Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 2008. / Source: Dissertation Abstracts International, Volume: 69-05, Section: B, page: 2958. Adviser: Michael J. Plewa. Includes bibliographical references (leaves 155-168) Available on microfilm from Pro Quest Information and Learning.

Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 2009. / Source: Dissertation Abstracts International, Volume: 70-06, Section: B, page: 3342. Adviser: Susan L. Schantz. Includes bibliographical references. Available on microfilm from Pro Quest Information and Learning.

Diesel emissions have been shown to elicit a variety of toxicological effects, and alternative fuels (i.e., biodiesel) are currently being assessed to determine their ability to reduce the risks of adverse health effects. Exhaust emissions were generated using ULSD and biodiesel blended fuels and extracts of diesel PM (i.e., filters and PUFs) were separated into polar aromatic and non-polar neutral compounds. Mutagenic activity was assessed using the Salmonella mutagenicity assay, and Ah-receptor agonism was assessed using the DRCALUX assay. Results indicate that organic extracts of diesel/biodiesel particles contain direct- and indirect-acting polar aromatic mutagens as well as polar and non-polar Ah-receptor agonists. The mutagenicity of direct-acting compounds decreases with increasing concentrations of biodiesel in the fuel; however, there is no change in the indirect-acting mutagenicity. Furthermore, the ability of polar and non-polar compounds to induce the Ah-receptor increases with increasing concentrations of biodiesel in the fuel. These results provide an initial framework for evaluating the toxicological hazards of biodiesel emissions.

Lead (Pb) exposure in the earliest stages of neurodevelopment leads to lasting deficits in cognitive function and behavior. Neural stem cells (NSCs) are multipotent stem cells and the first cells of the central nervous system, but little is known of their molecular response to Pb exposure. We exposed human NSCs to 1μM Pb for 24 hours and performed RNA sequencing. 16 of 19 differentially expressed transcripts are upregulated, and of these 10 are known targets of NRF2, the master transcriptional regulator of the cellular antioxidant response. One of the top Pb-induced genes, Secreted Phosphoprotein 1 (SPP1), was not a previously known NRF2 target. We show SPP1 is induced following activation of NRF2 by other known activators and by knockdown of its negative regulator KEAP1. In addition, the induction of SPP1 by Pb was attenuated after siRNA-mediated knockdown of NRF2. We identified a putative Antioxidant Response Element in the SPP1 promoter and confirmed its function by Chromatin immunoprecipitation (ChIP) of NRF2. To further investigate the role of SPP1 in neurodevelopment, we examined SPP1 single nucleotide polymorphisms (SNPs) in a longitudinal birth cohort of infants profiled at 24 months for the mental and psychomotor development indices (MDI and PDI, respectively) of the Bayley Scales of Infant Development. Sixteen single nucleotide polymorphisms (SNPs) in and near SPP1 were tested for main effect and effect modification. For main effect on MDI, eight SNPs are associated at p<0.05, but none pass multiple testing correction. In PDI analyses, SNP rs4693923 shows statistically significant effect modification on the PDI response to second trimester Pb exposure. A-allele carriers of this SNP show a positive correlation between Pb exposure and PDI, which is not seen among GG homozygotes. Together our studies show SPP1 is a novel target of NRF2 and suggest a critical role for SPP1 in modulating prenatal Pb neurotoxicity. / Biological Sciences in Public Health

There is a need to define an exposure-response curve for both copper excess and deficiency to assist in defining the acceptable range of oral intake. A copper exposure-response database has been developed where response data has been assigned to ordinal severity scores. A generalized linear model was used to estimate the probability of response associated with dose, duration and severity. The exposure-response model is defined to account for differences in animal species, route of exposure and age. The exposure-response curves for copper excess and copper deficiency have defined an optimal intake level of 2.0 mg Cu/day and an acceptable range of oral intake between 1.8 and 3.1 mg Cu/day. These results suggest that current recommendations for copper intake including the recommended dietary intake (0.9 mg/day) and the tolerable upper intake level (10 mg/day) may not protect the population from responses that might occur outside the limits of the homeostatic range.

