Tributyltin compounds have been used on a global scale for many decades now, and thus have become global environmental contaminants. These compounds are highly toxic, and deleterious effects on numerous organisms have been demonstrated. Yet, little is known of the molecular mechanisms of tributyltin's extreme toxicity. To obtain a better understanding of such mechanisms, a luxAB gene-fusion library of Escherichia coli was screened for changes in gene expression upon cellular exposure to tributyltin. Two clones, designated TBT1 and TBT3, were thus found, both showing an increased light emission in the presence of added tributyltin. Northern blotting analyses confirmed a marked increase in the transcription of the tributyltin-responsive gene identified from each clone. These genes appear to play a protective role when cells are exposed to tributyltin at concentrations ≧ 10 mug/ml, with minimal-dose responses of 0.1 mug/l when grown on LB media. Speciation studies indicated TBT+ as the active chemical species in eliciting these responses. Mapping and sequencing of these tributyltin-responsive genes revealed that the luxAB reporter element had inserted within the uhpT gene in the TBT1 clone. This gene encodes a sugar-phosphate transporter protein, which has been shown to be up-regulated by external glucose-6-phosphate and 2-deoxyglucose-6-phosphate. On a kinetic level, the increased expression of uhpT by tributyltin closely mirrors that produced by 2-deoxyglucose-6-phosphate. In addition to tributyltin, TBT1 also responds to dibutyltin, monobutyltin, trimethyltin, triethyltin, tripropyltin, trifluoroacetic acid, and vanadium. Similar mapping and sequencing experiments revealed the luxAB reporter genes within the stpA gene in the TBT3 clone, but in an antisense orientation, such that they were not under the regulatory control of stpA. The lack of an appropriate open reading frame for this 140-nucleotide transcript (identified by Northern blo

Thesis (Ph.D.)--Pacific Graduate School of Psychology, 1998. / Source: Dissertation Abstracts International, Volume: 59-07, Section: B, page: 3704. Adviser: Teresa Elliott.

Thesis (Ph.D.)--Indiana University, Dept. of Environmental Science, 2007. / Source: Dissertation Abstracts International, Volume: 68-05, Section: B, page: 2924. Adviser: Diane S. Henshel. "Title from dissertation home page (viewed Jan. 24, 2008)."

Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 2007. / Source: Dissertation Abstracts International, Volume: 68-07, Section: B, page: 4244. Adviser: Bettina M. Francis. Includes bibliographical references (leaves 57-63) Available on microfilm from Pro Quest Information and Learning.

A research gap in the fields of exposure assessment and toxicology that remains unaddressed is the assimilation of experimental conditions to those of the real world human exposure. Currently, there is a lack of understanding of the properties of particles released by nano-enabled products (NEPs). Thus, we designed a multi-tiered methodology to physico-chemically, morphologically and toxicologically characterize engineered nanomaterials (ENMs) released from NEPs (i.e., toner powder). It is well established that printers emit nanoparticles during their operation; however, the physico-chemical and toxicological characterization of real world printer-emitted nanoparticles (PEPs) remains incomplete, hampering proper risk assessment efforts. For example, a number of studies estimating the potential adverse effects of PEPs used bulk toner particles as test particles rather than the actual particulate matter released by laser printers. Thus, the public health implications of exposure to PEPs remain largely unknown. For this project, a printer exposure generation system suitable for the subsequent physico-chemical, morphological, and toxicological characterization of PEPs was developed and used to assess the properties of particulate matter released from the use of commercially available laser printers. The system consists of a glovebox type environmental chamber for uninterrupted printer operation, real-time and time-integrated particle sampling instrumentation for size fractionation and sampling of PEPs and an exposure chamber for inhalation toxicological studies. Results from our extensive analysis show that laser printers emit up to 1,300,000 particles/cm3, most of which are nanoparticles. Further, we confirmed that a number of ENMs incorporated into toner formulations (e.g., silica, alumina, titania, ceria,) become airborne during printing. Both in vitro and in vivo toxicological evaluation showed PEPs are biologically reactive and may cause significant cytotoxicity, membrane integrity damage, reactive oxygen species production, pro-inflammatory cytokine release, angiogenesis, cytoskeletal and epigenetic changes as well as lung inflammation. This work highlights the importance of understanding life-cycle nano environmental health and safety implications of NEPs and assessing real world exposures and their associated toxicological properties rather than focusing on ‘‘raw’’ materials used in the synthesis of an NEP. Such analysis can be achieved for pollutants emitted by any NEP by employing the multi-tiered methodology described in this dissertation. / Environmental Health

Methylmercury is both a potent neurotoxin and putative non-steroidal endocrine disruptor. Laboratory studies have provided evidence of reproductive impairment in many fish species after mercury exposure. Effects have been observed at every level of the reproductive axis including degeneration of neurons in the hypothalamus, decreased activity of gonadotrophs in the pituitary, and reduced steroidogenesis in the gonads. Despite the growing amount of research linking methylmercury exposure to reproductive impairment, the target tissues and mechanisms of action involved are still largely unknown. This thesis extends the body of evidence supporting the hypothesis that methylmercury is an endocrine disruptor in fish. To my knowledge, this is the first study to compare the effects of sub-chronic methylmercury exposure on adult goldfish at two different periods within the annual spawning cycle. The effects of endocrine disrupting toxins may differ depending on the season of exposure as goldfish exhibit seasonal fluctuations in gonad size, circulating sex steroids, and luteinizing hormone (LH). The present study demonstrates that ovarian steroidogenesis is impaired by methylmercury in both pre- and post-spawning fish. Analyses of pituitary and serum LH levels suggest that reductions in sex steroid levels are independent of alterations in LH. The possibility that reduced sex steroid levels in fish exposed to dietary methylmercury may be secondary to hypothalamic dysfunction remains to be addressed. Microarray analysis identified 59 genes differentially expressed in the hypothalamus after methylmercury accumulation. These candidate genes were categorized into discrete functional groups including apoptosis and stress response, calcium binding and transport, and protein synthesis, degradation, and transport. In addition, several neuroendocrine-related genes were differentially regulated including transcripts encoding peptides involved in stimulating the production and release of gonadotropin releasing hormone, secretion of LH, and gonadal steroidogenesis. This thesis demonstrates changes in the endocrine system linked to methylmercury exposure and provides the first step towards identifying the mechanistic relationship between changes in reproductive biomarkers and gene expression.

To investigate the effects of methylmercury (MeHg) on development, Xenopus tropicalis tadpoles were exposed to MeHg diets with concentrations of 0.42 (control), 44 (low), and 270 (high) ng/g wet weight. Increased mortality, decreased metamorphosis, increased size, and a greater number of days between tadpoles reaching metamorphosis were observed in the high MeHg group, suggesting disruption to the thyroid axis. Triiodothyronine levels, however, were not significantly different between groups. In both the control and low MeHg groups, total Hg and MeHg body burdens increased rapidly, reached a plateau and eventually declined with a lower percent MeHg body burden. In the high MeHg group, body burden concentrations increased throughout the experiment. This study demonstrates that at low dosages of MeHg, elimination may prevent toxic exposure whereas at high dosages, demethylation and selective excretion mechanisms may be overwhelmed and disruption of development or death may occur in tadpoles.

No description available.

No description available.

No description available.