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Date Lecturer Topic
7 January Palace Introduction and Course Format9 January Palace Types of toxicology
14 January Palace Physiological Mechanisms of toxicity
16 January Palace Cellular mechanisms of toxicity
21 January Palace Factors Affecting Toxicity, Routes of Exposure
23 January Palace Bioassays, Dose response functionAssignment distributed
28 January Palace Selenium
30 January Palace Biomarkers
4 February Friedrich Biomineralization
6 February Hanson Environmental Risk Assessment11 February Palace Legacy Contaminants PCBs, Dioxins, Furans
13 February Palace Mid Term Exam – in Class
Mid term break February 17 to February 21, 2014
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Replicate
– the repetition of a test or complete experiment
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Jan 14, 2014
Lecture 2
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Stress
A state produced by an environmental or other factor
which extends the adaptive responses of an organismbeyond the normal range or which disturbs the normal
functioning to such an extent that the chances of survival
are significantly reduced
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3 Phases of the GASGeneral Adaptation Syndrome
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Mazeud’s General Stress Response (GSR)
Exogenous stressorPhysical
Chemical
Central Nervous System
Hypothalmus = CRF
(Corticotropin Releasing factor)
Pituitary = CRH
Corticotropin
(ACTH)
Adrenocorticotropin Hormone
Interrenals Chromaffin
Cells
neuroendocrine cellsfound in the medulla ofthe adrenal glands
adrenal cortex
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Mazeud’s General Stress Response
InterrenalCells
(eg. Adrenal
Cortex)
ChromaffinCells
(eg. Adrenal
medula)
Corticosteroids
cortisol
cortisone
aldosterone
Catecholamines
adrenalin
noradrenalin
dopamine
Primary Effects
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Mazeud’s General Stress Response cont’d
A) Effects of Corticosteroids (Adrenal Cortex)
Liver – decreased glycogen
- altered electrolyte balance (↑or ↓)
Blood - increased glucose
- increased lactate
- altered fatty acids
(↑or ↓)
Other effects
- white blood cells decline
- immune system is inhibited
- muscle protein declines
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Mazeud’s General Stress Response cont’d
A) Effects of Corticosteroids
Liver – decreased glycogen
- altered electrolyte balance (↑or ↓)
Blood - increased glucose
- increased lactate
- altered fatty acids
(↑or ↓)
Other effects
- white blood cells decline
- immune system is inhibited
- muscle protein declines
S e c o n d
a r y E f f e c t s
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Mazeud’s General Stress Response cont’d
b) Effects of Catecholamines (Adrenal medula)
Liver – decreased glycogen
- altered electrolyte balance (↑or ↓)
Blood - increased glucose
- increased lactate
- altered fatty acids (↑or ↓)
Other effects- heart rate (gill blood flow)
increases
- increased drinking rate
- increased diuresis
- decline in melanocytes
(urine production)
(melanin producing cells)
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Mazeud’s General Stress Response cont’d
b) Effects of Catecholamines
Liver – decreased glycogen
- altered electrolyte balance (↑or ↓)
Blood - increased glucose
- increased lactate
- altered fatty acids (↑or ↓)
Other effects- heart rate (gill blood flow)
increases
- increased drinking rate
- increased diuresis
- decline in melanocytes
S e c o n d
a r y E f f e c t s
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Loss of Melanocyte Function - depigmentation
Kittilsen et al. 2012. PLOS One.
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Mazeud’s General Stress Response cont’d
Prolonged Secondary Effects
Decreased Growth
Inhibited Reproduction
Lower Survival
I ncreased Disease and parasitismBehavioural Changes
- migration
- courtship
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Mazeud’s General Stress Response cont’d
Prolonged Secondary Effects
Decreased Growth
Inhibited Reproduction
Lower Survival
Increased DiseaseBehavioural Changes
- migration
- courtship T e r t i a r y E f f e c t s
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Physiological Mechanisms of Toxicity
1) Growth
2) Reproduction
3) Development
4) Behaviour
Overlap between the categories!
Some evidence of impacts w/o GAS/GSR induction
(eg. EDCs)
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Physiological Mechanisms of Toxicity
1) Altered Growth
- bulk of energy used by basal metabolism,
growth and reproduction
- increased energy diversion for one = less
energy for another
energy expenditure at rest
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Metabolic Cost of Stress
Control
Fish
MercuryExposed
Fish
Time
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Scope for Growth
SFG(given in Joules or calories)
= Ef - (Er+Ee)
- where:
Ef = energy from food
Er = energy for respir.
Ee = energy excreted- measured under laboratory conditions
- does not consider other factors
present in field situations
- bivalves exposed to PAHs = Low SFG
polycyclicaromatic
hydrocarbons
SFG=scopefor growth
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Field Measures of Growth
- organism specific measures
- for fish = condition factor
- an integrative measure of both
weight and length
K = [Wt(g) L3
(cm)] X 100
- baseline measures = 0.7 to 1.1
Fulton’s condition factor, K, is a measureof an individual fish’s health that usesstandard weight. The higher the K valuethe healthier the fish.
