FINAL EXAM Flashcards
Lectures 7 and on
MANGANESE (Mn)
- Naturally occuring elelment in the Earth’s crust found at low levels in ________, ______, _______, and _________
- Essential element of the human _______
- Is a _________ for enzymes like glutamine synthetase, arginase, pyruvate carboxylase, etc
- Helps to regulate __________, energy _______________, _________ function, _____________ defenses, ___________ and _______________
water, air, soil, food
diet
cofactor
development… metabolism… immune… antioxidant… reproduction… digestion
MANGANESE (Mn)
- Can exist in _____ different __________ states
- ____-____% of ingested Mn is absorbed by _________________ tract
- ________ excretion is the predominant route of excretion
11… oxidation
3-5%… gastrointestinal
biliary
Mechanisms in place to maintain Manganese Homeostasis
Mn excess = decreased absorption and increased excretion
Mn deficiency = increase absorption and decreased excretion
3 groups are at risk to excessive Manganese intake from nutritional sources
- Neonates receiving intravenous total parenteral nutrition
- Bypasses the gastrointestinal control of absorption resulting in 100% Mn retention - Patients with hepatic encephalopathy and/or liver failure
- Interferes with excretion of Mn via biliary system - Individuals with iron deficiency
- Can increase Mn body burden
- Due to the use of common transports for uptake by Mn and iron
- Iron deficiency increases the expression of these transporters
Neurotoxic Effects of Manganese:
- No _____________ for the appears of Mn-induced neurotoxic effects in humans
- Can lead to a state of poisoning known as ______________
- Irreversible ___________ condition that resembles ___________ disease
threshold
manganism
progressive… Parkinson’s
Manganism VS Parkinson’s
MANGANISM
- Targets the _____________ (GP) and to a lesser extent the ________________________ (SNc)
- Shows preferential accumulation in the ______________
- Unclear whether manganism is associated with _____________ or ____________ of dopaminergic neurons
globus pallidus… substantia nigra pars compacta
globus pallidus
dgeneration… dysfunction
Manganism VS Parkinson’s
PARKINSON’S
- Targets _________________ (SNc)
- Associated with _______________ of dopaminergic neurons in ____________________
substantia nigra pars compacta
degeneration… substantia nigra pars compacta
Neurotoxic Effects of Manganese: Manganism
- Both manganism and Parkinson’s disease associated with cognitive and emotional problems (4)
intellectual deficits
mood changes
irritability
restlessness and sleep disturbances
Neurotoxic Effects of Manganese: Manganism
- Motor symptoms are distinct between manganism and Parkinson’s, due to different _______
- Manganism: Signs of __________, ________, milder _________ at rest, “_______-like” walk
- Parkinson’s: ____________, ________, _________, ___________ instability
targets
rigidity. .. dystonia… tremors… cock
bradykinesia. .. tremors… rigidity… postural
Neurotoxic Effects of Manganese: Manganism
____________, a treatment for ___________, is NOT very effective
- Current treatments use a combo of _____________ and ____________ therapy
levodopa. .. parkinson’s
levodopa. .. chelation
Manganese Deficiency
- In animals, associated with skeletal abnormalities, such as (3)
- Enlarged joints, deformed legs with thickened and shortened long bones
- Impaired reproductive function and testicular degeneration
- Altered lipid metabolism
Manganese Transport into the brain
- 3 major routes of uptake of manganese into brain tissue
- From the bloodstream across the blood brain barrier
- From the bloodstream through the cerebral spinal fluid
- From the nasal space through the olfactory nerve via olfactory epithelium
Manganese Transport into the Brain: Blood Brain Barrier
May be transported across the blood brain barrier via (4)
- Divalent metal transporter 1 (DMT1)
- Transferrin (Tf)
- Zinc transporters (ZIP8 and ZIP14)
- Calcium Channels
Manganese Transport into the Brain: Blood Brain Barrier: Divalent metal transporter 1 (DMT1)
- Can transport the ____________ form of manganese (Mn+2)
- DMT1 also found in the _______ __________where high levels of Mn accumulation have been reported
- Expression levels may increase with ______
- Increased expression of DMT1 has been found in the _________________ (SNc) of patients with ____________ Disease
- DMT1 also present in _________ which may allow for the uptake of Mn into __________
divalent basal ganglia age Substantia Nigra compacta... Parkinson's neurons... neurons
. Mn Transport into the Brain: Blood Brain Barrier: Transferrin (Tf)
- Transports the ________ form of manganese (Mn+3)
- ________ form of manganese (Mn+2) can be transported but must be __________ to Mn+3 first
- Mn+3 binds to _________ forming a Mn+3-Tf complex
- Transferrin ____________ (TfRs) are expressed in most cells including ________, _________, ____________, and _______________ cells of the blood brain barrier (BBB)
- The Mn+3-Tf complex binds to Tf __________ and enters _____________ cells of the BBB via ______________
- Within _____________cell, Mn+3 disassociates from Tf via ___________ ______________ and is released into the extracellular environment within the brain
- TfRs also found on _________ – may facilitate transport of Mn into neurons
trivalent divalent... oxidized transferrin receptors... neurons... microglia... astrocytes... endothelial receptor... endothelial... endocytosis endothelial... endosomal acidification neurons
Mn Transport into the Brain: Blood Brain Barrier: Zinc Transporters
- Role in Mn transport has been proposed based on __________ models
- No _______________ evidence has been established
- May be more relevant to ___________ route of exposure
in vitro
physiological
inhalation
Mn Transport into the Brain: Blood Brain Barrier: Calcium Channels
- Evidence that _________ ____________ calcium __________ can transport Mn into the brain
