Polychlorinated biphenyls (PCBs) are persistent, man-made toxicants that are linked to adverse health effects and diseases such as endocrine disruption, diabetes, obesity, cardiovascular effects, and cancer. Since their manufacturing began in 1929 for industrial use, and was banned in 1979, they have bioaccumulated in water, sediment, food, animals, humans and more. PCBs are also found in indoor air of older buildings and as inadvertent byproducts in the manufacture of paints and pigments. The lower chlorinated PCBs, those with fewer than 5 chlorine atoms, are readily metabolized to form hydroxylated PCBs (OH-PCBs) that are further converted to PCB-sulfates in reactions catalyzed by cytosolic sulfotransferases (SULTs). Steroid sulfotransferases SULT1E1 and SULT2A1 participate in regulating the homeostasis of estrogens and androgens, respectively, through the deactivation of active hormones. The estrogen sulfotransferase (SULT1E1) is also a potential key player in adipogenesis. Recent literature has shown that downregulating expression of SULT1E1 in cells derived from humans and mice caused opposite effects, where adipogenesis was inhibited or stimulated, respectively. Adipogenesis is the maturation of preadipocytes into mature adipocytes, which is regulated by peroxisome proliferating-activator γ (PPARγ). Adipocytes are a main component of adipose tissue, which is important for energy homeostasis, organ protection, and thermoregulation. Adipose tissue also secretes various cytokines such as adiponectin. Adipose tissue dysfunction can result from adipocyte dysfunction, which can be caused by alterations in cell signaling. The objective of this dissertation research was to determine if OH-PCBs and PCB-sulfates are inhibitors of SULT1E1 and SULT2A1 and if inhibition of SULT1E1 by OH-PCBs could potentially affect adipogenesis. We hypothesized that PCB metabolites would inhibit SULT1E1 and SULT2A1 and potentially affect adipogenesis in both human and murine cell models. Using purified recombinant human SULT1E1 and SULT2A1, I found that 4’-OH-PCB 3, 4-OH-PCB 8, 4-OH-PCB 11, 4’-OH-PCB 25, and 4-OH-PCB 52 were potent inhibitors of the sulfation of representative substrates (7.0 nM estradiol for SULT1E1 and 1.0 µM dehydroepiandrosterone for SULT2A1, Figures 3-3 and 3-4, respectively). Moreover, 4-OH-PCB 11 and 4-OH-PCB 52 were the most potent inhibitors of SULT1E1 and SULT2A1 with IC50 values of 7.2 nM and 1.5 μM, tables 3-1 and 3-2, respectively. The least potent inhibitor of SULT1E1 was 4’-OH-PCB 3, with an IC50 of 1300 nM. The PCB-sulfates were not potent inhibitors for either enzyme. 4-OH-PCB 11 inhibited the sulfation of estradiol in the cytosol of both pre-adipocytes and fully differentiated adipocytes (Figure 4-9). Immortalized human adipocytes were treated with 10 µM of triclosan (a known inhibitor of SULT1E1), 4’-OH-PCB 3 and 4-OH-PCB 11. Experiments included exposure to these toxicants for 1) 72 hours to preadipocytes, 2) 72 hours to preadipocytes followed by 11-day differentiation, 3) to differentiating adipocytes and for 48 hours post-differentiation. The lipid accumulation levels remained unaffected, as determined by microscopic imaging and quantification using AdipoRed. The mRNA expression levels of prominent adipogenic markers SULT1E1, PPARγ, and AdipoQ were measured using RT-Q-PCR. Changes in SULT1E1 and PPARγ expression were unaffected upon treatment before, during and after adipogenesis when compared to controls. However, the increase in AdipoQ expression was reduced upon treatment with 4-OH-PCB 11 in differentiated adipocytes and in preadipocytes exposed for 72 hours followed by 11-day differentiation (Figure 4-14). This could be an indicator of adipocyte dysfunction that was not manifested by a change in lipid accumulation. Murine 3T3-L1 cells were also treated with 10 µM of triclosan, 4’-OH-PCB 3 and 4-OH-PCB 11 for 48 hours to preadipocytes, during 8-day differentiation and for 48 hours after differentiation. The mRNA expression levels of prominent markers of cardiovascular and adipogenesis functions, ACE2, PPARγ, FABP4, and AdipoQ were measured using RT-PCR. Compared to controls, the increase in AdipoQ expression was reduced following treatment of preadipocytes with triclosan and 4-OH-PCB 11 and subsequent differentiation (Figure 5-11). The increase in PPARγ expression remained either unchanged from controls or slightly stimulated in differentiating and differentiated adipocytes (Figures 5-11 and 5-13). Angiotensin-converting enzyme 2 (ACE2) expression was decreased compared to control values, upon treatment with 4’-OH-PCB 3 (Figure 5-12), while fatty acid binding protein 4 (FABP4) expression was stimulated to the same extent across all treatment groups in differentiating adipocytes (Figure 5-12). The results, overall, show that these OH-PCBs did not affect lipid accumulation in human adipocytes, but they may affect other signaling pathways in adipogenesis. 4-OH-PCB 11 decreased adiponectin expression compared to the increase that was seen in unexposed differentiating human and mouse adipocytes. Adiponectin is secreted from adipose tissue, and this decrease could indicate a form of dysfunction. This finding is consistent with the results of the purified SULT1E1 study, where 4-OH-PCB 11 potently inhibited SULT1E1, but 4’-OH-PCB 3 did not (Figure 3-3 and Table 3-1). Thus, there is a potential for OH-PCBs to disrupt the expression of adiponectin and perhaps other vital adipokines and this could negatively affect adipose tissue function. Future studies will be needed to determine if these effects are indeed mediated by intracellular estradiol and SULT1E1. Moreover, the potential for in vivo disruption of circulating adiponectin by OH-PCBs and other toxicants that inhibit SULTs remains to be studied.

