Lead to Parkinsonogenic Effects? (“The Frozen Addicts”)
WHAT IS THE SYNAPTIC PROCESS
- MPP+ has a high affinity for dopamine transporters (DAT)
- MPP+ taken up via DATs into dopaminergic (DA) neurons
- Within DA neurons MPP+ inhibits enzymes in the mitochondrial electron transport chain
- Ultimately leading to cell death of the DA neuron
What can slow the progression of MPTP-Induced Parkinsonogenic Effects
Monoamine oxidase inhibitors
What is Acute Flaccid Myelitis (AFM)
- A medical condition that affects the nervous system, resulting in the weakening of muscles and reflexes
- Affects the gray matter of the spinal cord (may also be related to inflammation)
- Affects the gray matter of the spinal cord (may also be related to inflammation)
What is the cause of Acute Flaccid Myelitis (AFM)?
What is the treatment for AFM?
A singular cause of AFM remains a mystery
- Most promising hypothesis: Enterovirus
- No effective treatment to date
- Several drugs have been tried including intravenous immunoglobulins, corticosteroids, and even antidepressant, Fluoxetine. NONE were effective.
What are pesticides?
- Substances used for preventing, destroying, repelling or mitigating pets
- Designed to specifically target the undesirable -species
- Often not highly selective and can be toxic to many nontarget species
Four Classes of pesticides
Insecticides
Herbicides
Fungicides
Rodenticides
Within each class there are several subclasses of pesticides, which have substantially different chemical and toxicological characteristics
Pesticide Exposure
- 4 types of exposure
- What is occupational exposure
Exposure can occur via oral, inhalation, or dermal routes
- Dermal: 90% of all pesticide exposure
- Workers involved in production, transport, mixing, loading, and application or pesticides
- Workers involved in harvesting pesticide-sprayed crops
Toxic levels of the 4 types of pesticides
- Insecticides are the most acutely toxic
- Herbicides have low to moderate acute toxicity (exception of paraquat)
- Fungicides vary in their acute toxicity – usually low
- Rodenticides are highly toxic to rats, do not have same toxicity to humans
5 potential toxic effects of pesticides in nontarget species
- Mild irritant effects in the skin (most common)
- Disruptions in liver and lung function (Constriction of bronchial tubes, increased secretions, difficulty breathing)
- Carcinogenic
- Reproductive toxicity
- Endocrine disrupting properties (Mimic or block hormones or hormonal activity)
- Neurotoxicity
Possible effects of pesticides on the reproductivity of women
- Women using pesticides have 1.5 increased odds of longer cycles, missing a period
- May increase time to pregnancy
- Pesticide exposure may increase risk of birth defects, such as limb reductions, eye and heart defects, cleft palates, altered brain development, lower birth weight
Neurotoxic effects of pesticides
- Self-reported or clinical diagnosis of depression in female spouses of pesticide applicators
- Self-reported neurological symptoms in pesticide applicators associated with cumulative exposure to moderate levels of pesticides
EG. Headache, fatigue, insomnia, irritability, depression, numbness in hands or feet
Toxic Effects of high doses of pesticides
- Suicide attempts, accidental exposure
- Severe poisoning and death
- Approx. 3 million hospital admission per year for pesticide poisoning (WHO)
Toxic Effects of chronic low doses of pesticides
- General public
- Pesticide residues in food
- Contaminants in drinking water
All chemical insecticides in use today are…
Insecticides are not very…
neurotoxic
species-selective
Four classes of Insecticides (PCON)
- Cholinesterase inhibitors (organophosphates and carbamates)
- Pyrethroids
- Organochlorine compounds (DDT)
- Neonicotinoids
INSECTICIDES: Organophosphates (OPs)
- Compounds with a ______ moiety (_______ bound chemical structure) are _______________ active
- Most commonly used OPs contain a _________ bound to the _________________ atom
- Need to _____________ activated to exert _______________ effects
- ________________ is mediated by enzymes in the _______________ _______ family
P=O… double… toxicologically
sulfur… phosphorus
metabolically… toxicological
Bioactivation… cytochrome P450
INSECTICIDES: Organophosphates (OPs): Mechanism of Action
- Primary target is to ….