- Mechanism similar to that of _______
- Evidence that Mn can cross cell ____________ (including endothelial cells of the BBB) through ________-_____________ calcium channels
voltage gated… channels
lead
membranes… store-operated
Manganese Transport into the Brain: Blood-CSF Barrier
- Evidence that Mn can be transported via the blood-CSF barrier to the brain
- Examples
- Exception
- Hypothesis about exception
Brain regions that demonstrate higher uptake of Mn are adjacent to the ventricles
- EG: hippocampus, visual cortex, striatum
- EXCEPTION: globus pallidus
- Hypothesized that Mn is transported from striatum to globus pallidus
Manganese Transport into the Brain: Olfactory Pathway
3 major pathways facilitate movement of a xenobiotic from nose to brain:
1. Olfactory _________ pathway
- Transport within the _____________________
2. Olfactory ___________ pathway
- Transport along _______________ space around the __________________
- These TWO pathways provides a _____ connection to the CNS that bypasses the ______________________
- _______ _________ __________ pathway
- ________ membrane lining the _______ cavity: high vascularized
- Olfactory nerve pathway
- Transport within the olfactory nerve - Olfactory epithelial pathway
- Transport along perineuronal space around the olfactory nerve
direct. .. blood brain barrier
Nasal mucosa epithelium
Manganese Accumulation: Brain Regions
- Mn preferentially accumulations in brain regions high in ____________, such as the _________________
- Can also be found in regions that don’t have ___________, such as: (3)
- Likely related to the presence of various ___________ __________ in these regions
neuromelanin… basal ganglia
neuromelanin…. striatum, hippocampus, cerebral cortex
transporter proteins
Manganese Accumulation
What is Neuromelanin
an effective chelator with a high affinity for organic amines and metal ions, including Mn
Manganese Accumulation in Neurons & Astrocytes
- significantly higher levels of Mn in ___________
- Within the cells, Mn preferentially accumulates in _____________
- Transport may occur via _________________ (DAT)
- Decreased DAT ________ and _________ in patients chronically exposed to Manganese
astrocytes
mitochondria
dopamine transporter
density… activity
Manganese Efflux Mn can be exported out of the brain via: 1. \_\_\_\_\_\_\_\_\_\_\_\_ 2. \_\_\_\_\_\_\_\_\_\_\_\_ 3. \_\_\_\_\_\_\_\_\_\_\_\_ - Loss of \_\_\_\_\_\_\_\_\_\_\_ mutation in \_\_\_\_\_\_\_\_\_\_\_ gene associated with hereditary form of Mn-induced \_\_\_\_\_\_\_\_\_\_\_\_\_\_
Diffusion
ATPase 13A2
SLC30A10
function…. SLC30A10… parkinsonism
Manganese: Mechanism of Action
- ___________ Stress
- Accumulation of Mn in brain ______________ can inhibit ______ synthesis
- Results in decreased intracellular ______ levels and increased production of ____________________ (ROS)
- Mn can decrease the levels of free ______ and __________ groups in cellular ____________ proteins: Decreases ____________ capacity
Oxidative
mitochondria… ATP
ATP… reactive oxygen species
thiol… hydroxyl… antioxidant… antioxidant
Manganese: Mechanism of Action
- ____________ Stress CON’T
- Mn treatment is associated with an increase in ______________________________ (MnSOD)
- Located primarily in _______________
- Protects against ___________ injury by catalyzing the ____________ of ______________
- This may reduce the risk of ___________ stress?
- This happens in a normal system, but over time the system breaks down and you see dysfunction
Oxidative manganese superoxide dismutase mitochondria oxidative... dismutation... superoxide oxidative
Manganese: Mechanism of Action
- Role of __________
- Mn can substitute for __________ under physiological conditions
- Mn is taken up into ____________ via the _________ __________
- Intra_____________ Mn inhibits ______ synthesis
- Intra_____________ Mn can also inhibit the _______ of ____________
- result in disruption of ___________ integrity
- Which may affect energy production and result in _________ stress and ___________
Calcium
calcium
mitochrondria… calcium uniporter
mitochrondrial… ATP
mitochrondrial… efflux… calcium
membrane
oxidative… apoptosis
Manganese: 5 Mechanisms of Action
- Oxidative Stress
- Role of Calcium
- Exitotoxicity
- Dopaminergic dysfunction
- Alpha-synuclein (aSyn)
Manganese: Mechanism of Action
- _____________
- Accumulation of Mn in ____________ can increase the potential for excitotoxicity via altered ___________ ____________
- Mn decreases the ability of ___________ to clear ____________ from _________________ space
- Increases __________ in the __________ and results in overactivation of ____________ receptors
- Mn increases the sensitivity of ___________ receptors to ____________
- Results in ______________ of receptors
- Blocking ________ receptors prevents Mn-induced excitotoxicity
- Mn also disrupts the __________-___________ cycle
- Neurons cannot synthesize ___________ or ______
- Astrocytes take up both neurotransmitters and convert them to _____________
- ___________ is release by astrocytes which is taken up by neurons
- Serves as precursor to ___________ or _______
Exitotoxicity
astrocytes. .. glutamate metabolism
astrocytes. … glutamate…. extracellular
glutamate. .. synapse… glutamate
glutamate… glutamate
overactivation
NMDA
glutamate-glutamine glutamate... GABA glutamine glutamine glutamate... GABA
Manganese: Mechanism of Action
- _______________ Dysfunction
- ________ deficits associated with Mn exposure suggest the disruption of this system
- Hypothesized that the ______ deficits may be related to reduced ___________ (DA) availability at the synapse
- Due to impaired __________ or altered DA __________ (DAT)
Dopaminergic
motor
motor… dopamine
release… reuptake
Manganese: Mechanism of Action What is alpha-synuclein - can interact with.... - major component in... - primarily exists in...
