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Rojas D.,Curriculum in Toxicology | DeBussycher T.,Center for Bioinformatics | Ashley-Koch A.,Center for Human Genetics
Epigenetics : official journal of the DNA Methylation Society | Year: 2014

Cadmium (Cd) is prevalent in the environment yet understudied as a developmental toxicant. Cd partially crosses the placental barrier from mother to fetus and is linked to detrimental effects in newborns. Here we examine the relationship between levels of Cd during pregnancy and 5-methylcytosine (5mC) levels in leukocyte DNA collected from 17 mother-newborn pairs. The methylation of cytosines is an epigenetic mechanism known to impact transcriptional signaling and influence health endpoints. A methylated cytosine-guanine (CpG) island recovery assay was used to assess over 4.6 million sites spanning 16,421 CpG islands. Exposure to Cd was classified for each mother-newborn pair according to maternal blood levels and compared with levels of cotinine. Subsets of genes were identified that showed altered DNA methylation levels in their promoter regions in fetal DNA associated with levels of Cd (n = 61), cotinine (n = 366), or both (n = 30). Likewise, in maternal DNA, differentially methylated genes were identified that were associated with Cd (n = 92) or cotinine (n = 134) levels. While the gene sets were largely distinct between maternal and fetal DNA, functional similarities at the biological pathway level were identified including an enrichment of genes that encode for proteins that control transcriptional regulation and apoptosis. Furthermore, conserved DNA motifs with sequence similarity to specific transcription factor binding sites were identified within the CpG islands of the gene sets. This study provides evidence for distinct patterns of DNA methylation or "footprints" in fetal and maternal DNA associated with exposure to Cd.


Shannahan J.H.,Curriculum in Toxicology | Schladweiler M.C.,U.S. Environmental Protection Agency | Thomas R.F.,U.S. Environmental Protection Agency | Ward W.O.,U.S. Environmental Protection Agency | And 3 more authors.
Journal of Toxicology and Environmental Health - Part A: Current Issues | Year: 2012

Exposure to Libby amphibole (LA) asbestos is associated with increased incidences of human autoimmune disease and mortality related to cardiovascular diseases. However, the systemic and vascular impacts are less well examined because of the dominance of pulmonary disease. It was postulated that regardless of the type of exposure scenario, LA exposure might produce systemic and vascular inflammogenic and thrombotic alterations in healthy and cardiovascular compromised rat models. Samples from three independent studies were examined. In the first study, male Wistar Kyoto (WKY), spontaneously hypertensive (SH), and SH heart failure (SHHF) rats were intratracheally instilled once with 0 (vehicle), 0.25, or 1 mg/rat of LA. In the second study, F344 rats were instilled with vehicle or LA at 0.5, 1.5, or 5 mg/rat. In the third study, F344 rats were instilled with the same mass concentrations of LA delivered by biweekly multiple instillations over 3 mo to simulate an episodic subchronic exposure. Complete blood count, platelet aggregation, serum cytokines, and biomarkers of systemic and aortic effects were examined. LA reduced adenosine diphosphate (ADP)-induced platelet aggregation and decreased circulating platelets in WKY (1 mg/rat) and F344 (5 mg/rat) at the 3-mo time point but did not do so in SH or SHHF rats. A decline in circulating lymphocytes with age appeared to be exacerbated by LA exposure in F344 rats but the differences were not significant. Aorta mRNA expression for biomarkers of oxidative stress (HO-1, LOX-1), inflammation (MIP-2), and thrombosis (tPA, PAI-1, vWf) were increased at baseline in SH and SHHF relative to WKY. LA exposure upregulated several of these biomarkers and also those involved in aortic contractility of WKY rats at 3 mo, suggesting thrombogenic, vasocontractile, and oxidative stress-mediated impairments. The aorta changes in F344 rats were less remarkable than changes noted in WKY following LA exposure. In conclusion, exposure to LA decreased circulating platelets and platelet coagulability while increasing the expression of oxidative stress, thrombosis, and vasoconstriction biomarkers in the aorta of healthy rats. These changes were similar to those noted at baseline in SH and SHHF rats, suggesting that LA-induced pulmonary injury might increase the risk of developing cardiovascular disease in healthy individuals. © Copyright Taylor and Francis Group, LLC 2012.


Gavett S.H.,U.S. Environmental Protection Agency | Wood C.E.,U.S. Environmental Protection Agency | Williams M.A.,U.S. Environmental Protection Agency | Cyphert J.M.,Curriculum in Toxicology | And 9 more authors.
Inhalation Toxicology | Year: 2015

