The Toxicologist - Society of Toxicology

those with high nickel content are significant activators of the inflammasome. The
proposed mechanism involves uptake of the particles into lysosomes followed by
lysosomal rupture and release of cathepsin B. Active cathepsin B stimulates the assembly
of the NLRP3 inflammasome. Furthermore, a shift in macrophages towards
a distinct subset, potentially the Th2-associated alternatively activated phenotype,
may play a role in determining if ENM induces fibrosis. Supported by NIH
ES015497, ES018742, RR017670 and NSP CBET0834233.
1712 MACROPHAGE DIVERSITY AND POLARIZATION IN
IMMUNOPATHOLOGY.
A. Mantovani. Istituto Clinico Humanitas IRCCS, University of Milan, Milan, Italy.
Sponsor: D. Laskin.
Plasticity is a hallmark of cells of the myelomonocytic lineage. Mononuclear phagocytes
in response to innate recognition or to signals from lymphocytes undergo
adaptive responses. Shaping of monocyte-macrophage function is a key component
of resistance to pathogens, tissue damage and repair. Neutrophils have now revealed
considerable plasticity, reminiscent of their macrophage ‘cousins’. Orchestration of
myelomonocytic cell function is a key element linking inflammation and cancer
and provides a paradigm for macrophage plasticity and function. Better understanding
of the molecular basis of myelomonocytic cell plasticity opens new vistas
in immunopathology and therapeutic intervention. Thus, different macrophage
subsets, which differentially contribute to plaque infiltration and to atherosclerosis
complications, have been identified. Similarly, depending on different environmental
signals, plaque-associated macrophages can express polarized pro- and antiatherogenic
programs by influencing lipid metabolism, inflammatory responses,
and plaque stability. Thus, a “macrophage balance” plays a major role in the pathogenesis
of atherosclerotic plaques and affects the evolution and complications of
atherosclerosis.
1713 MECHANISMS OF MICROGLIAL ACTIVATION IN
RESPONSE TO TOXICANTS.
A. Gow. Pharmacology and Toxicology, Rutgers University, Piscataway, NJ. Sponsor:
D. Laskin.
Macrophages are known to adopt an activated phenotype when challenged with
pathogens or toxicants. Up-regulation of inducible nitric oxide synthase (iNOS) is
a fundamental characteristic of classically activated macrophages. However the biological
targets of iNOS-derived nitric oxide (NO) have not been fully elucidated
and hence the role of NO in the macrophage activation process unknown. We recently
identified a number of NO-related mechanisms for controlling macrophage
activation, particularly with regard to the resulting phenotpye, vis a vis classical
(M1) and alternative (M2) activation. The pulmonary collectin, surfactant protein-
D (SP-D), serves to regulate the macrophage phenotype in response to LPS. NOmediated
modification of SP-D can alter this function to favor M1 or M2 depending
upon its redox milieu. In this way iNOS-derived NO is both a regulator and
potential product of activation. A key factor in this NO-mediated regulation is the
redox state of the NO. Modification of SP-D by lower oxide NO leads to the generation
of S-nitrosylated or SNO-SP-D, while higher oxides lead to cross-linked
SP-D. SNO-SP-D favors M1 activation while cross-linked SP-D favors M2 activation.
Monocyte-derived microglial cells in the brain also up-regulate iNOS expression
in response to inflammatory activators, such as LPS. We found that NO-derived
from iNOS is critical to the adoption of a M1 phenotype in microglial cells.
Additionally, redox status appears to be key in this process. Redox active copper,
(Copper I) inhibits the release of NO by LPS-treated microglial cells. This is independent
of reduced iNOS expression or NF-κB activity. Immunofluorescence
analysis macrophage activation markers have established that Copper (I) induces
M2 type activation. As microglial activation is a critical step in neurodegeneration,
these interactions may have implications for the role of environmental factors in
aging-related neurological disease. Supported by NIH HL086621.
1714 MACROPHAGE DIVERSITY PROMOTES TUMOR
PROGRESSION AND METASTASIS.
J. W. Pollard. Department of Developmental and Molecular Biology, Albert Einstein
College of Medicine Yeshiva University, New York, NY. Sponsor: D. Laskin.
