Post on 03-Jan-2016
description
Toxicology Study of Inhalable Soil Dusts from the Paso del Norte
RegionDr. N. Shane Cutler, Ph.D.
University of UtahSalt Lake City, UT
SCERP grant A-05-06
Soil Dusts
• JE-Juarez City Street Dust, Mexico • WM-West Mesa, New Mexico • DD-Tooele Desert Dust, Utah• WTR-Well Test Road, Arizona• UTEP-U. of Texas, El Paso parking lot• MC-Mancos, Colorado• FB-Ft. Bliss, Texas• BA-Burned Artillery Range, New Mexico
Soil Dusts are collected from arid regions and separated out into an inhalable 2.5 μm diameter fraction. Cells are treated at 40 μg/cm2
Veranth, et al Environ Health Perspectives. 2006 Mar;114(3):341-9
Veranth, et al Environ Health Perspectives. 2006 Mar;114(3):341-9
Univariate correlations of soil-derived dust composition variables with the concentration of IL-6 in the cell media at 24 hr.(A) EC1 (R2 = 0.50). (B) OP (R2 = 0.46). (C) Calcium/aluminum (R2 = 0.21). (D) Endotoxin (R2 = 0.43). (E) Iron (R2 = 0.03). (F) Arsenic + selenium + mercury + lead (R2 = 0.01).
The MAP Kinase Pathways
Raf, Mos, Tpl2
Mek1/2
Erk1/2
MKK3/6
P38 MAPK α/β/γ
MLK3, TAK, DLK
MKK4/7
JNK1/2/3
U0126
p38i JNKi
Growth Factors, Mitogens, GPCR
Stress, Inflammatory Cytokines, Growth Factors, Mitogens, GPCR
Inflammation, Apoptosis, Growth, Differentiation
Growth, DifferentiationDevelopment
Stimulus
MAPKKK
MAPKK
MAPK
BiologicalResponse
MEKK1,4MLK3,ASK1
Inhibitors of Map Kinase Pathways Block IL-6 Production in vitro
0
20
40
60
80
100
120
BA
DD
FB JE MC
UTE
P
WM
WTR
Soil Dust
IL-6
(pg/m
L)
0U0126p38iJ NKiCONTROL
Inflammatory Dust Induces p38 MAPK phosphorylation
in vitro
TotalERK ►
U0126: - + - + - + - +
phosphop38 ►
GAPDH►
phosphoJNK►
TotalJNK ►
SOIL DUSTUTEP JE WM Nonep38i: - + - + - + - +
JNKi: - + - + - + - +
PhosphoERK ►
Tracheal Instillation of Soil Dust
----
Bronchial Alveolar Lavage
----
Bronchial Alveolar Lavage
----
Bronchial Alveolar Lavage
Neutrophil
Eosinophil
Basophil Lymphocyte
Monocyte
Lactate DehydrogenaseIL-6
Total Protein
Inhaled poorly
Inhaled well
Lactate Dehydrogenase
0.0
1.0
2.0
3.0
4.0
5.0
6.0L
DH
Ac
tiv
ity
Serum IL-6
0.00
0.050.10
0.15
0.20
0.250.30
0.35
0.40
Saline coarse JE
A45
0-A
540
Neutrophil
Eosinophil
Basophil Lymphocyte
Monocyte
%Neutrophils By Treatment
%N
eu
tro
ph
ils
0.20
0.25
0.30
0.35
0.40
0.45
0.50
0.55
Coarse Fine Saline
Treatment
Analysis Display
Oneway Anova
Summary of FitRSquareRSquare AdjRoot Mean Square ErrorMean of ResponseObservations (or Sum Wgts)
0.3225040.2182740.0883660.399189
16
Analysis of VarianceSourceModelErrorC Total
DF 2
13 15
Sum of Squares0.048321780.101511190.14983297
Mean Square0.0241610.0078090.009989
F Ratio 3.0942Prob>F 0.0796
Means for Oneway AnovaLevelCoarseFineSaline
Number 5 6 5
Mean0.4764440.3833710.340915
Std Error0.039520.036080.03952
Std Error uses a pooled estimate of error variance
%Neutrophils By Treatment
%N
eu
tro
ph
ils
0.20
0.25
0.30
0.35
0.40
0.45
0.50
0.55
Coarse Fine Saline
Treatment
Analysis Display
Oneway Anova
Summary of FitRSquareRSquare AdjRoot Mean Square ErrorMean of ResponseObservations (or Sum Wgts)
0.3225040.2182740.0883660.399189
16
Analysis of VarianceSourceModelErrorC Total
DF 2
13 15
Sum of Squares0.048321780.101511190.14983297
Mean Square0.0241610.0078090.009989
F Ratio 3.0942Prob>F 0.0796
Means for Oneway AnovaLevelCoarseFineSaline
Number 5 6 5
Mean0.4764440.3833710.340915
Std Error0.039520.036080.03952
Std Error uses a pooled estimate of error variance
phospho38
Saline Fine JE Coarse JE
phosphoJNK
Total JNK
The MAP Kinase Pathways
Raf, Mos, Tpl2
Mek1/2
Erk1/2
MKK3/6
P38 MAPK α/β/γ
MLK3, TAK, DLK
MKK4/7
JNK1/2/3
U0126
p38i JNKi
Growth Factors, Mitogens, GPCR
Stress, Inflammatory Cytokines, Growth Factors, Mitogens, GPCR
Inflammation, Apoptosis, Growth, Differentiation
Growth, DifferentiationDevelopment
Stimulus
MAPKKK
MAPKK
MAPK
BiologicalResponse
MEKK1,4MLK3,ASK1
Neutrophil Enrichment in Rat Bronchialveolar Lavage Fluid
0%
10%
20%
30%
40%
50%
60%
Saline Fine JE Coarse JE
% N
eu
tro
ph
ils
Neutrophil
Eosinophil
Basophil Lymphocyte
Monocyte