Publications (30) View all
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Article: Acute toluene exposure alters expression of genes in the central nervous system associated with synaptic structure and function.
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ABSTRACT: Toluene is a volatile organic compound (VOC) and a ubiquitous air pollutant of interest to EPA regulatory programs. Whereas its acute functional effects are well described, several modes of action in the CNS have been proposed. Therefore, we sought to identify potential pathways mediating direct or indirect effects of VOCs by investigating the genomic response of the rat CNS to acutely-inhaled toluene. Adult male Long-Evans rats inhaled clean air or 1000 ppm toluene vapor for 6 h. Specific brain regions were collected from the rats either immediately after 6 h of treatment or 18 h after removal from the exposure chambers (n=6/group/time). Total mRNA was extracted from the striatum and hybridized to Rat 230A Affymetrix arrays. Statistical analyses showed 226 and 3352 transcripts altered in the toluene-exposed groups relative to controls at the 6 h time point and after the 18 h recovery period, respectively. Relative to controls, toluene exposure was associated with induction or repression of genes in pathways associated with synaptic plasticity, including long-term depression, GABA receptor signaling and mitochondrial function. In each of these pathways, responses were characterized by changes in a small number of transcripts following the 6 h toluene inhalation and with substantial increases in numbers of changed transcripts at 18 h recovery following termination of exposure. This report provides the first global genomic evidence that CNS pathways affected by toluene are strongly associated with neurological processes participating in synaptic transmission and plasticity.Neurotoxicology and Teratology 07/2011; 33(5):521-9. · 2.98 Impact Factor -
Article: Transcriptional profile of diuron-induced toxicity on the urinary bladder of male Wistar rats to inform mode of action.
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ABSTRACT: Diuron (3-(3,4-dichlorophenyl)-1,1-dimethylurea) is a substituted urea herbicide that induces rat urinary bladder urothelial tumors at high dietary levels (2500 ppm). The specific mode of action and molecular alterations triggered by diuron, however, have not been clarified. The present study evaluated the dose-dependent effects of mucosal alterations and transcriptional changes in the urinary bladder of rats exposed to diuron. Six-week-old male Wistar rats were treated with 0, 60, 125, 1250, and 2500 ppm of diuron in the diet for 20 weeks. Histologic examination showed urothelial hyperplasia present in rats treated with either 1250 or 2500 ppm of diuron but not 60 or 125 ppm. Comprehensive gene expression analyses of urothelial cell RNA were conducted using Affymetrix microarrays. The numbers of differentially expressed transcripts between each treatment group and control increased with diuron dose. Based on similar histology and gene expression responses, the treatment groups were regrouped into a high-dose (1250 and 2500 ppm) and low-dose group (60 and 125 ppm). These data suggest that persistent exposure to high dietary concentrations of diuron induces oxidative stress, increases cellular metabolism, and enhances cell death that is associated with sustained urothelial hyperplasia.Toxicological Sciences 05/2011; 122(2):330-8. · 4.65 Impact Factor -
Article: Gene expression of normal human epidermal keratinocytes modulated by trivalent arsenicals.