a small protein that is expressed in the cytosol and presynaptic terminals near synaptic vesicles
- Can interact with lipid membranes
- Major component in Lewy bodies (hallmark of PD and other neurodegenerative disorders)
- Primarily exists in unfolded state
Manganese: Mechanism of Action
- _____________
- ____________ has a _______ affinity for many metals
- Mn has a _____ affinity for ___________
Evidence that __________ may protect against Mn-induced neurotoxicity:
- __________ can act as a metal scavenger – acting as a Mn ________
- Likely only protective ______ on with respect to Mn exposure
Evidence _________ may contribute to Mn-induced neurotoxicity:
- Mn exposure may increase ____________, ____________, and ____________ of _________
- May contribute to ___________________
α-Synuclein (aSyn)
aSyn… high
low… aSyn
aSyn
aSyn… store
early
aSyn
misfolding, aggregation, expression… aSyn
neurodegeneration
BIOTOXINS
What is a biotoxin
Natural toxins produced by living organisms
BIOTOXINS
6 classes of toxin-producing organisms
Viruses Bacteria Fungi Protozoa Plants Animals Algae
BIOTOXINS
- What is Tetrodotoxin (TTX)
- Found in…
- Historically found in seafood harvested in more…
- Produced by…
- Bacterial strains of the family __________________
- Organisms become contaminated with the bacteria by…
Therefore, Pufferfish born and raised in captivity _____ produce TTX
- Potent acute neurotoxin, extremely toxic
- Found in puffer fish, blue ringed octopus, rough-skinned newts, moon snails
- tropical waters in the Pacific Ocean
- produced by commensal bacteria found within the organism, not by the organism itself
Vibrionacease
eating food containing this bacteria
DON’T
BIOTOXINS
- Mutually Beneficial Relationship between TTX and Host Organisms
-Why aren’t host organisms affected?
Bacteria get a safe place to live, eat, and reproduce
Host organisms use the toxin for predation or defence
Single point mutation in the amino acid sequence in the voltage gated sodium channel
- TTX cannot bind to these mutated channels
BIOTOXINS
TTX: 3 Stages of Poisoning
Stage 1: Numbness
- Numbness in the face and extremities
- Sensations of lightness or floating
Stage 2: Increasing paralysis
- Some victims are unable to move, sitting may be difficult
- Increasing respiratory distress
- Speech is affect
Stage 3: Death
- Usually occurs within 4 to 6 hours
- Due to respiratory paralysis
BIOTOXINS: TTX
Structure of Voltage gated sodium channels (VGSC)
- Integral membrane protein consisting of ___ and ___ subunits
- Made up of ___ ____________ transmembrane domains
- Each of the domains are subdivided into:
- A ________ sensing domain (segments S1-S4)
- A _____ forming domain (segments S5-S6)
β and α
4 homologous
voltage
pore
Biotoxins: TTX: Mechanism of Action
- Highly ________ molecule
- Binds to _______ on VGSC
- Temporarily ________ the VGSC, prevents ________ of sodium, results in the inhibition of membrane ______________, prevents the generation of an ___________________
charged
site 1
blocks… influx… depolarization… action potential
Biotoxins: TTX: Mechanism of Action
- TTX prevents the generation of an action potential by blocking VGSC
- This can prevent the contraction of __________ and __________ _________
- Can lead to ______________ failure, ________ arrest, muscle ___________, and death
skeletal. .. cardiac muscles
respiratory. .. cardiac… paralysis
BIOTOXINS: Harmful Algal Blooms (HABs)
- algal blooms composed of…
- They can occur when…
- HABs can deplete the… block the…. and clog…
- Some HABs release toxins that are dangerous to animals and humans who…
phytoplankton known to naturally produce biotoxins
certain types of microscopic algae grow quickly in water
oxygen in the water… sunlight that other organisms need to live… clog fish gills
feed directly or indirectly on them
BIOTOXINS: Harmful Algal Blooms (HABs)
7 things that cause HABs
Eutrophication Warm temperatures Lots of sunlight Runoff Farming Human sewage Pesticides
BIOTOXINS: Harmful Algal Blooms (HABs)
What is Eutrophication
Occurs when bodies of water become overly enriched with minerals and nutrients
Leads to excessive growth
BIOTOXINS: Harmful Algal Blooms (HABs)
Climate change has had a big impact on the presence and location of HABs
Number of toxic HABs are increasing
- Due to increasing water temperature
Location of HABs is changing
- HABs are now occurring more temperate waters
- Due to increasing water temperature
BIOTOXINS: Harmful Algal Blooms (HABs)
Toxins are produced by 3 types of algae
Diatoms
Dinoflagellates
Cyanobacteria
BIOTOXINS: Algal Toxins
Toxins can be classified based on the body of water they are found in
5 Marine algal toxins
Paralytic shellfish poisoning (saxitoxins)
Amnesic shellfish poisoning (domoic acid)
Ciguatera toxins
Diarrheic shellfish poisoning (okadaic acid)
Neurotoxic shellfish poisoning (brevetoxin)
BIOTOXINS: Algal Toxins
Toxins can be classified based on the body of water they are found in
5 Freshwater algal toxins
Anatoxin Nodularin Microcystins Saxitoxins B-methylamino-L-alanine
BIOTOXINS: Algal Toxins
Toxins can also be classified depending on the vectors that they contaminant
- 4 Shellfish poisonings
- 1 fish poisoning
Shellfish
- Paralytic shellfish poisoning
- Neurotoxic shellfish poisoning
- Diarrheic shellfish poisoning
- Amnesic shellfish poisoning
Fish
- Ciguatera
BIOTOXINS: Algal Toxins
Humans can be exposed to algal toxins via (3)
- The consumption of contaminated seafood or drinking water
- Swimming in contaminated water
- Breathing in aerosolized algal toxins
BIOTOXINS: Algal Toxins: Seafood Vectors
- __________ accumulate toxins more quickly than other types of shellfish
- ____________ and ___________ store toxins longer than other species
mussels
Varnish clams and butter clams
Paralytic Shellfish Poisoning (PSP)
- _____ analogs identified
- Most well known analog: ___________ (STX)
- Produced by both ___________ and ________ algal species
19
saxitoxin
freshwater… marine
BIOTOXINS: Algal Toxins: Saxitoxin
The Red Tide
Not always toxic!
