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8.2 L. Budnik

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8.2 L. Budnik

  1. 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. 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. 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. 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. 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. 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. 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

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