Although the production of polychlorinated biphenyl (PCB) technical mixtures has been banned in the U.S. since the 70’s, they remain ubiquitous in the environment, particularly in indoor and ambient air. Due to the presence of PCB’s in air, inhalation is a significant route of exposure. PCBs released from various building materials have been shown to contaminate the indoor air in homes and schools. In the AESOP Study, an epidemiologic study of PCB exposures among school children and their mothers, PCB28 was found in the serum of over 20% of participants. Data are lacking on the absorption, distribution, metabolism, and excretion (ADME) of inhaled PCBs and on the biological fate and dose-specific toxicological endpoints. In order to inform toxicokinetic modeling for risk-assessment, we are conducting ADME toxicological studies with lung exposure to a representative trichlorobiphenyl, and evaluating the uptake from the lung and the distribution, metabolism, and excretion. Male Sprague-Dawley rats were exposed to [14C]PCB28 via intratracheal instillation at two different doses (42 µg/rat and 4.2 µg/rat). Digestive matter from five separate compartments of the gastrointestinal tract and thirty-six tissue types were excised and measured by scintillation counting. Exhaled air and excreta were also collected and analyzed. Measurements for the high dose were made at 12, 25, 50, 100, 200, 400, 720, and 1440 min, and for the low dose at 2, 12, 50, 200, and 720 min post-exposure. Data show that pulmonary uptake exceeded 99% in both doses. [14C]PCB28 entered the blood stream and distributed quickly to all tissues within minutes of dosing. In the high dose, the majority of radioactivity initially went to the muscle and liver, while in the low dose [14C]PCB28 initially distributed to the muscle, esophagus, and trachea, before being redistributed to the skin and adipose tissue, where it accumulated in both doses. In most tissues, elimination was biphasic, consisting of an initial fast phase with a half-life (t1/2) of 7-93 min (high dose) and t1/2 of 6-60 min (low dose), followed by a slower phase with t1/2 of 5-18 hours (high dose) and t1/2 of 3-18 hours (low dose). The metabolism of PCB28 was not extensive, with the parent compound as the major component in liver, kidney, serum, and adipose tissue. Excretion via urine and feces was limited, with 92% (high dose) and 88% (low dose) of radioactivity remaining in the tissues by the end of the time course, primarily in skin and adipose tissue. Low urinary concentration relative to serum, suggested that parent PCB28 in serum would serve as an accurate biomarker for assessment of exposure to inhaled trichlorobiphenyls. The time course and tissue distribution is comparable to [14C]PCB11, while metabolism and excretion of [14C]PCB28 is much less extensive.

