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1
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2
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3
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- Novel and powerful tool that can be used to assay global gene expression
patterns characteristic of frog adaptive response to atrazine
- Molecular road map can be produced to identify physiological systems
that are affected by atrazine
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4
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- Exposed developing tadpoles to 400 ppb atrazine ( a moderate to high
environmental dose).
- Chronic exposure from 5 days to stage 62.
- Microarray to Measure global gene expression
- QRT-PCR to confirm microarray data
- Extracted mRNAs from the frogs; mRNAs are the products of the expression
of genes
- Measured upregulated and down regulated gene expression in atrazine
treated frogs compared to control frogs
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5
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6
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- Mortality rate was not significantly different between treated and
control tadpoles.
- Atrazine treated tadpoles (n=60) showed a significantly decreased
metamorphic rate (p=0.0165) when compared to the control tadpoles
(n=80).
- Treated tadpoles were shorter and weighed less than control tadpoles.
- Treated tadpoles contained almost no body fat compared to control
tadpoles.
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7
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- Weights of atrazine treated tadpoles (n=21; t-test p=0.0001) were
significantly decreased as compared to control tadpoles (n=24).
- Tadpoles were all at NF stage 62.
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8
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9
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10
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11
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12
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13
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14
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15
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16
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- Atrazine is causing metabolic dysfunction in tadpoles which affects
energy accumulation vital for development and growth.
- A large body of evidence associates reduced growth rate and reduced
metamorphic rate in amphibians to malnutrition.
- Upregulated proteolysis genes and lack of body fat may indicate that
tadpole metabolism is unbalanced, relying on protein and fat instead of
carbohydrates for energy.
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17
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18
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- Decreased fibrinogen and serum albumin expression may indicate chronic
liver dysfunction and/or malnutrition.
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19
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- 4 globin genes were upregulated.
- These are heme containing proteins responsible for transport of oxygen.
- Under stressful conditions tadpoles show
- Increased basal metabolic rate
- Increased heart rate
- Increased oxygen consumption.
- Thus, tadpoles may be reacting to chemical stress caused by atrazine.
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20
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- Growing body of literature suggests that atrazine suppresses the immune
system of amphibians; downregulated genes included:
- MHC complex II, involved in antigen presentation to T helper cells
- Gluthathione S-transferase, used by most resistant plants, and some
animals, to detoxify atrazine by conjugation, making atrazine more
water soluble and easier to excrete
- Tyrosine phosphatase, involved in signaling in T-lymphocytes and
Natural killer cells
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21
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- Currently scientists have little understanding of what causes
Parkinson's, where a tiny group of dopamine-producing neurons deep
within an area of the brain known as the substantia nigra die.
- This cell death leads to a shortage of the neurotransmitter dopamine and
to the tremors, rigidity, and slow movement that mark the disease as it
progresses slowly over a period of years or decades.
- Parkinson's affects about 1 million people in North America.
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22
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23
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- A. Normal section from postmortem human brain (ponto-cerebellar tract in
pons) showing light background ICC staining for a-synuclein.
- B. a-synuclein aggregates as glial cytoplasmic inclusions appear in a
similar section from an MSA patient with Parkinsonism.
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24
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- Multiple system atrophy (MSA) is a sporadic neurodegenerative disease
characterized by varying degrees of Parkinsonism, cerebellar ataxia and
autonomic dysfunction.
- Two major forms of MSA have been
described; striato-nigral MSA (MSA-SND) in which predominant
degeneration occurs in the striatum and substantia nigra, and
olivopontocerebellar MSA (MSA-OPCA) which is characterized by major
damage to the brainstem and cerebellum.
- Patients with MSA-SND typically present with Parkinson-like symptoms,
while patients with OPCA show more advanced cerebellar ataxias, although
there is considerable overlap between the two subtypes.
- In addition, all patients show damage in the pons, a brainstem region
that relays information from the cortex and midbrain to the cerebellum
and brainstem
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25
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26
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27
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28
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29
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30
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- Gene expression in mitochondrial complexes I, III, and IV is
downregulated in MSA vs. control pons tissues.
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31
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- Proteasomal subunit gene expression is downregulated in MSA compared to
control pons tissue
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32
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- The Parkinsonian syndrome induced by pesticides is associated with the
impairment of mitochondrial function.
- Toxicants that inhibit selectively NADH-dehydrogenase activity, as
rotenone or pyridaben, also show a selective inhibition of O2 uptake in
rat brain.
- Paraquat produced a non-selective inhibition affecting all the
respiratory chain complexes.
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33
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- In MSA patients, gene expression deficits occurred in mitochondrial
complexes I, III, and IV
- Similarly, animal studies involving exposure to, for example, rotenone,
paraquat, diquat, pyridaben, fenpyroximate, fenazaquin, and/or
tebunfenpyrad defined alterations in function in mitochondrial complexes
specific for the different pesticides.
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34
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- Aging – caused by inefficient mitochondrial electron transport; free
oxygen radicals damage DNA, proteins, and other molecules.
- Free radical damaged proteasomes stop removing worn-out, misshapen
proteins, which leads to more cellular damage, and ultimately cell death
- Pesticides cause brain cells to age prematurely by disrupting electron
transport and proteasomal function
- Thus, environmentally induced neurological disease should increase as
more pesticides are placed in the environment
- More Parkinsonism cases occur in geographic areas where pesticides are
heavily used (e.g., the Midwest)
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Notes