- Role of _______ is to….. in the _____ and _____
- If _______ is inhibited….
- Resulting in the overstimulation of…..
phosphorylate acetylcholinesterase (AChE)
AChE… inactivate acetylcholine (ACh)… CNS and PNS
AChE…. ACh starts to accumulate at cholinergic synapse
muscarinic and nicotinic cholinergic receptors
INSECTICIDES: Organophosphates (OPs): Mechanism of Action
After AChE is phosphorylated by OPs, it can be: (3)
- Hydrolyzed by water
- Hydrolysis can be facilitated by certain chemicals (oximes)
- Age (Organophosphate Aging)
INSECTICIDES: Organophosphates (OPs): Hydrolysis of AChE
- Being hydrolyzed by water causes the AChe to return to… This process is…
- Hydrolysis can be facilitated by _________. This returns AChE to it’s _________ __________ much _________. Used in the treatment of ____ __________
active form (original state)... very slow oximes... active form... faster... OP poisoning
INSECTICIDES: Organophosphates (OPs): Ageing of AChE
- AChE cannot regenerate – stays in its inactive form
- Aging occurs due to the loss of one of the two alkoxy groups
- Results in chemical stabilization of the phosphate bond to AChE over time
- This bond cannot be hydrolyzed or broken by oximes
INSECTICIDES: Organophosphates (OPs): Acute cholinergic syndrome
- How does it occur
- Where does it occur
- Symptoms (7)
- How does death occur(3)
- Lasts until AChE levels return to normal
- Receptors are localized in most organs of the body
- slurred speech, confusion, depression, lethargy, tremors, muscular twitching, paralysis, death
Death is believed to be related to respiratory failure caused by
- inhibition of respiratory centers in the brain
- bronchoconstriction, increased bronchial secretion
- Flaccid paralysis of respiratory muscles
INSECTICIDES: Organophosphates (OPs) Toxicty: Intermediate Syndrome
- when does it occur
- mecahnisms
- symptoms
- Develops a few days after the poisoning
- Person may have completely recovered from initial cholinergic crisis
- Not related to the inhibition of AChE
- Mechanisms are unknown
- Perhaps nicotinic receptor desensitization?
- Symptoms include respiratory and muscle weakness
Organophosphate-induced delayed polyneuropathy (OPIDP)
- When does it occur
- symptoms
- mechanisms
- Can occur 2 to 3 weeks after a single exposure
- Symptoms include Tingling of hands and feet Sensory loss Progressive muscle weakness and flaccidity Ataxia
- Not related to AChE inhibition
- Axonopathy: lesions to the distal part of axon
INSECTICIDES: Long-term low-dose effects of OPs have been linked to (4)
cancers, diabetes, depression, neurodegenerative diseases
INSECTICIDES: Potential Mechanisms of Long-term low-dose effects of OPs (5)
- disruption of cholinergic system
- persistent alterations in axonal transport and cytoskeletal proteins
- induced free radical generation – enhanced oxidative stress
- disruption of lipid membrane and lipid rafts
- activation of inflammatory cytokines
INSECTICIDES: Carbamates: Similarities and differences from OPs
- Mechanisms
- Symptoms
- Mechanism of toxicity is similar to OPs: Inhibit AChE
- Unlike OPs, Carbamates do not require metabolic bioactivation
- And inhibition of AChE is transient and rapidly reversible
- Symptoms of carbamate poisoning are the same as OP poisoning
- Unlike, OPs, symptoms usually resolve within a few hours
INSECTICIDES: Pyrethroids
- Developed from…
- Used for…
- human poisonings
- Is very….