The constant growth in population worldwide over the past decades continues to put forward the need to provide access to safe, clean water to meet human needs. There is a need for cost-effective technologies for water and wastewater treatment that can meet the global demands and the rigorous water quality standards and at the same maximizing pollutant efficiency removal. Current remediation technologies have failed in keeping up with these factors without becoming cost-prohibitive. Nanotechnology has recently been sought as a promising option to achieve these goals. The use of iron oxide magnetic nanoparticles as nanoadsorbents has led to a new class of magnetic separation strategies for water treatment. We have developed magnetic nanocomposite systems able to capture polychlorinated biphenyls (PCBs), as model organic pollutants, in aqueous solution, providing a cost-effective water remediation technique. Two distinct methods were employed to develop these polyphenolic nanocomposite materials. The polyphenolic moieties were incorporated to create high affinity binding sites for organic pollutants within the nanocomposites. The first method utilized a surface initiated polymerization of polyphenolic-based crosslinkers and co-monomers on the surface of iron oxide magnetic nanoparticles to create a core-shell nanocomposite. The second method utilized a bulk polymerization method to create macroscale films composed of iron oxide nanoparticles incorporated into a polyphenolic-based polymer matrix, which were then processed into microparticles. Both methods produce nanocomposite materials that can bind chlorinated organics, can rapidly separate bound organics from contaminated water sources using magnetic decantation, and can use thermal destabilization of the polymer matrix for contaminant release and material regeneration. The polyphenol functionalities used to bind organic pollutants were quercetin multiacrylate (QMA) and curcumin multiacrylate (CMA), which are acrylated forms of the nutrient polyphenols quercetin (found in berries) and curcumin (found in turmeric), both with expected affinity for chlorinated organics. The affinity of these novel materials for PCB 126 was evaluated at equilibrium conditions using a gas chromatography coupled to electron capture detection (GC-ECD) for quantification purposes, and the data was fitted to the nonlinear Langmuir model to determine binding affinity (KD) and maximum biding capacity (Bmax). The KD values obtained demonstrated that the presence of the polyphenolic-based moieties, CMA and QMA, as crosslinkers enhanced the binding affinity for PCB 126, expected to be a result of their aromatic rich nature which provides sites for π – π stacking interactions between the nanoparticle surface and the PCBs in solution. These values are lower that the reported affinity coefficients for activated carbon, which is the gold standard for capture/binding of organic contaminants in water and waste water treatment. Furthermore, upon exposure to an alternating magnetic field (AMF) for a period of 5 minutes, over 90% of the bound PCB on these materials was released, offering a low-cost regeneration method for the nanocomposites. Additionally, this novel regeneration strategy does not require the use of large volumes of harsh organic solvents that oftentimes become harmful byproducts. Overall, we have provided strong evidence that these novel nanocomposites have a promising application as nanoadsorbents for specific organic contaminants in contaminated water sources providing high binding affinities, a low-cost regeneration technique and are capable of withstanding use under environmental conditions offering a cost effective alternative to current remediation approaches.

The overall hypothesis of this thesis addresses the release of polychlorinated biphenyls (PCBs) in the sediments of a highly contaminated harbor. I collected, analyzed and quantified PCB congeners in more than 130 samples of air, water and sediment. Then I constructed a chemical fate model as function of chemical concentrations, physical-chemical properties, local meteorological and hydraulic conditions. Indiana Harbor and Ship Canal in East Chicago (IHSC), Indiana, was selected for its expected high levels of PCBs in the sediment and because of future plans for dredging. I found that PCB concentrations in air, water and sediment in this area were much higher than background levels in the Great Lakes region. PCB sediment concentrations were above the threshold limit to designate IHSC as a Superfund site (≥ 50 ppm), although it is not. The PCB signature in surficial sediment strongly resembles the original Aroclor 1248 but deeper layers show evidence of mixtures of Aroclors and weathering processes. The fate model showed that IHSC contaminated sediments are a continuous source of PCBs to the water and overlying air, and also produce a PCB input to Lake Michigan, even under quiescent conditions. The PCB signature in sediment, water, and air support my determination that the contaminated sediment is a major source of PCBs into the water and air above it. Simulations considering different surficial sediment concentrations post-dredging demonstrated that PCB concentrations in the sediment should be considered in the dredging operation to minimize the release of PCBs into the environment. Finally, I examined the role of the dissolved sediment porewater concentration in the prediction of sediment-water soluble fluxes, using a passive sampler technique (SPME PDMS-fiber) and calculated values from a one-parameter linear free energy relationship (op-LFER). I determined that the latter overestimates the freely dissolved porewater concentration but are nevertheless the most appropriate values for predicting PCBs soluble release from contaminated sediments.

