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Shen, Min,Zhang, Luoping,Lee, Kyoung-Mu,Vermeulen, Roel,Hosgood, H. Dean,Li, Guilan,Yin, Songnian,Rothman, Nathaniel,Chanock, Stephen,Smith, Martyn T.,Lan, Qing Korean Society for Biochemistry and Molecular Bion 2011 Experimental and molecular medicine Vol.43 No.6
Benzene, a recognized hematotoxicant and carcinogen, can damage the human immune system. We studied the association between single nucleotide polymorphisms (SNPs) in genes involved in innate immunity and benzene hematotoxicity in a cross-sectional study of workers exposed to benzene (250 workers and 140 controls). A total of 1,236 tag SNPs in 149 gene regions of six pathways were included in the analysis. Six gene regions were significant for their association with white blood cell (WBC) counts ($MBP$, $VCAM1$, $ALOX5$, $MPO$, $RAC2$, and $CRP$) based on gene-region (P < 0.05) and SNP analyses (FDR <0.05). $VCAM1$ rs3176867, $ALOX5$ rs7099684, and $MPO$ rs2071409 were the three most significant SNPs. They showed similar effects on WBC subtypes, especially granulocytes, lymphocytes, and monocytes. A 3-SNP block in $ALOXE3$ (rs7215658, rs9892383, and rs3027208) showed a global association (omnibus P = 0.0008) with WBCs even though the three SNPs were not significant individually. Our study suggests that polymorphisms in innate immunity genes may play a role in benzene-induced hematotoxicity; however, independent replication is necessary.
High-resolution metabolomics of occupational exposure to trichloroethylene
Walker, Douglas I,Uppal, Karan,Zhang, Luoping,Vermeulen, Roel,Smith, Martyn,Hu, Wei,Purdue, Mark P,Tang, Xiaojiang,Reiss, Boris,Kim, Sungkyoon,Li, Laiyu,Huang, Hanlin,Pennell, Kurt D,Jones, Dean P,Rot Oxford University Press 2016 International journal of epidemiology Vol.45 No.5
<P><B>Background:</B> Occupational exposure to trichloroethylene (TCE) has been linked to adverse health outcomes including non-Hodgkin’s lymphoma and kidney and liver cancer; however, TCE’s mode of action for development of these diseases in humans is not well understood.</P><P><B>Methods:</B> Non-targeted metabolomics analysis of plasma obtained from 80 TCE-exposed workers [full shift exposure range of 0.4 to 230 parts-per-million of air (ppm<SUB>a</SUB>)] and 95 matched controls were completed by ultra-high resolution mass spectrometry. Biological response to TCE exposure was determined using a metabolome-wide association study (MWAS) framework, with metabolic changes and plasma TCE metabolites evaluated by dose-response and pathway enrichment. Biological perturbations were then linked to immunological, renal and exposure molecular markers measured in the same population.</P><P><B>Results:</B> Metabolic features associated with TCE exposure included known TCE metabolites, unidentifiable chlorinated compounds and endogenous metabolites. Exposure resulted in a systemic response in endogenous metabolism, including disruption in purine catabolism and decreases in sulphur amino acid and bile acid biosynthesis pathways. Metabolite associations with TCE exposure included uric acid (<I>β</I> = 0.13, <I>P</I>-value = 3.6 × 10<SUP>−5</SUP>), glutamine (<I>β</I> = 0.08, <I>P</I>-value = 0.0013), cystine (<I>β</I> = 0.75, <I>P</I>-value = 0.0022), methylthioadenosine (<I>β</I> = −1.6, <I>P</I>-value = 0.0043), taurine (<I>β</I> = −2.4, <I>P</I>-value = 0.0011) and chenodeoxycholic acid (<I>β</I> = −1.3, <I>P</I>-value = 0.0039), which are consistent with known toxic effects of TCE, including immunosuppression, hepatotoxicity and nephrotoxicity. Correlation with additional exposure markers and physiological endpoints supported known disease associations.</P><P><B>Conclusions:</B> High-resolution metabolomics correlates measured occupational exposure to internal dose and metabolic response, providing insight into molecular mechanisms of exposure-related disease aetiology.</P>