- Two classes
- Derived from pyrethrins (chrysanthemum flowers)
- Widely used as agricultural and household insecticides
- Used for the topical treatment of scabies and head lice
- Considered to have low mammalian toxicity
- very lipophilic, can pass BBB
- Type I and Type II compounds
INSECTICIDES: Type I Pyrethroids
- duration of effects
- symptoms
- Mechanism of Action: Holds _____ channels open for _________
- ____________ membrane above the ___________ for action potential generation leading to __________ __________
Shorter duration of effects
Symptoms of poisoning include:
- Marked behavioural arousal
- Reflex hyperexcitability
- Increased startle response
- Sympathetic activation
- Fine body tremor progression to whole-body tremor
Na+…. <10ms
Depolarize… threshold… repetitive firing
INSECTICIDES: Type II Pyrethroids
- duration of effects
- symptoms
- Mechanism of Action: Holds _____ channels open for _________
- Cause greater membrane ______________, diminishing the ______ ________________ gradient and ____________ of subsequent action potentials
- _______________-____________ Block: Membrane becomes _____________ to a point at which the generation of an ________ ____________ is not _____________
Longer acting due to the addition of cyano group (C≡N)
Symptoms of poisoning include:
- Salivation
- Coarse tremor
- Sympathetic activation
- Seizures
- Choreoathetosis
Na+… >10ms
depolarization… Na+ electrochemical… amplitude
depolarization-dependent… depolarized… action potential… possible
INSECTICIDES: Pyrethroids: Mechanism of action
Bind to voltage dependent Na+ channels keeping them in the open confirmation and delaying inactivation
- Allows for the continuous entry of Na+
INSECTICIDES: Organochlorine Compounds (OCs)
- Acute toxicity is __________ (less than _____)
- Chronic toxicity is thought to be associated with _________ _________ _________
- EXAMPLE: ______
moderate…. OPs
adverse health effects
DDT
INSECTICIDES: DDT: Mechanism of Action
- Similar to….
- Delays the….
- Prevents the…..
- results in…
- may also inhibit the ability to…
Type I pyrethroids
closing of Na+ channels
opening of the potassium gates
repetitive firing (hyperexicitability)
transport Ca+2
INSECTICIDES: DDT: Toxicity
5 symptoms
- earliest effect is paresthesia of the mouth and face
- altered motor function leading to ataxia
- dizziness, confusion, general malaise, headache, fatigue
- tremor of the hands
- concussions
INSECTICIDES: Low doses of DDT have been shown to mimic or block certain hormones (4)
- Estrogenic effects
- Anti-androgenic effects
- Anti-progestin effects
- Anti-thyroid effects
INSECTICIDES: DDT as an Endocrine Disruptor
- effects
Endocrine disruption is not an effect, but a mechanism of toxicity
- Can have many effects including infertility, low sperm count, early puberty, brain development etc.
Hyperthyroidism VS hypothyroidism
DDT has been linked to….
Hyperthyroidism (overactive): Produce too much thyroxine (T4)
Hypothyroidism (underactive): Don’t produce enough T4
hypothyroidism
Herbicides
- What are they
- Most mechanisms of action are unique to plants, except for….
- 3 plant processes inhibited by herbicides
Chemicals that are toxic to plants paraquat - Photosynthesis - Amino acids and proteins - Growth regulation
HERBICIDES: Glyphosate
- primary ingredient in
- Inhibits plant enzyme… which is important for the synthesis of…
- Humans do not have….
Roundup
EPSP synthase
aromatic amino acids
EPSP enzymes
HERBICIDES: Glyphosate: Neurotoxicity
- Exposure leads to degeneration of….
- Linked to increased __________ in…
- Decreased…. and increased… in rat hippocampal slices
- Decreased levels of… (3) in rat hippocampal slices
- interferes with…. causing increased….