Not always possible to see when STX levels are elevated
Only occurs when dinoflagellates rapidly accumulate turning the water a red/brown colour
BIOTOXINS: Algal Toxins: Saxitoxin
Exposure symtpoms
Disorientation, dizziness, memory loss, headache, vomiting, numbness (tongue, lips, fingertips), weakness, diarrhea, motor incoordination, diplopia (double vision), swallowing difficulties, flaccid paralysis, respiratory failure
BIOTOXINS: Algal Toxins: Saxitoxin Mechanism of Action
- Identical mechanism of action as _______
- STX has a high affinity for the _______________ on the _______
- Temporarily inhibits the ________ of ______ by binding
- primarily acts on _________ in the ______ and _________ muscles
TTX
binding site 1 … VGSC
influx… sodium
VGSC… PNS… skeletal
Amnesic Shellfish Poisoning (ASP)
- ____ analogs identified
- most well known analog: ____________ (DOM)
- Toxins produced by ________________ and _________
- Heterocyclic _________ compound, similar in structure to ________ acid and ____________
8
domoic acid
dinoflagellates and diatoms
nitrogen… kainic… glutamate
BIOTOXINS: Algal Toxins: Domoic Acid
- Two main categories of symptoms
- Onset for 2 categories
- 2 sources of exposure
- Gastrointestinal: Vomiting, diarrhea
- Neurological: Confusion, memory loss, disorientation, seizure, coma, death
- Gastrointestinal symptoms within 24 hours
- Neurological symptoms within 48 hours
- Pseudo nitzschia – phytoplankton that produces DOM
- Consumption of contaminated shellfish that feed on phytoplankton
BIOTOXINS: Algal Toxins: Domoic Acid Toxicokinetics
The potential toxicity is mitigated by its toxicokinetics (3)
- DOM is poorly absorbed by the gut
- DOM poorly penetrates the blood brain barrier (BBB)
- DOM has a very short half life in most tissues
BIOTOXINS: Algal Toxins: Domoic Acid Mechanism of Action
- Structurally related to ___________ and _______ acid
- DOM has a high affinity for __________ receptor
- DOM acts as a ___________ agonist, upregulating _____________ production
- When __________ is expelled from the ___________ cell’s vesicle, it then binds to the __________, which triggers _________ channels to open
- With __________ being overwhelmed by DOM, __________ channels do not close on the _______________ cell.
- Influx of __________ on the ____________ cell leads to constant ____________ action potentials being produced. This can lead to _________ and cell _______.
- DOM can also decrease ___________ uptake by ____________, increasing __________ levels.
glutamate… kainic
kainate
glutamate…. glutamate
glutamate… presynaptic… receptor…. calcium
receptors… calcium… postsynaptic
calcium… postsynaptic… excitatory… seizures… death
glutamate… astrocytes… synaptic
Calcium Overload – Why is it Dangerous? (2)
- Excessive stimulation of neurons by excitatory action potentials leads to excitotoxicity/apoptosis
- Constant calcium influx into cells inadvertently activates degradative enzymes such as phospholipases, endonucleases, and proteases that destroy the lipid bilayer, DNA, and other components of the extracellular matrix in the CNS
BIOTOXINS: Algal Toxins: Domoic Acid Pathology
In acute exposure, brain damage occurs in the form of neurodegenerative changes such as (5)
Areas particularly hard hit were the _____________ and ____________________
- Neuronal shrinkage
- Edema
- Cytoplasmic swelling
- Neuronal cell loss
- Reactive astrocytes and gliosis
hippocampus… cerebral cortex
BIOTOXINS: Algal Toxins: Domoic Acid Pathology
Other affected areas include (2)
- The inner nuclear layer of the retina of the eye
- Spinal chord
BIOTOXINS: Algal Toxins: Domoic Acid Pathology
Chronic low-level exposure to DOM associated with
tremors and changes in brain structure in nonhuman primate model
Significant changes in internal capsule, brainstem, corpus callosum
BIOTOXINS: β-N-methylamino-L-alanine (BMAA)
BMAA has been proposed as a possible causative agent in neurodegenerative diseases, such as (3)
- Amyotrophic lateral sclerosis (ALS)
- Amyotrophic lateral sclerosis/ parkinsonism dementia complex (ALS/PDC)
- Alzheimer’s disease (AD)
BIOTOXINS: β-N-methylamino-L-alanine (BMAA)
- What is it?
- What is it produced by?
- Found in what protein form?
- Small, hydrophilic, non-proteinogenic amino acid
- Produced by several species of marine and freshwater cyanobacteria, marine diatoms and dinoflagellates
- Found in both free and protein bound forms
BIOTOXINS: β-N-methylamino-L-alanine (BMAA)
- In which people has BMAA been found in?
- Where is the BMAA in the brains of Canadians and Americans coming from?
BMAA was detected in the brains of ALS patients and AD patients in Canada and America
- BMAA-producing cyanobacteria, diatoms, and dinoflagellates found in marine and freshwater ecosystems
- Aquatic organisms that directly or indirectly feed on these algal species may become contaminated with BMAA
- Not possible to ascertain a direct link between shellfish consumption and existence of this ALS cluster!
BIOTOXINS: β-N-methylamino-L-alanine (BMAA)
Distribution of BMAA in mussel tissues is opposite of the pattern of distribution observed for all other phycotoxins
Lower concentrations reported in the digestive glands Higher concentrations reported in the remaining flesh
Vice versa for all other phycotoxins
BIOTOXINS: β-N-methylamino-L-alanine (BMAA)
Is BMAA linked to the development of neurodegenerative diseases outside of Guam?
Epidemiological evidence is weak and does not support a causal role for BMAA in neurodegenerative diseases
BIOTOXINS: β-N-methylamino-L-alanine (BMAA) Toxicokinetics
BMAA In the brain
- BBB?
- localization?
