The main aim of this thesis is to investigate whether residence near hazardous waste landfill sites is associated with an increased risk of congenital anomaly. The thesis reports results of a multi-centre case-control study carried out in 10 regions in 6 European countries. Cases were live births, stillbirths, and induced abortions with major congenital anomalies resident at birth within a 7 km area around hazardous waste landfill sites. Controls, two per case, were non-malformed births resident in the same area. A total of 1089 cases of non-chromosomal anomaly, 270 cases of chromosomal anomaly, and 2508 controls were selected around 26 landfill sites. A 3 km zone around sites was defined as the zone of most likely exposure. An expert panel of four landfill specialists scored each landfill site according to their potential to cause exposure of nearby residents. A statistically significant 33% excess in risk of non-chromosomal anomalies was found for living within 3 km of a hazardous waste landfill site. The risk of non-chromosomal anomaly declined steadily with increasing distance from a site. Confounding factors or biases do not readily explain these findings. Risk of chromosomal anomalies was raised near sites but did not reach statistical significance. There was little evidence for relative risk of congenital anomaly (non-chromosomal or chromosomal) close to landfill sites to be associated with hazard potential of landfill sites, adding little support to a possible causal relationship. However, in the absence of a 'gold-standard' for the classification of hazard potential, misclassification of sites may have occurred. Lack of information on exposure of residents near the study sites or near landfill sites in general, limits interpretation of the results. Socio-economic status is a potential confounding factor in the current study but little is known in the literature about socio-economic status as a risk factor for congenital anomaly. This study finds a higher risk of non-chromosomal congenital anomaly and certain specific malformation groups in more deprived populations. These findings require follow-up in studies with larger geographical coverage.