Min Shen,H. Dean Hosgood,Luoping Zhang,이경무,Roel Vermeulen,Guilan Li,Songnian Yin,Nathaniel Rothman,Stephen Chanock,Martyn T. Smith,Qing Lan 생화학분자생물학회 2011 Experimental and molecular medicine Vol.43 No.6
Benzene, a recognized hematotoxicant and carcinogen,can damage the human immune system. We studied the association between single nucleotide polymorphisms (SNPs) in genes involved in innate immunity and benzene hematotoxicity in a cross-sectional study of workers exposed to benzene (250 workers and 140 controls). A total of 1,236 tag SNPs in 149gene regions of six pathways were included in the analysis. Six gene regions were significant for their association with white blood cell (WBC) counts (MBP,VCAM1, ALOX5, MPO, RAC2, and CRP) based on gene-region (P < 0.05) and SNP analyses (FDR <0.05). VCAM1 rs3176867, ALOX5 rs7099684, and MPO rs2071409 were the three most significant SNPs. They showed similar effects on WBC subtypes, especially granulocytes, lymphocytes, and monocytes. A 3-SNP block in ALOXE3 (rs7215658, rs9892383, and rs3027208) showed a global association (omnibus P =0.0008) with WBCs even though the three SNPs were not significant individually. Our study suggests that polymorphisms in innate immunity genes may play a role in benzene-induced hematotoxicity; however, independent replication is necessary.
Lerro, Catherine,Freeman, Laura Beane,Portengen, Lutzen,Kang, Dahee,Lee, Kyoungho,Blair, Aaron,Lynch, Charles,Bakke, Berit,Roos, Anneclaire de,Vermeulen, Roel BMJ Publishing Group Ltd 2016 Occupational and environmental medicine Vol.73 No.suppl1
<P><B>Introduction</B></P><P>Reactive oxygen species, potentially formed through environmental or lifestyle exposures, can overwhelm an organism’s antioxidant capabilities resulting in oxidative stress. Long-term oxidative stress is linked with chronic diseases including breast, prostate, and lung cancers. We utilised a longitudinal study of corn farmers and non-farming controls in Iowa to examine the impact of exposure to atrazine and 2,4-dichlorophenoxyacetic acid (2,4-D) on markers of oxidative stress. These pesticides are associated with oxidative stress in vivo, as well as cancer, and are among the most widely used herbicides in the United States. </P><P><B>Methods</B></P><P>The study included 225 urine samples collected through the growing season (pre-planting, planting, growing season, harvest, and off-season) of 10 controls who did not apply pesticides occupationally and 30 farmers who did; all were non-smoking men ages 40 to 60 years. Atrazine mercapturate (an atrazine metabolite), 2,4-D, and oxidative stress markers (malondialdehyde [MDA], 8-hydroxy-2′-deoxyguanosine [8-OHdG], and 8-isoprostaglandin-F2α [8-isoPGF]) were measured in urine samples. We calculated β estimates and p-values for each pesticide-oxidative stress marker combination using linear mixed-effect models adjusted for creatinine, time, and other covariates in order understand the impact of exposure to these herbicides on oxidative stress. </P><P><B>Results</B></P><P>Overall, farmers had higher urinary atrazine mercapturate and 2,4-D levels compared to controls. In multivariate linear mixed-effect regression models, after natural log transformation, 2,4-D was associated with elevated levels of 8-OHdG (β = 0.047, p = 0.048) and 8-isoPGF (β = 0.076, p = 0.075). We saw no associations with 2,4-D and MDA. Atrazine mercapturate was not associated with any of the oxidative stress markers.</P><P><B>Discussion</B></P><P>Our data suggest 2,4-D exposure may be associated with oxidative stress because of increases of 8-OHdG, a marker of oxidative DNA damage, and 8-isoPGF, a product of lipoprotein peroxidation with exposure. Future studies should attempt to understand the role of 2,4-D-induced oxidative stress in the pathogenesis of human disease, particularly cancer.</P>