- Can cross the blood-brain barrier (BBB)
- Transfer rate into an adult rodent brain is poor
- No localization of BMAA within discrete brain regions in adult rodents
- Detected in ventricles, choroid plexus, and whole-brain gray matter structures
BIOTOXINS: β-N-methylamino-L-alanine (BMAA)
Toxicokinetics in Neonates
- placental barrier
- milk
- uptake into brain
- localization
- Evidence that BMAA can be transferred across the placental barrier to the fetus and through milk to suckling neonates
- Uptake of BMAA into the brains of developing rodents more efficient and selective than adults
- Distinct localization of BMAA in the neonatal brain: Higher levels found in the striatum, hippocampus, thalamus, cerebellum, and brain stem
BIOTOXINS: β-N-methylamino-L-alanine (BMAA) Toxicokinetics
Transport of BMAA across the BBB is mediated by
the L-type large neutral amino acid carriers (LAT1 and LAT2)
BIOTOXINS: β-N-methylamino-L-alanine (BMAA) ANimal Data
- Repeated oral exposure of BMAA for up to 12 weeks in macaques caused… (5)
- Chronic dietary exposure to BMAA for up to 140 days in Vervet monkeys caused…. (2)
- motor neuron dysfunction in the forelimbs
- muscle weakness
- loss of muscle mass
- tremor
- neurodegenerative changes in the primary motor cortex and anterior horn of the spinal cord
- neurofibrillary tangles and B-amyloid plaques
BIOTOXINS: β-N-methylamino-L-alanine (BMAA) 3 Mechanisms of Action
- Excitotoxicity
- Hyperphosphorylation of tau protein
- Protein incorporation of BMAA
BIOTOXINS: β-N-methylamino-L-alanine (BMAA) Mechanism of Action: EXCITOTOXICITY
- BMAA overstimulates ________________________
- This disrupts ____________________________
- Which increases intracellular levels of __________
- Results in _____________
inotropic glutamate receptors
calcium homeostasis
calcium
apoptosis
BIOTOXINS: β-N-methylamino-L-alanine (BMAA) Mechanism of Action: HYPERPHOSPHORYLATION OF TAU PROTEIN
- Can lead to the formation of ___________________
- BMAA disrupts tau phosphorylation by inhibiting protein ______________________ (PP2A)
- PP2A is normally bound to ___________ receptors
- When BMAA binds to ___________ receptors is causes PP2A to ____________ from receptor
- ________________ PP2A is then inactivated by _____ family _________
4. Resulting in ___________ levels of tau hyperphosphorylation
neurofibrillary tangles phosphatase 2A (PP2A) mGluR5 mGluR5... disassociate disassociated... Src... kinase increased
BIOTOXINS: β-N-methylamino-L-alanine (BMAA) Mechanism of Action: PROTEIN INCORPORATION OF BMAA
- BMAA may be misincorporated into proteins as a substitute for __________
- Once BMAA is incorporated into the chain, the protein can no longer ________ properly
- Clumps of ____________ proteins may form ____________ characteristic of neurodegenerative diseases
- Hypothesis largely ____________
- No conclusive evidence that BMAA incorporated into proteins in normal biological systems
serine
fold
misfolded… aggregates
disproven
ORGANIC SOLVENTS/ VOLATILE ORGANIC COMPOUNDS (VOCs)
- What are they?
- 3 common characteristics
A wide group of chemicals extensively used in many industrial and domestic situations
- Volatile liquids at normal temperatures
- Strongly lipophilic
- Can result in CNS depression at sufficiently large doses
Organic Solvents: Toxicokinetics
Rapid absorption through 3 routes
Distribution dependent on 3 factors
- Inhalation route (volatile solvents)
- Transdermal route
- Ingestion
- Related to lipid content of solvent
- Related to vascularity of tissues
- Adipose and lipid-rich tissues are depots for storage
Organic Solvents: Toxicokinetics
- Metabolism: usually detoxified via __________
- In some cases evidence of _______________ to __________________
Excretion through 3 methods
liver
bioactivcation… toxic metabolites
- Urine – as conjugated products
- Feces – as conjugated products
- Expired air – as volatile solvents
Acute Central Neurotoxicity of Organic Solvents (5)
- General anesthesia-like activity
- Narcosis
- Euphoria
- Agitation (disinhibition)
- Dyscoordination, ataxia, dysarthria
Chronic Central Neurotoxicity of Organic Solvents
- Painter’s Syndrome (4)
“Painter’s syndrome”
- Depression
- Retarded psychomotor performance
- Personality change
- Decline in short-term memory
Problems in Assessing Neurotoxicity of Organic Solvents (6)
- Nonspecific…
- Replication of…
- Variability in….
- Nonspecificity of…
- Confounded with…
- Mixed…
- Nonspecific case definition
- Replication of prevalence rates
- Variability in neurobehavioural tests
- Nonspecificity of physiological measures
- Confounded with ethanol, trauma, other factors
- Mixed Exposures
Organic Solvents: BENZENE
- Found in…
- Used in…
- Produced naturally by…
- Major source of exposure is…
- Found in crude oil and is a major part of gasoline
- Used in the production of plastics, resins, dyes, detergents, drugs, pesticides, etc.
- Produced naturally by volcanoes and forest fires
- Major source of exposure is tobacco smoke
Organic Solvents: Benzene: Toxicokinetics
- primary route of exposure: ____________
- Readily ______________ and widely ___________ in body, preferentially stored in ______
- ____________________ required for the expression of benzene toxicity
- Easily crosses ______ and __________________
- Eliminated primarily via ____________
inhalation absorbed... distributed... fat Bioactivation BBB... placental barrier exhalation
Organic Solvents: Benzene: Human Data
- Primary effects associated with chronic benzene exposure in humans are (2)
- Neurotoxic effects in humans include (8)
Anemia and leukopenia
Dizziness, headache, and vertigo at low levels
Drowsiness, tremor, delirium, and loss of consciousness at medium levels
Death at exposure to high, acute levels
Organic Solvents: Benzene: Mechanism of Action
- Neurotoxic effects
- hemopoietic endpoints
- Mechanism of action for neurotoxic effects if unknown
- Mechanism of action for hemopoietic endpoints
- Related to the suppression of hemopoietic myeloid progenitor cells by benzene
Organic Solvents: TOLUENE
- What is it?
