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8.2 L. Budnik
1. 1
Circulating mitochondrial DNA as an effect-biomarker
after exposure to halo-alkane based pesticides
Lygia T. Budnik1, Stefan Kloth1, Xaver Baur2,,
Alexandra M. Preisser 1, Heidi Schwarzenbach 3
1 Institute for Occupational and Maritime Medicine, Department of Occupational Health, School of
Medicine, University of Hamburg, Hamburg, Germany
2 Institute for Occupational Medicine, Campus Benjamin Franklin, Charité-School of Medicine,
Berlin, Germany.
3 Department of Tumor Biology. School of Medicine, University of Hamburg, Hamburg, Germany
LBudnik@uke.de
There is a need for a panel of suitable effect biomarkers for
detection of environmental chemical exposure
leading to the initiation or progression of degenerative diseases
or potentially cancer.
2. 2
Since peripheral blood contains increased levels of circulating
cell-free DNA in diseased individuals, we aimed to evaluate this
DNA as effect biomarker recognizing vulnerability after
exposure to environmental chemicals.
intox. target organes
release cell-free DNA
in to the blood
stream
zf-DNA-Extraktion
Container and other transport units are un-loaded deep within the country sides outside
the harbour areas. Workers and Bystanders can be exposed to fumigant residues in
storage rooms
Short-term high exposure Symptoms: (latency period of 2-48 h -3 days)
Central nervous system depression, neuropsychiatry abnormalities
(headache, nausea, dizziness)
Inflammation of the bronchi and lung, Pulmonary edema
(flu like symptoms, phlegm, chest pain, shortness of breath)
“Pesticides used as fumigants are often at least as poisono-
us to humans as to the pests against which they are used”
IMO, 2005 (International Maritime Organisation).
3. 3
164 subjects with presumed intoxication to fumigants
(plus 30 controls).
78% male and 22% female subjects at median age of 44; 66% smoker, 34% non-smoker
The exposure assessment was performed with human
biomonitoring (methyl bromide, ethylene dichloride,
dichloromethane, other halo-alkanes).
Exposure-
Biomonitoring Diagnosis
Ambient-
monitoring Effect-
Biomonitoring
Budnik et al., 2013 PLoS ONE 8(5)
4. 4
Confirmed: 86 exposures to halo-alkanes above the non-cancer
reference doses (RfD), but (mostly) lower than the occupational
exposure limits
Data from: Budnik et al., 2013 PLoS ONE 8(5)
. Cell-free DNA may provide information from intoxicated organs
Data from: Budnik et al., 2013 PLoS ONE 8(5)
5. 5
Exposure was associated with elevated serum levels of
circulating mitochondrial DNA (in size of 79 bp, mtDNA-79).
serum mtDNA-79 level serum mtDNA-79 level
All exposed vs Controls
MeBr exposed vs Controls
Data from: Budnik et al., 2013 PLoS ONE 8(5)
serum mtDNA integrity
p=0.0158
serum mtDNA-230 level
p=0.005
The increased integrity of mtDNA (mtDNA-230/mtDNA-79) in
exposed individuals implicates apoptotic processes.
Data from: Budnik et al., 2013 PLoS ONE 8(5)
6. 6
Patient subgroups
P1 current intoxication
P2 short-term past exposure (weeks, up to 4 months)
P3 long-term past exposure (interim time at least 5 months)
Patient subgroups
P1 current intoxication
P2 short-term past exposure (weeks, up to 4 months)
P3 long-term past exposure (interim time at least 5 months)
The relative amounts of mtDNA-79 in serum were positively associated with the lag-time
after intoxication of these chemicals (r=0.99, p<0.0001).
The relative amounts of mtDNA-79 in serum were positively associated with the lag-time
after intoxication of these chemicals (r=0.99, p<0.0001).
Data from: Budnik et al., 2013 PLoS ONE 8(5)
AUC=0.79
95% CI (0.64-0.95)
p=0.004
Serum mtDNA-79 level
AUC=0.77
95% CI (0.65-0.88)
p=0.003
mtDNA-Integrity
The specificity for this biomarker increased from 30% to
97% several months post-exposure in patients with
intoxication symptoms.
Specificity and sensitivity
Data from: Budnik et al., 2013 PLoS ONE 8(5)
7. 7
ConclusionsConclusions
Our findings:
show enhanced cell free mtDNA levels in patients exposed to halogenated
hydrocarbone pesticides
corraborate the data showing increased mtDNA in patients exposed to low levels
of benzene (<100 ppb)
Our findings:
show enhanced cell free mtDNA levels in patients exposed to halogenated
hydrocarbone pesticides
corraborate the data showing increased mtDNA in patients exposed to low levels
of benzene (<100 ppb)
The findings indicate that mitochondrial DNA has a potential to serve as a biomarker
recognizing vulnerable risk groups after exposure to toxic/carcinogenic chemicals
The findings indicate that mitochondrial DNA has a potential to serve as a biomarker
recognizing vulnerable risk groups after exposure to toxic/carcinogenic chemicals
But also:
Open many questions regarding possible molecular mechanisms
But also:
Open many questions regarding possible molecular mechanisms
Thank you