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ABSTRACT: Chronic exposure to inorganic arsenic (iAs) is associated with the development of benign and malignant human skin lesions including nonmelanoma skin cancers. The precise arsenical form(s) responsible for this carcinogenic effect are unknown, although trivalent inorganic arsenic (iAs(III)) and two of its toxic metabolites, monomethylarsonous acid (MMA(III)) and methylarsinous acid (DMA(III)), are attractive candidates. In an effort to better understand and compare their toxic effects in the skin, we compared the global gene expression profiles of normal human epidermal keratinocytes (NHEKs) exposed to varying noncytotoxic/slightly cytotoxic concentrations of iAs(III), MMA(III), and DMA(III) for 24 h. Exposure to each arsenical treatment group exhibited a dose effect in the number of altered genes and the magnitude of expression change in NHEKs. The most significant gene expression changes associated with iAs(III) and MMA(III) exposure were consistent with several key events believed to be important to As-driven skin carcinogenesis, namely induction of oxidative stress, increased transcript levels of keratinocyte growth factors, and modulation of MAPK and NF-κB pathways. At both comparable arsenical concentrations and comparable NHEK toxicity, greater potential carcinogenic effects were observed in MMA(III)-exposed NHEKs than those exposed to iAs(III), including involvement of more proinflammatory signals and increased transcript levels of more growth factor genes. In contrast, none of these above-mentioned transcriptional trends were among the most significantly altered functions in the DMA(III) treatment group. This study suggests the relative capacity of each of the tested arsenicals to drive suspected key events in As-mediated skin carcinogenesis is MMA(III) > iAs(III) with little contribution from DMA(III).Molecular Carcinogenesis 09/2010; 49(12):981-98. · 3.16 Impact Factor -
Article: Functionally charged polystyrene particles activate immortalized mouse microglia (BV2): cellular and genomic response
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ABSTRACT: The effect of particle surface charge on the biological activation of immortalized mouse microglia (BV2) was examined. Same size (850–950 nm) spherical polystyrene microparticles (SPM) with net negative (carboxyl, COOH-) or positive (dimethyl amino, CH3)2-N- zeta potentials were exposed to BV2 microglia (5–20 µl/ml). Both stimulated an oxidative burst, increased Caspase 3/7 activity and caused inflammatory cytokine release. Ultrastructure indicated that SPM particles were phagocytosed as single particles but formed large intra-cellular 4–6 µm agglomerates. Microarray analysis indicated that negatively charged SPM-COOH- affected approximately 146 genes while the positively charged SPM-(CH3)2-N- affected approximately 2580 genes. Only 30 genes were significantly affected in common. Of the 48 genes associated with oxidative stress pathways, 33 genes were coordinately down-regulated by SPM-(CH3)2-N- and up-regulated by SPM-COOH- exposure. Together, these data indicate that functionally charged, inert submicron-size particles differentially activate BV2 microglia along oxidative stress and inflammatory pathways.07/2009; 2(3):130-143. -
Article: Transcriptional responses in rat brain associated with sub-chronic toluene inhalation are not predicted by effects of acute toluene inhalation.
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ABSTRACT: A primary public health concern regarding environmental chemicals is the potential for persistent effects from long-term exposure, and approaches to estimate these effects from short-term exposures are needed. Toluene, a ubiquitous air pollutant, exerts well-documented acute and persistent CNS-mediated effects from a variety of exposure scenarios, and so provides a useful case for determining whether its persistent effects can be predicted from its acute effects on the CNS. We recently reported that acute inhalation of toluene produced transcriptional effects in rat brain 18h following a single, acute 6-h exposure to toluene. The goal of the present study was to determine whether these acute effects are also evident after long-term (sub-chronic) exposure to toluene, and thereby provide a mechanistic basis for predicting its persistent effects from short-term exposures. Male Long-Evans rats were exposed to toluene via inhalation (0, 10, 100, 1000ppm, n=5/dose), 6h/day for 64days, excluding weekends. The day following the final exposure, total mRNA was extracted from the cerebral cortex and striatum, and gene expression evaluated using Affymetrix arrays. Principal component analysis using all samples showed a clear discrimination of tissues, with striatum having more within-group variance than cortex. Differentially-expressed genes (DEGs) whose expression was altered by toluene were identified in each tissue by ANOVA followed by mapping to pathways. Analysis of striatum revealed 22, 57, and 94 significant DEGs for the 10ppm, 100ppm, and 1000ppm doses, respectively, far fewer than the 3352 DEGS previously observed after acute exposure. In addition, the direction of change in the 57 DEGs common to both exposures differed between acute and sub-chronic exposure scenarios. Thus, relative to acute toluene exposure, sub-chronic exposure yielded both quantitative and qualitative differences in transcriptional response. Based on the current data, long-term gene expression changes after toluene inhalation cannot be readily predicted by acute responses.Neurotoxicology and Teratology 08/2012; 34(5):530-3. · 2.98 Impact Factor