Circulating levels of the potent vasoconstrictor endothelin (ET) are increased after inhalation of urban pollutants. This effect could explain the association of air pollution and cardiovascular morbidity and mortality. However, the timing, source, and specific molecular basis of the increased endothelin release are not well defined. We hypothesized that inhalation of urban pollutants rapidly activates pulmonary endothelin system genes, resulting in increased production and spillover of the peptide into circulation. A time-course study confirmed rapid and transient increases of pulmonary preproET-1 and endothelin-converting enzyme-1 mRNA in rats exposed to particulate matter and ozone. Dose-response studies revealed that each pollutant individually activated endothelin system genes, consistent with the concomitant increase of the 21 amino acid peptide ET-1[1-21] and its precursor, bigET-1, in plasma. In contrast, pulmonary preproET-3 mRNA did not correlate with plasma ET-3 levels. Analyses in other organs revealed ozone-induced increases of endothelin gene expression in the brain, pituitary, and heart, substantiating the notion of extrapulmonary effects of pollutants. Surprisingly, co-exposure to particles and ozone increased pulmonary preproET-1 mRNA but not plasma ET-1[1-21] immediately after exposure. This coincided with an increase of matrix metalloproteinase-2, an enzyme that cleaves bigET-1 to ET-1 [1-32], suggesting that factors released during acute lung injury can modify circulating endothelin levels. To examine the effect of particle inhalation on existing lung pathology, we undertook microarray studies using SP-C/TNF-alpha mice with chronic lung inflammation and their wildtype littermates. Real-time PCR confirmed that inhalation of particles increased pulmonary preproET-1 and cytochrome p450 polypeptide 1 a1 mRNA, validating delivery of a biologically effective dose. Remarkably, microarray analyses failed to detect effects of particle exposure on pulmonary gene expression. Our data reinforce the notion that adverse health effects of acute exposure to urban particles may be dominated by physiological response cascades, with some transcriptional regulation such as activation of the endothelin pathway in target cells, rather than widespread changes in genes escaping homeostatic control. The rapid effects on a key vasoregulatory pathway in the lungs and brain provide a biological basis to explain the acute cardiovascular and cerebrovascular events that occur within hours of increased levels of air pollution.

Exposure to air particulate matter (PM) is epidemiologically associated with increased incidence of respiratory and cardiovascular disease in humans. Although inflammation, oxidative stress and toxicity have been implicated in the pathophysiological response to air pollution, the physicochemical properties of the particles responsible for the adverse effects are yet to be elucidated. In vitro assays are widely used to study the toxicity of particles, however, they have not been comprehensively validated in vivo. This work aimed to evaluate in vitro cytotoxicity and inflammatory cytokine assays as screening tools for relative toxicity of PM, validate their capacity to predict toxicity of PM in BALB/c mice, develop a cell-interaction model for the study of the biological effects of PM, and evaluate its performance in relation to PM effects in animals. Results show that in vitro assays conducted in macrophage (J774A.1) and alveolar epithelial (A549) cell lines can discriminate between PM, based on their cytotoxic and inflammatory potency. SRM- and EHG-type particles were more potent than DWR1 (PM2.5) and mineral particles both in vitro and in vivo, although PM rankings varied considerably between assays. PM with different compositions had different toxic potencies. Combinations of 2 to 4 in vitro assays showed a predictive potential for PM-induced effects in vivo, represented by bronchoalveolar lavage (BAL) neutrophilia in mice. In a co-culture, epithelial (A549) and macrophage (THP-1) cells synergistically modulate their production of pro-inflammatory cytokines (IL-1beta, IL-6, IL-8, MCP-1 and TNF-alpha), ICAM-1 and VEGF in response to PM exposure. Cellular mediators from PM-exposed co-cultures can activate endothelial cells (HPAE) to produce cytokines (IL-6, IL-8, GM-CSF, MCP-1) and adhesion factors (ICAM-1, VCAM-1 and E-selectin). Exposure of mice to EHG6802, DWR1 and SRM-1650 particles led to BAL neutrophilia and elevated cytokines (IL-6, KC, MIP-1alpha, TNF-alpha, with a stronger inflammatory response at 2 hrs then 24 hrs. Statistical comparison of the cell interaction model responses with PM-induced BAL neutrophilia in vivo shows that the co-culture model correlates well with biological effects of particles in mice. Along with its ability to simulate physiologically relevant cell-cell interactions, it is a good model for studying mechanisms of PM toxicity, and for relative toxicity screening of particles.

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