- Used for…
- Commonly used by…
- Toluene is benzene with an extra methyl group added to the ring
- A chemical commonly used in Printing and industrial painting, Crude oil and gasoline, Tobacco smoke
- inhalant abusers
Organic Solvents: TOLUENE Exposure
Breathing in contaminated workplace air
- Levels of 100 ppm are considered safe
- Levels of 2000 ppm are considered toxic
- Breathing automobile exhaust
- Drinking contaminated water
- Living near uncontrolled hazardous water sites that contain toluene products
Organic Solvents: Toluene: Toxicity Acute exposure - 200 ppm - 600 ppm - 800 ppm - 4000 ppm
-Acute effects of toluene are generally
- 200 ppm: Fatigue, headache, paresthesias, and slowed reflexes
- 600 ppm: confusion
- 800 ppm: Euphoria
- 4000 ppm: Death
reversible and not associated with neuroimaging changes
Organic Solvents: Toluene: Toxicity
toluene leukoencephalopathy
- Degeneration of…
- Severity of this disorder is correlated to the degree of…
- Significant neuronal loss in the… (3)
- Giant ________ degeneration in the long tracts of the spinal cord
- ______________
- Intense reactive _________
- Degeneration of white matter in the brain
- degree of white matter injury in the brain
- cerebral cortex, basal ganglia, and cerebellum
axonal
demyelination
gliosis
Organic Solvents: Toluene: Toxicity
Chronic exposure to toluene also associated with widespread cognitive dysfunction including (5)
Neuropsychological profile consistent with diffuse white matter degeneration
- Inattention
- Apathy
- Memory dysfunction
- Visuospatial impairment
- IQ reduction
Organic Solvents: Toluene: Mechanism of Action
- ______________
1. Hypothesized that its toxicity may be related to its high __________ - Toluene is preferentially distributed to ______- ______ regions of the brain
- Proposed that _________ may be the primary target for damage
2. Hypothesized that toluene may share common actions with _____________, ________________, and _________ - Toluene inhibits ________ receptors and _________ ________________ receptors (excitatory ion channels)
- Toluene also stimulates _______ and _________ receptors (inhibitory ion channels)
3. Toluene also is associated with increase production of _____________________________ in the CNS - could be related to ______ _________________ (i.e., the oxidative degradation of _______)
unknown
lipophilicity
lipid-rich
myelin
barbiturates, benzodiazepines, and alcohol
NMDA… nicotinic acetylcholine
GABA… glycine
reactive oxygen species
lipid peroxidation
lipids
ORGANOHALOGENS
- What are they
- Organic compounds that contain chlorine, bromine or fluorine atoms
- Anthropogenic compounds
- Classified as a persistent organic pollutant (POPs)
ORGANOHALOGENS
Common characteristics include:
1. Persistence in the _____________
2. _________________ in living organisms
3. Long-range ___________ beyond the ________________ region of their use
4. Long-term ________ effects in wildlife and humans
environment
Bioaccumulation
transport… geographical
health
ORGANOHALOGENS
Examples (3)
Flame retardants
Polybrominated Diphenyl Ethers (PBDEs)
Polychlorinated Biphenyls (PCBs)
Polychlorinated Biphenyls (PCBs) PCBs can enters the environment through (3)
- Are very _______ in the environment and _________ in water
- PCBs are extremely ______ ___________
- Most common exposure routes are via (2)
- PCBs are known _______________
- Run off
- Poorly maintained hazardous waste sites
- Burning of waste in incinerators
stable… insoluble
fat soluble
ingestions and inhalation
carcinogens
Polychlorinated Biphenyls (PCBs): Developmental Toxicity
Children exposed to PCBs prenatally and/or through breast milk showed:
- Disruptions or delays in…
- ___________
- Other _______ impairments including…
- Reduced _____ scores
- Reduced ______________ comprehension
- Deficits in ____________________ and other _________ abilities
In most cases, delays were found in early development, and at the follow up in later years…
- Disruption or delays in motor development
- hypotonia (low muscle tone)
- Other motor impairments included: clumsy movement, slowness, jerkiness
- reduced IQ scores
- reduced reading comprehension
- Deficits in short term memory and other cognitive abilities
no differences were observed
Polychlorinated Biphenyls (PCBs): 5 Mechanisms of Action
- _________________ system
- ___________ homeostasis
- _________ stress and cell __________
- __________________________ (TH) system
- Changes in _______ _____________ and ________ _____________
- Dopaminergic system
- Calcium homeostasis
- Oxidative stress and cell viability
- Thyroid hormone (TH) system
- Changes in brain structure and synaptic plasticity
Polychlorinated Biphenyls (PCBs): Mechanism of Action: DOPAMINERGIC SYSTEM
- The effect on dopamine (DA) depends on whether animal was exposed as an ________ or during _____________:
- Decreased DA levels in ________
- Increased DA levels in _____________
- PCBs inhibits _____________________________ (VMAT) in synaptic vesicles and the DA transporter
adult… development
adults
development
vesicular monoamine transporter (VMAT)
Polychlorinated Biphenyls (PCBs): Mechanism of Action: CALCIUM HOMEOSTASIS
- PCBs ____________ intracellular calcium levels
1. Due to release of calcium from ______________ calcium stores - PCBs induces calcium release from ________-______________ (IP3) sensitive calcium stores in __________________ ___________
2. Due to release of calcium from _______________ calcium stores - PCBs activates _______ receptors resulting in sustained _________ of calcium
- Increased intracellular calcium levels can lead to ___________
increases intracellular inositol-triphosphate (IP3) ... endoplasmic reticulum extracellular NMDA... influx apoptosis
Polychlorinated Biphenyls (PCBs): Mechanism of Action: OXIDATIVE STRESS AND CELL VIABILITY
- PCBs exposure in vitro induced __________ and __________ cell death
- PCBs increased the formation of __________ __________ _________ (ROS)
- PCBs decreased the formation of _____________ species in the cerebellum, cerebral cortex, hippocampus, and hypothalamus
apoptotic… necrotic
reactive oxygen species
antioxidants
Polychlorinated Biphenyls (PCBs): Mechanism of Action: THYROID HORMONE (TH) SYSTEM
- The TH system is vulnerable to ___________, especially during early __________________
- TH deficiency during ___________ causes cretinism, with severe ___________ and/or _________ disorders
- The molecular structure of PCBs are similar to those of ____________ (T4)
- PCBs can act on TH ___________ and TH-transport protein (____________), and have a higher _________ for _________________ than T4, but a lower affinity for TH ___________.
