The Toxicologist - Society of Toxicology
The Toxicologist - Society of Toxicology
The Toxicologist - Society of Toxicology
You also want an ePaper? Increase the reach of your titles
YUMPU automatically turns print PDFs into web optimized ePapers that Google loves.
century include high-throughput screening technologies to identify cellular interactions<br />
with NMs for efficacy and safety. This session will present ongoing genomics,<br />
proteomics, and metabolomics studies <strong>of</strong> interactions between natural and engineered<br />
NMs and biological systems. Findings <strong>of</strong> novel interactions <strong>of</strong> NMs and biological<br />
systems will be highlighted and the feasibility <strong>of</strong> these approaches for future<br />
comprehensive studies <strong>of</strong> NM efficacy and safety will be discussed. Examples<br />
<strong>of</strong> in vitro cellular interactions with a variety <strong>of</strong> NMs will be provided which include<br />
mRNA, miRNA, and proteomic expression pr<strong>of</strong>iles <strong>of</strong> human and mammalian<br />
cells exposed to nanotubes, nanocrystals (quantum dots), dendrimers and<br />
nano-scale particles <strong>of</strong> both terrestrial and extra-terrestrial origin. Selective activation<br />
<strong>of</strong> specific genes, proteins, and cellular signaling pathways will be related to<br />
possible mechanisms <strong>of</strong> action. We will highlight how the addition <strong>of</strong><br />
metabolomics to other ‘omics based studies can further define the effects <strong>of</strong> NMs<br />
on biological systems after environmental exposures. <strong>The</strong> final presentation will expand<br />
upon the systems biology approach and show how multiple ‘omics technologies<br />
can provide mechanistic meaning when individual data sets are analyzed ranging<br />
from a global to subcellular view. This session should be <strong>of</strong> interest to all<br />
investigators interested in state-<strong>of</strong>-the-art ‘omics technologies for screening the effects<br />
<strong>of</strong> foreign materials, including NMs, in humans and other organisms.<br />
2040 MESSENGER RNA AND MICRORNA EXPRESSION<br />
PROFILING OF NANOMATERIAL INTERACTIONS<br />
WITH PRIMARY HUMAN SKIN AND LUNG CELLS.<br />
M. Cunningham. Nanomics Biosciences, Inc., Cary, NC.<br />
A variety <strong>of</strong> nanomaterials (e.g. carbon nanotubes, dendrimers, lunar dust, quantum<br />
dots, nano- and low micron-scale particulates) were exposed to primary<br />
human skin, lung, and neuronal cells in vitro. <strong>The</strong> activities <strong>of</strong> mRNAs and<br />
miRNAs were pr<strong>of</strong>iled in an effort to elucidate tissue-specific responses to various<br />
NMs. <strong>The</strong> data were analyzed and compared between the different cell types and<br />
materials. Results highlighting the selective activation <strong>of</strong> unique sub-cellular signaling<br />
pathways in different cell types representing different exposure routes and the<br />
consequences <strong>of</strong> NM exposure will be presented.<br />
2041 CARBON NANOPARTICLE EXPOSURE ALTERS<br />
BARRIER EPITHELIAL CELL FUNCTION: PROTEOMIC<br />
AND ELECTROPHYSIOLOGICAL ANALYSES.<br />
F. A. Witzmann. Department <strong>of</strong> Cellular & Integrative Physiology, Indiana<br />
University School <strong>of</strong> Medicine, Indianapolis, IN.<br />
Murine kidney barrier cells (mpkCCDcl4) were exposed to various concentrations<br />
<strong>of</strong> fullerenes, single-walled carbon nanotubes, and unrefined and functionalized<br />
multi-walled carbon nanotubes, in vitro. Differential protein expression was assessed<br />
independently by label-free quantitative mass spectrometry and 2DE.<br />
Transepithelial electrical resistance and hormone stimulated transport were also<br />
measured as physiological endpoints. Results highlighting exposure-related alterations<br />
in protein expression including cell adhesion and tight-junctional proteins,<br />
and barrier cell function unique to nanoparticle type, dose, and degree <strong>of</strong> functionalization<br />
will be presented.<br />
2042 GENOMIC SIGNATURES FOR SIZE-DEPENDENT<br />
BIOLOGICAL EFFECTS OF GOLD NANOPARTICLES.<br />
F. F. Chen. Life Sciences, Lawrence Berkeley National Lab, Berkeley, CA. Sponsor:<br />
M. Cunningham.<br />
Nanoparticles are used increasingly in consumer products and biomedical applications,<br />
yet the cellular interaction mechanism is not well understood for nanomaterials<br />
<strong>of</strong> different physico-chemical properties. Gold nanoparticles (Au-NPs) are<br />
used as the model system to help understand the size-dependent biological effects<br />
<strong>of</strong> nanoparticles. Cells treated with Au-NPs ranging from 2 nm to 200 nm were<br />
studied. Whole genome expression measurements indicate size-dependent effects at<br />
the molecular level. Gene function, promoter and pathway analyses reveal differential<br />
signaling processes that are correlated with nanoparticle sizes.<br />
2043 IN VITRO AND IN VIVO METABOLOMIC AND<br />
PROTEOMIC BIOMARKER STUDIES OF III-V<br />
SEMICONDUCTORS ON RENAL PROXIMAL TUBULE<br />
CELLS.<br />
B. A. Fowler 1 , E. A. Conner 2 and H. Yamauchi 3 . 1 Division Tox and Env.Med.,<br />