There is persuasive clinical and experimental evidence that macrophages promote
cancer initiation and malignant progression. During tumor initiation, they create
an inflammatory environment that is mutagenic and promotes growth. As tumors
progress to malignancy, macrophages stimulate angiogenesis, enhance tumor cell
migration and invasion, and suppress antitumor immunity. At metastatic sites,
macrophages prepare the target tissue for arrival of tumor cells, and then a different
subpopulation of macrophages promotes tumor cell extravasation, survival, and
subsequent growth. Specialized subpopulations of macrophages with distinct phenotypes
may represent important new therapeutic targets. Supported by NIH grant
CA131270.
1715 WHEN IS EXPOSURE NOT EXPOSURE? DEFINING
THE DOSE-RESPONSE REGION BETWEEN “EFFECT”
AND “ADVERSE EFFECT” IMPLICATIONS FOR
HUMAN HEALTH RISK ASSESSMENT.
C. English. NSF International, Ann Arbor, MI.
‘Omics technologies demonstrate global changes in gene regulation and expression
following chemical exposure, causing toxicologists to revisit the question, what is an
adverse effect and what isn’t. Dose-dependent transitions in genomic and related responses
reflect the levels of exposure that cause detectable perturbations to the biological
system under study. We will focus on two transitions, having both dose and
temporal dimensions, which are advanced as being pivotal to understanding mode
of action and prediction of toxicity. The first transition is from no-detectable-effect
on the biological system relative to unexposed controls, to the first-perceptible-effect
at the global genome level; observed as up- and down-regulation of genes that
regulate adaptive responses. The second transition is from the adaptive response region
to the first adverse response or critical effect region of the dose-response relationship.
We will explore if and how ‘omic phenomena elicited by chemical exposures
translate into useful information for risk assessors. Consideration of the
adaptive capacity of the biological system and severity of the effect might further inform
our definition of the term adverse and inform the magnitude of traditional
uncertainty factors used. Understanding dose-dependent transitions combined
with dosimetry models that characterize the exposure-tissue concentration relationship
might permit risk assessors to define exposures delimited by safe and adverse
boundaries. We will conclude by describing emerging advances in high-throughput
quantitative ‘omic technologies, and findings from studies with endogenous and
exogenous compounds and nanoparticulates, to address how we move from the vast
array of ‘omic data generated to practical risk assessment applications.
1716 USE OF THE HIERARCHICAL OXIDATIVE STRESS
PARADIGM FOR HAZARD AND RISK ASSESSMENT IN
RESPONSE TO AMBIENT ULTRAFINE AND
ENGINEERED NANOPARTICLE TOXICITY.
A. E. Nel. Medicine, University of California Los Angeles, Los Angeles, CA. Sponsor:
A. Nel.
The hierarchical oxidative stress paradigm describes the cellular or tissue response
to incremental levels of oxidative stress in response to pro-oxidative ambient ultrafine
(UFP) and engineered nanoparticles (ENM). The paradigm is useful for elucidating
dose-dependent oxidative stress outcomes in which the critical effect could
manifest as Nrf2-mediated antioxidant defense or pro-inflammatory signal pathway
responses that vary with the particle oxidant potential and the level of redox
disequilibrium. Clinically, this could manifests as adaptive or pro-inflammatory responses
in the lung that can be detected by oxidative stress biomarkers. I will discuss
the utility of the hierarchical oxidative stress paradigm in in vitro and in vivo
studies looking at UFP and nano-ZnO effects. I will show how conventional and
rapid throughput in vitro cellular screening can be used to demonstrate the hierarchical
oxidative stress response to these particles and how the cellular response relates
to pulmonary inflammation in rodents. I will demonstrate that Nrf 2 knockout
exacerbates airway inflammation and that changing of the dissolution
characteristics of nano-ZnO can affect the exposure dose and the severity of lung
inflammation. In summary, the critical effect to pro-oxidative nanoparticles could
be a useful screening tool for hazard ranking and risk prevention.
1717 HUMAN EXPOSURE CONTEXT FOR NANOPARTICLE
TOXICITY ASSESSMENT BY BIOLOGICAL PATHWAY
BASED DOSE-RESPONSE MODELING.
J. G. Teeguarden 1 , M. N. Costa 2 , K. M. Waters 2 and J. E. McDermott 2 .
1 Biological Monitoring and Modeling, Pacific Northwest National Laboratory,
Richland, WA and 2 Computational Biology and Bioinformatics, Pacific Northwest
National Laboratory, Richland, WA.
Dose-response modeling of in vitro gene expression profiles hold great promise for
differentiating between mechanisms of action and between low-dose adaptive effects
and more serious higher-dose toxicity, i.e. critical effects driving toxicity and
SOT 2011 ANNUAL MEETING 369