Measuring the Effects of Mouse Allergen and Black Carbon Exposure on Children Living in New York City with Allergic Diseases Medina Samira Jackson-Browne Background: Exposure to allergens and combustion by-products are risk factors for allergic health outcomes in children. The connection between exposure to allergens and allergic diseases such as asthma, in some children, is through the development of a biological condition known as allergic sensitization. In susceptible children, sensitization may occur when early-life exposure to an allergen causes the production of immunoglobulin E (IgE) antibodies. In asthmatic children, repeated exposures to this allergen may lead to clinical manifestations including airway inflammation, airway mucous production, bronchospasms, and bronchial hyper-responsiveness. Sensitization and repeated exposure to allergens may, therefore, be important risk factors for asthma morbidity in children. Findings from a cross-sectional asthma study of children living in NYC published previously by our group found a positive association between cockroach and dust-mite allergens measured in bed dust and sensitization risk to these allergens consistent with other studies. However, contrary to previously published research, no association was observed between mouse allergen measured in bed dust and mouse sensitization risk in our study. In urban areas such as New York City (NYC), exposure to combustion by-products, including black carbon (BC), has been shown to be associated with both asthma development and asthma morbidity. BC has been proposed to exacerbate asthma symptoms directly through airway irritation or by behaving as an adjuvant, enhancing the production of IgE antibodies following exposure to an allergen in sensitized individuals. Our group previously observed an association between indoor measured BC concentrations and airway inflammation, however no association was found between BC and asthma symptoms for children living in NYC. In the present study, we sought to address some of the limitations of the previous work. These limitations included a singular measurement of mouse allergen exposure, a shorter-term BC exposure measurement, and a cross-sectional study design for asthma symptom risks. My overarching hypothesis for this dissertation is that exposures to mouse allergen and BC are significant risk factors for allergic sensitization and asthma morbidity, respectively, for children living in NYC. I tested these hypotheses in three separate manuscripts by assessing multiple mouse exposure measurements with the risk for mouse sensitization (Chapter 2), testing the correlation between 7-day measured indoor BC and particulate matter smaller than 2.5 microns (PM2.5) concentrations with annual modeled outdoor BC and PM2.5 concentrations (Chapter 3), and determining whether annual modeled outdoor BC concentration is associated with persistent asthma symptoms, over a three-year period, for asthmatic children in NYC (Chapter 4). Methods: For all manuscripts, data from an asthma case-control cohort of children (age 7-8 years) previously established by our group, the NYC Neighborhood Asthma and Allergy Study (NAAS), was utilized for analysis (n=350). Kitchen floor and bed settled dust samples were collected from the children’s home during the initial home visit. Mouse allergen concentrations were quantified from both kitchen floor and bed dust samples using an enzyme-linked immunosorbent assay (ELISA). Blood samples were also collected during this visit. IgE antibodies to mouse allergens were measured by ImmunoCAP (Phadia, Uppsala, Sweden) from these blood samples. Information on the frequency of mouse sightings in the previous 12 months was extracted from a questionnaire administered to parents of NAAS children. Neighborhood and school mouse sightings were collected from reports from the NYC Department of Health and Mental Hygiene (DOHMH). Indoor PM2.5 and BC samples were collected from air samplers placed in NAAS children’s home for an average of 7 days. In collaboration with the NYC DOHMH, we were given access to 2-year averaged modeled outdoor PM2.5 and BC concentrations collected from air monitors at 124 street-level locations throughout NYC from 2008-2010. After the initial home visit, asthmatic NAAS children were followed-up annually for asthma symptoms. The questionnaire data collected from the asthmatics followed were used to evaluate the persistence or remittance of asthma symptoms over the 3-years following the initial home visit. Results: In our mouse study we found that increasing mouse allergen measured from kitchen floor dust and children whose parents reported greater than weekly mouse sightings in the previous 12 months has an increased risk of mouse sensitization (prevalence risk (PR) = 1.09 [1.02-1.17], p=0.04 and PR= 3.84 [1.95-6.97], p=0.001 respectively). Neither mouse allergen measured from settled bed dust (PR = 1.06 [0.95-1.19], p=0.46) nor neighborhood rodent reports (PR = 1.25 [0.94-1.68], p=0.16) were significantly associated with an increased risk of sensitization to mouse. Exposure to mouse at school was also not associated with an increased risk of mouse sensitization (PR=0.66 [0.35-1.26], p=0.30). Results from the correlation study indicated both annual modeled outdoor PM2.5 and BC concentrations were weakly correlated with 7-day measured indoor PM2.5 and BC concentrations (r = 0.21 and 0.39, respectively, p < 0.01). However, annual modeled outdoor BC concentrations predicted almost 20% of the variability of 7-day measured indoor BC (R2=0.19, p<0.001) compared to only 4% of the variability of 7-day indoor PM2.5 explained by annual modeled outdoor PM2.5, which predicted measured indoor PM2.5 (R2 = 0.04, p < 0.001). Our regression analysis of the asthma morbidity study found no significant association between longer-term neighborhood modeled BC concentrations at study participant’s home (PR = 0.87 [0.58-1.29, p=0.49] and school addresses (PR =1.09 [0.77-1.56], p=0.60) and persistent asthma symptoms. Conclusions: My findings suggest that mouse allergen measured from kitchen floor dust and parent reported mouse sightings are important risk factors of mouse sensitization for children living in urban areas such as NYC. The results of the BC analysis indicate a moderate correlation between annual modeled outdoor BC concentrations and 7-day measured indoor BC concentrations. The annual modeled outdoor BC also predicted 20% of the variability in 7-day measured indoor BC. Conversely, PM2.5 analysis indicate that annual modeled outdoor PM2.5 is not correlated with 7-day measured indoor PM2.5 concentrations. Finally, regression analysis of BC exposure and asthma morbidity indicate that annual modeled outdoor BC is not predictive of persistent asthma symptoms in our cohort.