Toxicity of exhaust from combustion of petroleum diesel (B0), soy-based biodiesel (B100), or a 20% biodiesel/80% petrodiesel mix (B20) was compared in healthy and house dust mite (HDM)-allergic mice. Fuel emissions were diluted to target fine particulate matter (PM2.5) concentrations of 50, 150, or 500 μg/m3. Studies in healthy mice showed greater levels of neutrophils and MIP-2 in bronchoalveolar lavage (BAL) fluid 2 h after a single 4-h exposure to B0 compared with mice exposed to B20 or B100. No consistent differences in BAL cells and biochemistry, or hematological parameters, were observed after 5 d or 4 weeks of exposure to any of the emissions. Air-exposed HDM-allergic mice had significantly increased responsiveness to methacholine aerosol challenge compared with non-allergic mice. Exposure to any of the emissions for 4 weeks did not further increase responsiveness in either non-allergic or HDM-allergic mice, and few parameters of allergic inflammation in BAL fluid were altered. Lung and nasal pathology were not significantly different among B0-, B20-, or B100-exposed groups. In HDM-allergic mice, exposure to B0, but not B20 or B100, significantly increased resting peribronchiolar lymph node cell proliferation and production of TH2 cytokines (IL-4, IL-5, and IL-13) and IL-17 in comparison with air-exposed allergic mice. These results suggest that diesel exhaust at a relatively high concentration (500 μg/m3) can induce inflammation acutely in healthy mice and exacerbate some components of allergic responses, while comparable concentrations of B20 or B100 soy biodiesel fuels did not elicit responses different from those caused by air exposure alone. © 2015, Informa Healthcare. All rights reserved.


Shannahan J.H.,Curriculum in Toxicology | Ghio A.J.,U.S. Environmental Protection Agency | Schladweiler M.C.,U.S. Environmental Protection Agency | Richards J.H.,U.S. Environmental Protection Agency | And 3 more authors.
Inhalation Toxicology | Year: 2012

The induction of the NALP3 inflammasome complex is shown to be necessary for the development of fibrosis after asbestos exposure. Libby amphibole (LA) induces lung inflammation and fibrosis, while complexation of iron (Fe) on fibers inhibits inflammation. In this study we examined the ability of LA to induce the inflammasome cascade and the role of Fe in modulating inflammasome activity. Spontaneously hypertensive rats were exposed intratracheally to either saline (300 μl), deferoxamine (Def) (1mg), FeCl3 (21 μg), LA (0.5mg), Fe-loaded LA (Fe + LA), or LA + Def. Activities of oxidative stress-sensitive enzymes, expression of inflammasome-specific genes, and cytokine proteins in bronchoalveolar lavage fluid were analyzed. Lung enzymes at 4h and 24h post-exposure were unchanged. LA increased lung expression of genes including interleukin-1β (IL-1β), cathepsin-B, ASC, NALP3, interleukin (IL)-6 and NFκB. LA+Fe significantly reduced IL-1β and NFκB with a trend of reduction in ASC, NALP3, cathepsin-B and IL-6 expression. Def treatment did not reverse the inhibitory effect of Fe on IL-1β and ASC but reversed IL-6 expression. CCL-7, CCL-12, CXCL-3 and COX-2 were induced by LA while LA+Fe tended to reduce these responses. Phosphorylation of ERK but not MEK was increased at 4h after LA but not LA+Fe exposure. In conclusion, components of the NALP3 inflammasome are transcriptionally activated acutely during LA-induced inflammation. The key inflammatory regulators IL-1β and NFκB were inhibited in the presence of surface-complexed Fe possibly through decreased ERK signaling upstream of the NALP3 inflammasome. The inflammasome activation by LA may contribute to fibrosis, and Fe may reduce this response and alter compensatory mechanisms in individuals exposed to LA. © 2012 Informa Healthcare USA, Inc.


Padilla-Carlin D.J.,Curriculum in Toxicology | Schladweiler M.C.J.,U.S. Environmental Protection Agency | Shannahan J.H.,Curriculum in Toxicology | Kodavanti U.P.,U.S. Environmental Protection Agency | And 3 more authors.
Journal of Toxicology and Environmental Health - Part A: Current Issues | Year: 2011

Increased incidences of asbestosis have been reported in workers from Libby, MT, associated with exposures to amphibole-contaminated vermiculite. In this study pulmonary and histopathological changes were investigated following Libby amphibole (LA) exposure in a rat model. Rat respirable fractions of LA and amosite (aerodynamic diameter >2.5 μm) were prepared by water elutriation. Male F344 rats were exposed to single doses of either saline (SAL), amosite (0.65 mg/rat), or LA (0.65 or 6.5 mg/rat) by intratracheal instillation. At times from 1 d to 3 mo after exposure, bronchoalveolar lavage (BAL) was performed and right and left lungs were removed for reverse-transcription polymerase chain reaction (RT-PCR) and histopathological analysis, respectively. Data indicated that 0.65 mg amosite resulted in a higher degree of pulmonary injury, inflammation, and fibrotic events than LA at the same mass dose. Exposure to either amosite or high dose LA resulted in higher levels of cellular permeability and injury, inflammatory enzymes, and iron binding proteins in both BAL fluid and lung tissue at most time points when compared to SAL controls. However, mRNA expression for some growth factors (e.g., platelet-derived growth factor [PDGF]-A and transforming growth factor [TGF]-1β), which contribute to fibrosis, were downregulated at several time points. Furthermore, histopathological examination showed notable thickening of interstitial areas surrounding the alveolar ducts and terminal bronchioles. On a mass dose basis, amosite produced a greater acute and persistent lung injury for at least 3 mo after exposure. However, further testing and analysis of LA are needed with regard to the dose metric to fully evaluate its potential fibrogenicity and carcinogenicity. Copyright © Taylor & Francis Group, LLC.

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