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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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A) Effects of Corticosteroids




- 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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b) Effects of Catecholamines (Adrenal medula)




- 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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b) Effects of Catecholamines




- 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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Prolonged Secondary Effects

Decreased Growth

Inhibited Reproduction

Lower Survival

I ncreased Disease and parasitismBehavioural Changes

- migration

- courtship

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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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Normal Liver Necrotic Liver

Pyknosis

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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.

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