Blood gene expression markers to detect and distinguish target organ toxicity

Umbright, Christina; Sellamuthu, Rajendran; Li, Shengqiao; Kashon, Michael L.; Luster, Michael I.; Joseph, Pius

doi:10.1007/s11010-009-0272-5

Cited by 41 publications

(31 citation statements)

References 28 publications

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“…The authors also identified distinct gene expression markers capable of detecting neurotoxicity. 37 Gene expression effects identified during our research are weaker then the effects reported in other PCB exposure studies. As mentioned before, the majority of the studies used dioxins, DL PCBs, or Aroclor mixtures that contain the more potent DL PCBs.…”

Section: Chemical Research In Toxicologycontrasting

confidence: 71%

Perinatal Exposure to Purity-Controlled Polychlorinated Biphenyl 52, 138, or 180 Alters Toxicogenomic Profiles in Peripheral Blood of Rats after 4 Months

Boever

Wens

Boix

et al. 2013

Chem. Res. Toxicol.

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It is known from controlled animal experiments and human epidemiologic studies that early life exposure to mixtures of polychlorinated biphenyls (PCBs) is a risk factor for developmental neurotoxicity. The importance of non-dioxin-like PCBs in the context of the observed effect is uncertain because of the blending with the more potent dioxin-like PCBs. Previously, a controlled rat perinatal exposure study with individual, purity-controlled, non-dioxin-like congeners (PCB52, PCB138, or PCB180) was set up. Impaired motor coordination, motor activity, and learning has been reported for the offspring at an age of approximately 4 months. Here, we report on the gene expression responses that have been observed in the blood of the same animals. ANOVA analysis called 1412 genes differentially expressed 4 months after the PCB treatment was stopped. Subsequently, each PCB exposure condition was compared to the corresponding vehicle control using a fold change analysis. The gene lists contained between 82 and 348 differentially expressed genes. Expression patterns were complex with sets of differentially expressed genes being specific for a particular PCB exposure and other sets in common between several exposure conditions. Thirty-two genes were differentially expressed under all conditions. Bioinformatic overrepresentation analysis identified enriched biological terms such as lipid metabolism, molecular transport, small molecule biochemistry, and cell signaling and proliferation. Gene lists were particularly enriched for nervous system development and function ontology. In conclusion, we have documented for the first time differential gene expression in a well-controlled animal study that reported behavioral effects of purity-controlled individual non-dioxin-like PCBs.

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Section: Chemical Research In Toxicologycontrasting

confidence: 71%

Perinatal Exposure to Purity-Controlled Polychlorinated Biphenyl 52, 138, or 180 Alters Toxicogenomic Profiles in Peripheral Blood of Rats after 4 Months

Boever

Wens

Boix

et al. 2013

Chem. Res. Toxicol.

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“…Application of blood as a surrogate tissue to extract genomic indicators for cross tissue prediction of target organ injury has been reported in several studies (Bushel et al, 2007; Lobenhofer et al, 2008; Huang et al, 2010; Umbright et al, 2011). Blood transcriptomic changes have been shown to precede appearance of traditional markers of tissue injury and it has been suggested that blood toxicogenomics might provide novel biomarkers to identify patients who will develop severe liver toxicity after taking overdoses of APAP (Cui and Paules, 2010).…”

Section: Discussionmentioning

confidence: 99%

Identification of Identical Transcript Changes in Liver and Whole Blood during Acetaminophen Toxicity

Zhang¹,

Bushel²,

Chou³

et al. 2012

Front. Gene.

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The ability to identify mechanisms underlying drug-induced liver injury (DILI) in man has been hampered by the difficulty in obtaining liver tissue from patients. It has recently been proposed that whole blood toxicogenomics may provide a non-invasive means for mechanistic studies of human DILI. However, it remains unclear to what extent changes in whole blood transcriptome mirror those in liver mechanistically linked to hepatotoxicity. To address this question, we applied the program Extracting Patterns and Identifying co-expressed Genes (EPIG) to publically available toxicogenomic data obtained from rats treated with both toxic and subtoxic doses of acetaminophen (APAP). In a training set of animals, we identified genes (760 at 6 h and 185 at 24 h post dose) with similar patterns of expression in blood and liver during APAP-induced hepatotoxicity. The pathways represented in the coordinately regulated genes largely involved mitochondrial and immune functions. The identified expression signatures were then evaluated in a separate set of animals for discernment of APAP exposure level or APAP-induced hepatotoxicity. At 6 h, the gene sets from liver and blood had equally sufficient classification of APAP exposure levels. At 24 h when toxicity was evident, the gene sets did not perform well in evaluating APAP exposure doses, but provided accurate classification of dose-independent liver injury that was evaluated by serum ALT elevation in the blood. Only 38 genes were common to both the 6 and 24-h gene sets, but these genes had the same capability as the parent gene sets to discern the exposure level and degree of liver injury. Some of the parallel transcript changes reflect pathways that are relevant to APAP hepatotoxicity, including mitochondria and immune functions. However, the extent to which these changes reflect similar mechanisms of action in both tissues remains to be determined.

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“…This work revealed multiple up-regulated genes involved in metabolism, cell cycle, apoptosis and antioxidant activities, among others [38]. In another study, the use of microarray analysis from the global gene expression profile of rat blood identified distinct gene expression markers capable of detecting and distinguishing if hepatotoxicity and neurotoxicity could be induced by different chemical agents [39]. Another common occupational health hazard is exposure to radiation.…”

Section: Evaluation Of Gene Expressionmentioning

confidence: 99%

The Role of Molecular Biology in the Biomonitoring of Human Exposure to Chemicals

Muñoz

Albores

2010

IJMS

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Exposure to different substances in an occupational environment is of utmost concern to global agencies such as the World Health Organization and the International Labour Organization. Interest in improving work health conditions, particularly of those employees exposed to noxious chemicals, has increased considerably and has stimulated the search for new, more specific and selective tests. Recently, the field of molecular biology has been indicated as an alternative technique for monitoring personnel while evaluating work-related pathologies. Originally, occupational exposure to environmental toxicants was assessed using biochemical techniques to determine the presence of higher concentrations of toxic compounds in blood, urine, or other fluids or tissues; results were used to evaluate potential health risk. However, this approach only estimates the presence of a noxious chemical and its effects, but does not prevent or diminish the risk. Molecular biology methods have become very useful in occupational medicine to provide more accurate and opportune diagnostics. In this review, we discuss the role of the following common techniques: (1) Use of cell cultures; (2) evaluation of gene expression; (3) the “omic” sciences (genomics, transcriptomics, proteomics and metabolomics) and (4) bioinformatics. We suggest that molecular biology has many applications in occupational health where the data can be applied to general environmental conditions.

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Blood gene expression markers to detect and distinguish target organ toxicity

Cited by 41 publications

References 28 publications

Perinatal Exposure to Purity-Controlled Polychlorinated Biphenyl 52, 138, or 180 Alters Toxicogenomic Profiles in Peripheral Blood of Rats after 4 Months

Perinatal Exposure to Purity-Controlled Polychlorinated Biphenyl 52, 138, or 180 Alters Toxicogenomic Profiles in Peripheral Blood of Rats after 4 Months

Identification of Identical Transcript Changes in Liver and Whole Blood during Acetaminophen Toxicity

The Role of Molecular Biology in the Biomonitoring of Human Exposure to Chemicals

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