- Transport of PCB into the fetus is facilitated by binding to ____________ which can crosses the __________ barrier
- Reduced levels of __________ (due to PCB exposure) can disrupt _______ expression and interfere with normal ____________________
toxicants. .. development
gestation. .. cognitive… mental
thyroxine
receptors. .. transthyretin… affinity… transthyretin… receptors
transthyretin. .. placental
thyroxine. .. gene… neurodevelopment
Polychlorinated Biphenyls (PCBs): Mechanism of Action: BRAIN STRUCTURE AND SYNAPTIC PLASTICITY
- Structural or plasticity changes may underlie PCB induced deficits in (3)
- Evidence that PCBs can reduce _____ in the _______ cortex and _____________ in vitro and in vivo
- PCB exposure may interfere with the normal development of ____________
memory, learning, and motor functioning
LTP… visual… hippocampus
dendrites
Polybrominated Diphenyl Ethers (PBDEs)
What are they
- PBDEs are a family of flame retardants
- Use in clothing, upholstery, electronic equipment
- Are structurally similar to PCBs
Polybrominated Diphenyl Ethers (PBDEs)
Associated with developmental neurotoxicity (5)
- Impaired memory
- Learning deficits
- Hyperactivity
- Altered motor behaviour
- Reduced IQ
Polybrominated Diphenyl Ethers (PBDEs): Mechanism of Action
- Similar to…
PCBs
- Dopaminergic system
- Calcium homeostasis
- Oxidative stress and cell viability
- Thyroid hormone system
PLASTICS
2 components in plastics that are capable of leaching out and known to be toxic
Bisphenol A (BPA) Di(2-ethylhexyl) phthalate (DEHP)
PLASTICS: What is BPA
- BPA has been used in (7)
- 3 sources of exposure
- BPA is an organic building block of several plastics (monomer). It is also used as an additive in plastics (plasticizer)
Coating of food cans, baby bottles, food containers, water bottles, dental sealants, toys, makeup, lotion, shampoo
- Ingestion (food and drink sources)
- Inhalation (dust!)
- Dermal (receipts!)
PLASTICS: What is DEHP
- a common organic additive used to impart plasticity (fluidity) to materials such as plastic
- Another type of plasticizer
PLASTICS: BPA: Toxicokinetics
- Absorption: ____%
- Nearly entire ______ dose is _______________ during _______ pass
- BPA conjugated with ______________ acid to form _______________
- _____________ completely excreted via _______ within 24 hours
5%
oral. .. metabolized… first
glucoronic. .. glucoronide
glucoronide. .. urine
PLASTICS: BPA: 4 Mechanisms of Action
- ____________ receptors
- ____________-related receptors
- ____________ receptors
- _____________ ____________-activated receptors
- Estrogen Receptors
- Estrogen-related receptors
- Androgen Receptors
- Peroxisome proliferator-activated receptors (PPARs)
BPA: Mechanism of Action: ESTROGEN RECEPTORS
- ___________ receptors: Can exert effects via the control of __________________________
- BPA can bind to ERs __________ (alpha and beta)
- BPA displays a lower ________ to the ERs compared to 17β-estradiol
- BPA is considered a ________ estrogen
Nuclear… gene transcription
subtypes
affinity
weak
BPA: Mechanism of Action: ESTROGEN-RELATED RECEPTORS
- A subfamily of ________ _________ receptors closely related to __________ receptors
- ___________ do NOT bind to ERRs,
- __________ ___________ elements bind to ERRs: a _____________ factor that regulates expression of estrogen-____________ _______
orphan nuclear… estrogen
estrogens
estrogen response… transcription… responsive… genes
BPA: Mechanism of Action: ANDROGEN RECEPTORS
- BPA may have __________________ activity
- Can inhibit ______________ induced _________ translocation of the androgen receptors
antiandrogenic
testosterone… nuclear
BPA: Mechanism of Action: Peroxisome proliferator-activated receptors (PPARs)
- PPARs are important for the induction of…
- Some evidence that BPA can _______ to PPARs (specifically _________________)
- Affinity of BPA for PPARs is ________ than affinity for ERs
adipose tissue
bind… PPAR gamma
lower
CLARITY-BPA (Core Study)
Findings…
NO BIOLOGICALLY SIGNIFICANT FINDINGS!!
BPA: Academic Research
findings….
Some of the CLARITY-BPA academic researchers are reporting findings at low doses
PHALATES
- What are they?