- Associated with __________________ and _______________
GABA and dopamine neurons in C. elegans
apoptosis… human umbilical, embryonic, and placental cells
Decreased glutamate uptake and increased glutamate release
glutamine synthetase, aspartate aminotransferase (AST), and alanine amino aminotransferase (ALT)
glutamate metabolism … glutamate in synapse (excitotoxicity)
oxidative stress and neuroinflammation
HERBICIDES: Paraquat
- acute toxicity
- exposure methods
- lethal dose
- accumulates where in the body
- Has one of the highest acute toxicity among herbicides
- Very toxic when ingested
- Skin absorption is poor
- Inhalation is a possible route of exposure
- Lethal dose is 1-4 grams
- accumulates in lung and secondarily in the kidney
HERBICIDES: Paraquat
- Paraquat is __________ charged and _______ soluble
- Argued that it cannot easily pass the…
- _________ _______ ______ transporters (LAT-1) may transport paraquat into the brain
- undergoes _______ __________ to form superoxide _______ _________
Positively… water
BBB
Neutral amino acid transporters (LAT-1)
redox cycling… free radical
HERBICIDES: Paraquat
- Exposure to paraquat has been linked to the etiology of…
- Major target of paraquat in the CNS :
- Exposure to paraquat can also induce…
- Hypothesized that… reduce….
- results in accumulation of _________ in the _________
- In _________, __________ is metabolized by __________________ which generates _____________________
- May trigger….
Parkinson’s disease
dopaminergic neurons (susceptibility of DA neurons to oxidative damage)
α-synuclein aggregation (Lewy bodies) inside neurons
α-synuclein Lewy bodies reduce vesicle number in dopamine neurons
dopamine… cytoplasm
cytosol… dopamine… monoamine oxidase… reactive oxygen speciesoxidative stress and the initiation of the apoptotic cascade
What are heavy metals
- naturally occurring elements found throughout the Earth’s crust
- Sometimes referred to as “trace elements”
- Have a high atomic weight
Some metals may also be essential nutrients including: (5)
Essential heavy metals required for…
Copper, Iron, Manganese, Selenium, Zinc
biochemical and physiological functions in plants and animals
Most exposure to heavy metals is due to anthropogenic activities, such as… (3)
- Mining and smelting operations
- Industrial production and use
- Domestic and agricultural use of metal and metal-containing compounds
Heavy Metals: Environmental contamination can also occur through (5)
- Metal corrosion
- Atmospheric deposition
- Soil erosion of metal ions and leaching of heavy metals
- Sediment re-suspension
- Metal evaporation from water resources to soil & ground water
- Natural phenomena (volcanic eruptions)
Lead (Pb) has been found in three forms
- metallic lead
- inorganic lead and lead compounds (lead salts)
- organic lead
unique properties of lead (Pb) (5)
- high resistance to corrosion
- softness
- low melting point
- high density
- relative low conductivity
Lead is extremely persistent in …
both water and soil
Exposure to lead may occur from many sources such as… (7)
- food or beverages stores, cooked or served in lead-containing containers
- food grown in contaminated soils
- cosmetics
- traditional remedies
- smoking
- air pollution
- contaminated water
Define body burden
the total amount of a particular chemical present in a human’s or animal’s body, typically a radioactive element or other toxic substance.