ATSDR/CDC, Atlanta, GA, 2 Laboratory <strong>of</strong> Experimental Carcinogenesis, NCI,<br />
Bethesda, MD and 3 Pharmaceutical Sciences, Kitasato University, Tokyo, Japan.<br />
Recent studies from a number <strong>of</strong> laboratories have demonstrated size - dependent<br />
glomerular clearance <strong>of</strong> nanoparticles <strong>of</strong> various compostitions with vacuolar accumulation<br />
in several renal cell types and subsequent cellular toxicity. Nanoparticles<br />
<strong>of</strong> the III-V semiconductors gallium arsenide (GaAs) and indium arsenide<br />
(InAs)are being used for a variety <strong>of</strong> microelectronic and imaging applications but<br />
the toxicological database on these materials is limited. In order to provide basic scientific<br />
information on cellular responses to GaAs and InAs particles, a series <strong>of</strong> rodent<br />
studies using intracheally administered 4-5 micron particles <strong>of</strong> GaAs or InAs<br />
were conducted to evaluate in vivo proteomic (protein expression patterns) and<br />
metabolomic(heme pathway) responses to these agents in renal tubule cells.<br />
Complimentary in vitro studies using primary cultures <strong>of</strong> renal proximal tubule<br />
cells from both rodents and humans were conducted to examine molecular responses<br />
<strong>of</strong> this target cell population to soluble Ga, In, and As compounds alone or<br />
as combinations. Metabolomic and proteomic biomarker endpoints were monitored<br />
to assess early cellular responses to these agents and manifestations <strong>of</strong> cell injury.<br />
Overall, results <strong>of</strong> these combined in vivo and in vitro studies demonstrated<br />
both element/combination-specific heme pathway and proteomic biomarker patterns<br />
and the importance <strong>of</strong> gender in mediating observed cellular responses.<br />
Oxidative stress and stress protein response patterns appear to be major factors in<br />
mediating the cellular toxicity <strong>of</strong> these agents in renal tubule cell populations.<br />
2044 DYNAMIC NETWORK ANALYSIS OF NANOSILICA-<br />
INDUCED TOXICITY PATHWAYS USING<br />
MICROARRAY AND PROTEOMIC DATA.<br />
K. Waters. Computational Biology & Bioinformatics, Pacific Northwest National<br />
Laboratory, Richland, WA. Sponsor: M. Cunningham.<br />
Nanosilica exposures to mouse macrophage and alveolar epithelial cells were used<br />
to investigate and determine the modes <strong>of</strong> action for nanomaterial-induced inflammation<br />
and cytotoxicity in the lung. Microarray studies in cells exposed to nanosized<br />
amorphous silica demonstrated time- and dose-dependent regulation <strong>of</strong> biological<br />
pathways that can be correlated to cytotoxicity endpoints. Global<br />
proteomics analysis <strong>of</strong> secreted proteins identified extracellular factors that are<br />
known to modulate the inflammatory response. Network inference analyses determined<br />
critical control points in the response pathways that have were subsequently<br />
validated as determinates <strong>of</strong> responses to nanosilica using siRNA and pharmacological<br />
knockdown studies in cells. Response biomarkers for these toxicity pathways<br />
provide a foundation for dose-response modeling <strong>of</strong> nanosilica biocompatibility.<br />
2045 THE PROCESS OF DEFINING RISK FOR<br />
ENVIRONMENTAL CHEMICALS HAVING<br />
SIGNIFICANT SKIN EXPOSURE AND ABSORPTION<br />
POTENTIAL.<br />
W. G. Reifenrath 1 and J. H. Ross 2 . 1 Stratacor, Inc., Richmond, CA and 2 Risk<br />
Sciences, LLC, Sacramento, CA.<br />
Skin exposure and subsequent absorption <strong>of</strong> environmental contaminants are <strong>of</strong>ten<br />
critical issues for regulatory decisions concerning the treatment <strong>of</strong> contaminants or<br />
remediation at hazardous waste sites. Likewise, these issues are important in the registration<br />
or re-registration <strong>of</strong> pesticides. To address these points, laboratory studies<br />
are generally conducted with excised skin or animal models to determine the extent<br />
(percent absorption) or rate <strong>of</strong> penetration (permeability constant) <strong>of</strong> a chemical in<br />
question. In addition, exposure determinations, <strong>of</strong>ten based on field studies, determine<br />
the form and amount <strong>of</strong> chemical that can potentially reach the skin.<br />
Biomonitoring studies can integrate the processes <strong>of</strong> skin exposure and systemic absorption.<br />
<strong>The</strong> forgoing studies generate numbers, which require a translation into<br />
the potential for bioeffect, and the significance <strong>of</strong> that effect, which leads to a risk<br />
assessment. Regulators, such as the U.S. EPA, then make decisions based on the assembled<br />
data. <strong>The</strong> process works best when there is communication between all<br />
parties, starting with the design <strong>of</strong> experimental protocols. In recent years, there has<br />
been an increasing reliance on in vitro permeation data. While test guidelines are<br />
available for percutaneous absorption, actual studies have unique aspects that need<br />
434 SOT 2010 ANNUAL MEETING