The purpose of the present study was to determine: (1) that dental office personnel would be exposed to more toxic chemicals in the workplace than the non-dental office controls; (2) that exposure should lead to a reduction in the efficiency of the immune system in the individuals in the dental office; and (3) the immunological deficit should manifest itself in psychological and/or physiological pathology as measured on the Profile of Mood States (POMS) and Bender Gestalt.

No description available.

Polybrominated diphenyl ethers (PBDEs) are flame retardant chemicals of toxicological concern present in humans, wildlife, and the environment. Deca-BDE is the highest production product due to historical use patterns and recent regulatory limitations on the other two commercial formulations (Penta-BDE and Octa-BDE) in the U.S and Europe. The EU banned Deca-BDE starting July 1, 2008. However, it remains in usage in North America and elsewhere in the world. BDE-209 is the dominant congener in all Deca- BDE commercial products. BDE-209 has been reported to under go metabolic debromination to lesser brominated and more toxic and bioaccumulative congeners. However, insufficient data are available on this process. It has also been observed that congener profiles and BDE-209 levels in terrestrial organisms differ from most aquatic species, indicating accumulation or metabolic dissimilarity. The goal of this in ovo study is to determine the biotransformation and tissue distribution of BDE-209 after injection into the yolk-sac of embryonic chickens. An emulsion formulation was employed to better distribute the hydrophobic BDE-209 within the eggs in an attempt to better mimic “natural” exposure of embryos. Acute mortality from BDE-209 yolk injection was observed. An LD50 value of 44 μg/egg (740 ng/g ww) was determined for embryonic chickens in this study. Concentrations of BDE-209 and possible metabolic degradates were determined in five compartments of the embryos (yolk, brain, liver, heart and remaining carcass). The results indicated that some BDE-209 was mobilized from the yolk, into the carcass, liver, brain, and heart tissues of the developing chicken embryo prior to pipping. However, 80% of the dose was detected as BDE-209 in the yolk sac. Additional BDE-209 would likely have been assimilated following hatching and resorption of the remaining yolk. Nona-BDEs were detected in all of the liver and yolk samples from BDE-209 exposed eggs. The congener profiles of the different tissues did not indicate that significant metabolic debromination of BDE-209 occurred within the developing embryos.

Neurturin (NRTN), a member of the glial cell-line derived neurotrophic factor(GDNF) family, is required in the development of parasympathetic cholinergic neurons. It signals through binding to a glycosyl-phophatidyl inositol (GPI)-linked receptor, GDNF family receptor α2 (GFRα2), which couples to Ret tyrosine kinase. Studies of NRTN knockout mice have shown that NRTN is essential for normal cholinergic innervation of the heart, but the precise role of NRTN remains unknown. For NRTN to evoke a biological response, GFRα2 must be localized to the surface of target neurons. The aim of this study was to determine the expression and localization of GFRα2 at two developmental time points in the atria of mouse hearts, postnatal day (P)1 and P18. Atria were used because of their extensive cholinergic innervation, particularly at the sinoatrial node and the right atrium. By P21, neurons are adult sized and substantial growth of cholinergic nerve fibers has occurred; therefore, it was hypothesized that GFRα2 signaling would be higher in P1 neuronal fibers than in P18 fibers. Because NRTN only activates surface receptors, and once activated, internalization occurs, we further hypothesized that GFRα2 would be cytoplasm localized when treated with NRTN. Atria were analyzed for GFRα2 expression in cholinergic neurons by immunohistochemistry with and without Triton X-100, a cell membrane permeabilizing detergent, to visualize cytoplasmic localization in one group and cell membrane localization in the other. In an additional group, excised P1 atria were cultured in petri dishes with and without NRTN (400 ng/ml, 3h) to determine if GFRα2 was internalized in response to NRTN treatment. Stained atria were viewed using a fluorescence microscope, and digital images were collected using a confocal microscopy system. Within each age group, Triton X-100 treated tissues exhibited cytoplasmic localization within ganglia; however, P1 neurons had distinct membrane staining, whereas in the P18 model, the majority of the GFRα2 was localized to the cytoplasm. NRTN-treated P1 ganglia showed a substantial decrease in membrane localization in central cell bodies and an increase in localization in perimeter cell bodies compared to the non-NRTN group. The results from this study show that GFRα2 is extensively localized to the cell membrane in P1 cholinergic neurons and is primarily localized to the cytoplasm in P18 cholinergic neurons. NRTN treatments lead to internalization of GFRα2 and may lead to a better understanding of GFRα2 trafficking. These findings suggest that GFRα2 cellular localization may be increased in periods of elevated nerve fiber growth and may serve as a regulator of responsiveness to NRTN.