Most common source of lead exposure in children
Paint chips and leaded dust and soils released from ageing painted surfaces or during renovation
Average amount of lead exposure per day in USA
USA exposure ranged from 2 to 9 μg/day for various age groups
Approx. 4 μg/day for children 2 years or younger
Biological Markers of Exposure to lead: BONE
Exposure to lead over time results in the progressive accumulation in bone
Greater than 95% of total lead body burden
Great indicator of lifetime exposure to lead
Biological Markers of Exposure to lead: BLOOD/PLASMA
- Intervention level in blood is 10 μg/dL in US
- Reflect both recent and past exposures
- 90% or more of blood lead consists of mobilized bone-lead in exposed children
Biological Markers of Exposure to lead: 4 reliable measures
- Bone
- Blood/plasma
- teeth
- urine
Biological Markers of Exposure to lead: TEETH
Suitable for children only (baby teeth)
Biological Markers of Exposure to lead: URINE
Has been used to monitor relative levels of exposure in workers with chronic occupational exposure
Biological Markers of Exposure to lead: 4 Ineffective measures
- nails
- hair
- saliva
- placenta (not evenly distributed)
Main target of lead toxicity is
the CNS
8 Early symptoms of lead poisoning
lethargy, abdominal cramps, irritability, headache, encephalopathy, hallucinations, memory loss
Over a period of days to weeks, symptoms of lead poisoning progresses to… (6)
vomiting, clumsiness, ataxia, coma, seizures, death
Lifetime blood lead exposure < 5μg/dL may produce…
learning deficits greater than higher exposures
Greater number of children are being exposed to greater levels of lead in … countries
developing and industrialized nations
- Latin American, Russia, China
Developmental Effects of Lead (Bellinger et al., 1987)
- Infants in the high ______________ group scored __________ than infants in the medium and low groups
- Blood lead and measures of _______________ are __________ related
in utero… lower
intelligence… inversely
Developmental Effects of Lead (Rosen et al., 1992)
- Evidence of direct link between low-level lead exposure during early development and…
- ______ _____ point reduction associated with an _________ in blood lead levels from 2.4 to 30 μg/dL
- Impact of increase in blood lead levels on ______________ __________ was greater for children with ________ blood lead levels
deficits in intellectual impairment late in childhood
6.9 IQ… increase
intellectual functioning… lower
Developmental Effects of Lead (Wright et al., 2008)
Increased blood lead levels before birth and during early childhood associated with …
- Increased _____________ associated with blood lead levels of 15 μg/dL in children aged 4 to 5
- higher rates of arrest for any reason
- higher rates of arrest for violent crimes
aggression
Lead and Socioeconomic Status (Brody et al., 1994)
- _______________ and _______________ is associated with blood lead levels
- Could be related to increased likelihood of living in ______________ or ____________________
Location of home and family income
older homes… unmaintained homes
Lead and Socioeconomic Status
- Could be related to poor nutrition (3)
- Deficiencies in calcium, iron, and zinc are risk factors
- Calcium and iron deficiency increased retention of lead and severity of its toxic effects
- Zinc deficiency increases lead absorption which in turn increase zinc excretion (vicious cycle)
Lead and Environmental Enrichment
- Environmental enrichment can reverse the learning deficits resulting from developmental lead exposure
Lead Exposure and Attention Deficit Hyperactivity Disorder (ADHD)
- Blood lead levels of < 10 μg/dL and even < 5 μg/dL have been linked to ADHD
- Increased odds ratio of 2.52 of having ADHD with every log unit increase in blood lead levels
Lead Exposure and Alzheimer’s Disease (AD)
- Associated with overexpression of __________________ (APP) and aggregation of _________________
- Increased ________________, senile __________ deposition, and upregulates
__________
- enhances expression of AD-associated _________ _____, alters ____________ markers of AD, and __________ ________________ in mice
amyloid precursor protein… amyloid beta plaques
amyloidogenesis… plaque… APP proteins
protein tau… epigenetic… cognitive impairment
Lead Exposure and Schizophrenia
Chronic exposure of mDISC1 mice to Pb2+ (1500 ppb) produced phenotypes relevant to schizophrenia:
- _____________
- Mildly ___________ __________ inhibition (PPI) of the acousitc startle
- Enlarged _______ __________
hyperactivity
impaired prepulse
lateral ventricles
Lead Toxicokinetics
- _____________ exposure to lead is a more efficient route of absorption than ingestion
- Absorption from the ____________ is mediated by passive and facilitated diffusion
Inhalation
intestine
Lead Toxicokinetics:
- Calcium binding protein “calbindin”
can bind to both calcium and lead
Lead Toxicokinetics:
- Divalent metal transporter 1 (DMT1)
- overexpression of DMT1 increased lead absorption
- knockdown of DMT1 does not abolish lead transfer