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Acidification – Effect On Condition
Acidification doesn't affect fishdirectly, but does negatively impactthe microorganisms on which theyfeed. Hence, less food means less
growth and smaller fish.
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0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
C
o n d i t i o n ( K
)
1999 -2000- ---2001--- ---2002--- -2003-
Lake 114 Lake 442 Lake 260
Stress and Growth
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Truss Measures for Growth
- expanded approach
- in perch, found that caudal peduncle
measures more reflective of growth
than CF (condition factor, "K")
caudal peduncle
C diti M
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Condition Measures
Or …Bioelectrical Impedance Analysis
or horn growth
or bird size
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Physiological Mechanisms of Toxicity Cont’d
2) Altered Reproduction
Strong link between growth and reproduction
eg. Fathead minnows exposed to Mirex
had increased growth rates but reproduction
was greatly inhibited
Measure of Reproductive success = # of progeny that survive
to reproduce
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2) Altered Reproduction cont’d
There are a number of ways that contaminants canalter reproduction:
a) Lower fecundity
- hormonal changes (EDC Lecture)
- gonad function
b) Reduced Fertilization
c) Teratogenesis
d) Lower Survival of Progeny
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2) Altered Reproduction cont’d
Possible Contaminant Intervention Points
1) Brain
2) Gonad3) Gametes
4) Development
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I hi h i f Pi i (GH S i i )
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Control
Mercury
Exposed
Immunohistochemistry of Pituitary (GH Staining)
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2) Gonad
Contaminant Intervention Points
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2) Contaminant Effects on Gonads
There are two Possibil i ties
a) Cytotoxicity
Organisms exposed to Cd have damaged vascularbeds in the gonad, but there is no change in
pituitary gonadotropins
Result is still lower gonadal steroid production
b) Endocrine Disruption
More in the EDC lecture
(i.e. GtH like FSH and LH levels are fine)
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3) Contaminant Effects on Gametes
a) Altered Hormone Environment
b) Altered Nutritive Cell Function
c) Altered Seminal or Ovarian Fluid Constituents
d) Direct Toxicity to Gametes
Don’t assume that no toxicity to adultsmeans that there is no toxicity at other
stages! !
E G t T i it M i Fi h Ti
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Eg. Gamete Toxicity: Mercury in Fish Tissues
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4th Point of Intervention for Reproduction:
Early development (teratogenesis)
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15% thinning = much higher breakage (~ 4ppb)
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3) Altered Behaviour
- comparatively few studies
- probably due to difficulties with:
1) high variability
2) low applicability of lab to field
measures
3) difficulty in scoring behaviours
subjectively
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1) Preference/Avoidance Troughs
Contaminant Input
Flow
A B C Fresh
Water
Input
Outflow
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Haloperidol Induced Catelpsy
The higher the [haloperidol],the longer the catalepsy time
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HBCD Affects Haloperidol Induced Catelepsy
Lil ienthal et al. 2009 Toxic ol. Lett.
As shown below, it takes less time for theorganism to retract its foreleg to avoid the
aversive stimulus (less latency time).
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Next Lecture
• Cellular Mechanisms of Toxicity
1) Necrosis2) Apoptosis
3) DNA Modification
4) Enzyme dysfunction
5) Cancer6) Oxidative Stress
S lli i d t d f ti
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1) Necrosis
Definition: Cell death due to disease or injury.
Most often demonstrated histologically
Hallmarks of Necrosis
-edema or swelling of membranes and cell
- organelle swelling, pyknosis
- nucleus does not change drasticallynucleoli often still visible
-early stages are reversible, but later more severe swelling
precedes cell death
Irreversible condensation ofchromatin in the nucleus of a cellundergoing necrosis or apoptosis
Swelling is due to dysfunctionof permeability in membranes
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1) Necrosis cont’d
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Necrotic Mechanism
Necrosis vs Apoptosis: http://genesdev.cshlp.org/content/20/1/1.full
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1) Necrosis cont’d
Normal Liver Necrotic Liver
Pyknosis
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1) Necrosis cont’d
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1) Necrosis cont’d
Mechanism of Necrosis:
Appears to be loss of control of cell volume due to
changes in membrane permeability
Loss of ion balance used as a marker for necrosis
Types of Necrosis
A) CoagulativeB) Liquefactive
C) Caseous
D) Gangrenous
E) Fatty
A) Coagulative Necrosis
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A) Coagulative Necrosis
Necrotic Areacaused by ischemia(restriction in blood
supply to tissues) orinfarction (local lack ofoxygen)
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B) Liquefactive Necrosis
due to destructive effects oflytic enzymes generated byneutrophils & macrophagesin infected tissues
tissue maintains a cheese-like
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C) Caseous Necrosis tissue maintains a cheese-likeappearance, often seen intuberculosis
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D) Gangrenous Necrosis
A combination of coagulative and liquefactive
necrosis but usually resulting from a puncture or
ischemia and subsequent infection
Lipase releases fatty acids fromtriglycerides The fatty acids then
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E) Fatty Necrosis triglycerides. The fatty acids thencomplex with calcium to form soaps.These soaps appear as white chalkydeposits.