- What are they used in (5)
- All phthalates are derived from ________ ________
- Are ____________, ____________, and have low _________
- Are ___________ substances
- Synthetic chemicals used as plasticizers since the 1920s
- Food storage containers, children’s toys, pharmaceuticals, cosmetics, personal care products
- phthalic anhydride
colourless, odorless… volatility
lipophilic
PHALATES
Can be divided into three categories based on the length of the ester sides chains
- ______________ phthalates appear to show the greatest toxic potential
- Low molecular weight: Have short straight sides chains of 3 or less carbon atoms
- High molecular weight: Have ring structure or long straight sides chains of 7 or more carbon atoms
- Transitional or mid-molecular weight: Have side chains made up of 4 to 6 carbons that are either straight or branched
transitional
PHALATES: DEHP
- DEHP is one of the most commonly used phthalates
- DEHP tends to permeate ______ soluble substances more readily than _______ soluble substances
- Ex: ________ concentrations of DEHP found in milk, cheese, fats and oils
- Most common route of exposure: ________
lipid… water
Higher
ingestion
PHALATES: DEHP
Two methods to estimate DEHP exposure
1. __________ sources
- Levels of DEHP are estimated from _____________________ of items that contain DEHP
- And the length of ______ individuals spend in ______________ where exposure many occur
2. _________ sources
- Measure levels of DEHP metabolites in _______
- BUT, this assumes individuals __________ DEHP at a __________ rate, AND assumes people are __________ to DEHP at a _________ rate
External known usage patterns time... environments Internal urine metabolizes... constant exposed... constant
PHALATES: DEHP: Toxicokinetics
- DEHP is __________ absorbed upon ingestion
- Approx. 80% of an oral dose is metabolized upon ingestion into ______________________ (MEHP)
- DEHP metabolites, such as ________, are believed to be responsible for the toxic effects of DEHP
- DEHP is distributed _________, with Highest concentrations detected in _________ tissue and _______
- DEHP does not _______________
rapidly mono ethylhexyl phthalate MEHP widely.... adipose... liver bioaccumulate
PHALATES: DEHP: Reproductive/Developmental Toxicity
- Severe disorders in developing ______ ____________ organs (external __________, undescended ________, , ____________ lesions, etc)
- Permanent _____________ of the male ___________ system
- Delayed onset of _________ in rates
male reproductive…. genitalia… testes… testicular
feminization… reproductive
puberty
PHALATES: DEHP: 2 Mechanisms of Action
- Estrogenic Effects
2. Anti-Androgenic Effects
PHALATES: DEHP: Mechanism of Action: ESTROGENIC EFFECTS
- DEHP ________ activates _______ __________ receptor α
- Decreased serum levels of (2)
- Hypothesized that may be related to the suppression of __________ __________
- May affect secretion of _____________:
1. ___________ hormone (LH): important for testosterone synthesis in Leydig cells. LH transcripts ___________ and LH receptors ____________.
2. ________-__________ hormone (LSH): important in promoting normal gonadal function via increasing ________ levels. MEHP reduced ability of FSH to elevate ________ levels
weakly… human estrogen
estradiol and progesterone…. aromatase transcripts
gonadotrophins
Luteinizing… up-regulated… down regulated
Follicle-stimulating…. cAMP… cAMP
HALATES: DEHP: Mechanism of Action: ANTI-ANDROGENIC EFFECTS
- Does not appear to involved the androgen _________ (AR)
- Decreased serum ______________ levels
- DEHP effect on ____________ hormone may indirectly affect ________________ levels
- Developmental exposure to DEHP disrupts _______ and Leydig cell function: _________ cells play a critical role in brain ______________ and ______________
receptors
testosterone
Luteinizing… testosterone
Sertoli…. Sertoli… masculinization… defeminisation
HALATES: DEHP: Hippocampus of male rats was more vulnerable to DEHP exposure
- DEHP-treated male rats had reduced levels of ______________ in the ________ _______
- Reduced ______ _________ in the CA3 stratum pyramidale of DEHP-treated
- No change in _____________ caspase-3 transcripts
- Reduced _______ ____________ in the CA3 stratum oriens
- Reduced ______ ________ on CA3 basal and apical ___________
- Reduction in hippocampal _______ transcripts
neurogenesis... dentate gyrus cell density hippocampal axonal innervation spine density... dendrites BDNF
Factors that Contribute to Emerging Food Issues
- New ___________ ___________
- Increasing _______ __________ and __________ as it relates food quality and safety
- Changes in ______________ practices, _______ patterns, __________
- ______________ of food industry
- Food product ____________
- New Scientific Research
- Increasing public interest and perception as it relates food quality and safety
- Changes in production practices, trade patterns, climate
- Globalization of food industry
- Food product innovation
MICROPLASTICS
- What are they?
- Size?
- Two types
- the most predominant form of microplastic in the environment: _____________
Heterogeneous mixture of plastics particles present in the environment that vary in size, shape, and chemical composition
- 100 nanometers (nm) to 5 mm
- Primary Microplastics: Plastic particles intentionally engineered
- Secondary microplastics: Formed when larger plastic debris in the environment degrades and fragments into smaller plastics particles
- Secondary
6 Types of Microplastics based on shape
- Fibers
- Pellets
- Films
- Fragments
- Microbeads
- Foam
Microplastics: Sources
- most comment detected shape is: _______
Why?
fibers
- More and more clothing is being made form synthetic fibers
- Fibers can be released from these clothing items during manufacturing, but also during regular household washing
Microplastics: Toxicokinetics
- __________ absorption is low
- plastic particles can translocate across the _____
- Plastic particles expected to penetrate into _______
- Majority of orally ingested microplastics will be excreted via _______
- Probably aren’t ___________ since microplastics don’t degrade
intestinal gut organs feces metabolized
Microplastics: Toxicity
- Biochemical parameters suggest exposure to 5 and 20 μm microbeads may: (2)
- Change in _________ activity in the _______ – not brain, affecting the ______
- Decreased ________ secretion in the ______
- Altered the richness and diversity of ________________
- __________ barrier dysfunction – reduced ____ transport
- Microplastics may act as ________ to ________ toxic chemical into animals and humans
- Microplastics are made up of __________ and _________ that can leach out once ingested
- Microplastics can also _________ contaminants from the environment/_________
- Negatively affect energy and lipid metabolism
- Contribute to oxidative stress
AChE… liver… PNS
mucus… gut
gut bacteria
ion
vectors. .. transport
monomers. .. addititves
absorb. .. metals