Lead Toxicokinetics:
- Once in the ____________, lead most likely crosses the _____ through __________ ___________
- Lead can accumulate in _____________ _______ of the _____ and ____________ cells of the blood-CSF barrier causing them to become _______
- Lead exposure can decrease the _______ and protein levels of _________
- ________ are ______________ proteins that form the backbone of the tight junctions at the _____
bloodstream… BBB… passive diffusion
endothelial cells… BBB… epithelial… leaky
mRNA… claudin-1
claudins… transmembranal… BBB
Lead Toxicokinetics
- Lead may also be transferred across the _____ by _________ transporters like _______
- Brain efflux may also be mediate via _____-dependent _________ _______
- Lead can substitute for _________ _____ and _______ the _____
BBB… cation… DMT1
ATP… calcium pumps
calcium ions… cross… BBB
Brain Calcification
- Related to increased calcium in the ________ or _______________ or __________ to the brain
- Significant correlation between calcification in the brain and _________ ________ lead levels
- Associated with _________, loss of ________ _______, __________ episodes
blood… inflammation… damage
raised blood
dementia… visual acuity… psychotic
Modifying Factors of Lead Exposure
- Children deficient in ________ and ______ are more likely to have _____________ blood lead levels
- ______ deficient diets increase the levels of ______ _______, which increases the levels of _______ proteins
calcium… iron… elevated
Iron… DMT1 mRNA… DMT1
Absorption of lead can be regulated through…
______ is regulated at the…..
the DMT1
DMT1 … the mRNA level by iron
- Lead reduces cell proliferation in the…
- Lead reduces cell survival in the…
- Lead reduces the _________ and _________ of DCX-labelled fibres in the _______ ____________ ________ (OML) of the dorsal dentate gyrus (DG)
- Lead alters ______ _____________ of DCX-positive neurons in the ______ DG
- In lead exposed rats, ________ cells frequently had
___________ ____________of apical dendrites
hippocampus dentate gyrus (DG) dorsal dentate gyrus (DG) length... density... outer molecular layer cell morphology... dorsal granule... irregular orientation
Effects of Lead at Cellular Level
- Overall, chronic lead exposure in early life alters _________ cell ________________ and _____________ in the ______________ of young adult rats
- These effects are likely to alter __________ _________ in the ________________ with detrimental effects on __________ ___________ and ____________
granule.. neurogenesis… morphology… hippocampus
neuronal circuitry… hippocampus… synaptic plasticity… learning
Mechanisms of Lead Toxicity
The main reason lead is so toxicity is due to its ability to substitute for…
diverse polyvalent cations, including calcium, zinc, and magnesium at their binding sites
Calcium, zinc, magnesium have 3 diverse functions within the body
- Are used in many proteins as structural components
- Signalling networks are based on the association and dissociation of these cations from the proteins which they bind
- Catalytic roles
One of the most important targets of lead in the nervous system are
voltage-gated calcium channels
- NMDA receptor
Mechanisms of Lead Toxicity: Role of Calcium
- The higher affinity of lead for the 4 __________ (EEEE) locus on VGCCs causes
- Lead to displace __________ from the locus,
- Lead to slowly flow through the _______ acting as a _________ blocker
- The peak ____________ of ______-induced currents are preferentially __________ by lead
glutamate
calcium
pore… channel
amplitude… NMDA… inhibited
Mechanisms of Lead Toxicity: Role of Calcium
- ______ expression is a key __________ dependent pathway
- Exposure to lead can reduce _______ ____________ and ________ levels
- _______ _______________ can fully _________ the effects of lead exposure on _____________ function and _________ expression
BDNF… calcium
BDNF… transcripts… protein
BDNF transcripts… protein
BDNF supplementation… mitigate… presynaptic
Mechanisms of Lead Toxicity: Role of Calcium
- ____________________ (PKC) is another calcium dependent pathway
- Lead can ___________ for calcium and can result in the activation of _____
- Impaired _____ function can compromise __________ ______________ systems within the cells
- May lead to altered _______ expression and _________ synthesis
Protein Kinase C
substitute… PKC
PKC… second messenger
Gene… protein
Mechanisms
of Lead Toxicity: Oxidative Stress
- Lead can accumulate in ________________, which regulate _______________ calcium concentrations
- Increased ________ into ______________ can increase the production of __________ ___________ _________ (ROS)
- Results in ______________ stress, ______________ and ____________
mitochondria. .. intracellular
calcium. .. mitochondria… reactive oxygen species
oxidative. .. inflammation… apoptosis
Exposure to lead in vitro and in vivo can inhibit…
Long-term Potentiation
The most toxicologically important forms of mercury is
Methylmercury (MeHg)
MeHg: Toxicokinetics
- Absordbed through….