This study tested the ability of a novel adipose tissue derived cytokine, C1q TNF Related Protein 3 (CTRP3), to prevent alcohol-induced hepatic lipid accumulation, or alcoholic fatty liver disease (ALD). Previous work has demonstrated that CTRP3 is effective at preventing high fat diet-induced fatty liver, however, the potential of CTRP3 to inhibit ALD has not been explored. To test the potential protective effects of CTRP3, transgenic mice overexpressing CTRP3 (Tg) or wildtype littermates (WT) were subjected to one of two different models of ALD. In the first model, known as the NIAAA model, mice were fed control or alcohol-containing liquid diets (5% v/v) for 10 days followed by a single gavage of ethanol (5 g/kg). In the second model, the chronic model, mice were fed control or alcohol-containing diets for 6 weeks with no gavage. This study found that CTRP3 reduced triglyceride accumulation in the chronic model of alcohol consumption by ~50%, whereas no reduction was observed in the NIAAA model. Further analysis of isolated primary hepatocytes from WT and Tg mice demonstrated that CTRP3 increased oxygen consumption in the presence of fatty acids, indicating that CTRP3 increases hepatic fatty acid utilization. In conclusion, this study indicates that CTRP3 attenuates hepatic triglyceride accumulation in response to long-term chronic but not short-term alcohol consumption.

Diabetes is a highly prevalent chronic disease among US adults, and its prevalence among US veterans is even higher. This study aimed to examine the prevalence of and trends in diabetes in US veterans by using data from the US National Health and Nutrition Examination Survey from 2005 through 2014. The overall prevalence of diabetes and undiagnosed diabetes was 20.5% and 3.4%, respectively, and increased from 15.5% in 2005–2006 to 20.5% in 2013–2014 (P = .04). Effective prevention and intervention approaches are needed to lower diabetes prevalence among US veterans and ultimately improve their health status.

Key understanding of potential transformations that may occur on silver nanoparticle (AgNP) surface upon interaction with naturally ubiquitous organic ligands (e.g., −SH (thoil), humic acid, or −COO (carboxylate)) is limited. Herein we investigated how dissolved organic carbon (DOC), −SH (in cysteine, a well-known Ag+ chelating agent), and −COO (in trolox, a well-known antioxidant) could alter the colloidal stability, dissolution rate, and toxicity of citrate-functionalized AgNPs (citrate–AgNPs) against a keystone crustacean Daphnia magna. Cysteine, DOC, or trolox amendment of citrate–AgNPs differentially modified particle size, surface properties (charge, plasmonic spectra), and ion release dynamics, thereby attenuating (with cysteine or trolox) or promoting (with DOC) AgNP toxicity. Except with DOC amendment, the combined toxicity of AgNPs and released Ag under cysteine or trolox amendment was lower than of AgNO3 alone. The results of this study show that citrate–AgNP toxicity can be associated with oxidative stress, ion release, and the organism biology. Our evidence suggests that specific organic ligands available in the receiving waters can differentially surface modify AgNPs and alter their environmental persistence (changing dissolution dynamics) and subsequently the toxicity; hence, we caveat to generalize that surface modified nanoparticles upon environmental release may not be toxic to receptor organisms.

No description available.