- Bound to ______ containing molecules such as ________
- Binds to ______ and looks similar to L-methionine, mimics it to cross _____ and __________ via neutral _______ ________ systems
Well absorbed from the gastrointestinal tract
thiol. .. cysteine
cysteine. .. BBB… placenta… amino acid
Methylmercury
- MeHg is slowly metabolized to… by….
- 90% is eliminated via…
- Half-life of MeHg is….
- Accumulates in…
inorganic Hg… microflora in intestines
- feces
- 45-70 days
hair
Clinical Symptoms of ACUTE Mercury Poisoning: CNS
Tremors, convulsions
Irritability, lethargy, confusion
Decreased reflexes, nerve conduction, hearing
Clinical Symptoms of CHRONIC Mercury Poisoning: CNS
Tremors, ataxia, unsteady gait Insomnia, memory loss Shyness, depression, anorexia Headache, dysarthria, paresthesias Death
Developing organisms are more vulnerable to mercury intoxication due to 2 reasons:
- They are undergoing a period of rapid development
- They have not fully developed the capacity to breakdown and excrete MeHg
MeHg Toxicity
- MeHg readily crosses the…
- Also found in…
placenta
maternal milk
MeHg: Toxicity
- _______________ are the preferential site of MeHg accumulation
- However, _________
seem to be more susceptible to MeHg-induced toxicity
Astrocytes
neurons
MeHg: Cerebellum
Post-mortem analyses of brain tissue of human infants exposed in utero to high levels of dietary MeHg revealed … (3)
- In vivo, MeHg intoxication resulted in ___________ (or the abnormal _________ in astrocytes)
- Reductions in cerebellar white matter volume and cerebellar width
- Abnormal migration of cerebellar granulae and Purkinje cells
- Large numbers of gemistocytic astrocytes
astrocytosis… increase
MeHg: Astrocytes
- Astrocytes do what in response to neuronal damage
- MeHg prevents…
Astrocytes also swell in response to neuronal damage
Astrocytes also swell in response to neuronal damage
Behavioural outcomes related to cerebellar damage following MeHg exposure include impairments in… (4)
balance, motor coordination, fine motor movement, and locomotor activity
Mechanisms of MeHg Toxicity: Oxidative Stress
- Interaction with ______________ (GSH): Hg atom interacts with ______ group of GSH, _________ levels of GSH, making the brain susceptible to ______
- Interferes with normal ____________ of the _______________ GSH system during weanling period
- Disrupts _______________ electron __________ chain
glutathione
Thiol… reducing… ROS
maturation…. antioxidant
mitochondrial… transport
_______________ _________________ is another critical target of MeHg toxicity:
- Increases the _________ of ___________ in synaptic cleft
- Inhibits ________ _______
Glutamate dyshomeostasis
release… glutamate
glutamate uptake
Mechanisms of MeHg Toxicity
- Increased glutamate in the synapse can leads to the overactivation of NMDA glutamate receptors resulting in increased calcium influx into neurons, resulting in the calcium having 2 effects…
The influx of calcium can active important pathways involved in cell death
The calcium can be taken up by mitochondria where it can stimulate the generation of ROS