No description available.

<p>PCBs are well known environmental pollutants. They are also precursors to metabolites, as the hydroxy-PCBs and the methylsulfonyl-PCBs. This thesis presents a validated methodology for analysis of PCB metabolites and a structural identification of 38 hydroxy-PCBs in human blood. Further methodological development resulted in an identification of a similar number of methylsulfonyl-PCBs.</p><p>The analytical method has been applied in two extensive studies of humans, consisting of maternal and cord blood from Dutch women and of blood from humans living in Slovakia. The Dutch shows that the relative transfer of hydroxy-PCBs from the mother to the foetus is higher compared to the PCBs. Even though the chemical plant in Michalovce in Slovakia had been shut down for over 20 years, the concentrations of PCB and its metabolites were among the highest detected in European human blood.</p>

Graduation date: 1996

PCBs are well known environmental pollutants. They are also precursors to metabolites, as the hydroxy-PCBs and the methylsulfonyl-PCBs. This thesis presents a validated methodology for analysis of PCB metabolites and a structural identification of 38 hydroxy-PCBs in human blood. Further methodological development resulted in an identification of a similar number of methylsulfonyl-PCBs. The analytical method has been applied in two extensive studies of humans, consisting of maternal and cord blood from Dutch women and of blood from humans living in Slovakia. The Dutch shows that the relative transfer of hydroxy-PCBs from the mother to the foetus is higher compared to the PCBs. Even though the chemical plant in Michalovce in Slovakia had been shut down for over 20 years, the concentrations of PCB and its metabolites were among the highest detected in European human blood.

It was hypothesized that alterations in plasma concentrations of corticosterone (CS) and prolactin (PRL) may be at least partially responsible for polychlorinated biphenyl (PCB)-induced immunosuppression. A 2 by 2 factorial experiment examined the interactions of PCB and P815, an allogeneic tumor, on plasma concentrations of CS and PRL, and on body, spleen, and thymus weights. The PCB dosage used (10 mg/kg) was previously shown to suppress immune response to the tumor. The four study groups were: Group A (vehicle control), Group B (tumor only), Group C (PCB only), and Group D (tumor plus PCB). Mice received one dose of PCB (Groups C and D) or carrier (Groups A and B) on day -1; tumor (Groups B and D) or carrier (Groups A and C) was injected intraperitoneally on day 0. In Experiment 1, animals were killed on days -1, -0.6, 0 through 10, 21, 42, and 84. Body, spleen, and thymus weights were measured. Plasma samples were obtained for CS and PRL measurements. In Experiment 2, the study was repeated with samples obtained only on days 3 and 10. Group A body weights increased steadily throughout Experiment 1. Relative to Group A, the weight gain in Group B was significantly (p < 0.05) higher. Group C lost weight on days 0 through 6, and gained significantly (p < 0.05) less weight than Group A. Group D gained significantly (p < 0.05) less weight than Groups A, B, and C. As a percent of body weight, spleen weight remained constant over 21 days in Experiment 1 in both Groups A and D. Compared to Group A, Group B showed significantly (p < 0.05) increased spleen percent body weight while Group C showed significantly (p < 0.05) decreased spleen percent body weight. As a percent of body weight, thymus weight remained constant for 21 days in Experiment 1 in Group A. Groups Band C were similar (p > 0.05) and showed a decreased thymus percent body weight compared to Group A. Group D showed significantly (p < 0.05) decreased thymus percent body weight relative to the other three groups. Mean CS concentrations in Experiment 1 in Groups A and B were similar (p < 0.05). Relative to Groups A and B, Group C CS concentrations were elevated, with a peak of 126.1 ng/ml on day 4. Group D CS concentrations were higher than the other three groups, peaking at 294.1 ng/ml on day 10. There was no significant difference in PRL concentrations in Groups A, B, and C in Experiment 1 (p > 0.05). Mean PRL concentration in Group D was significantly (p < 0.05) lower than in the other three groups. The results of Experiment 2 validated those of Experiment 1. Although absolute values differed, the pattern of changes seen in body and organ weights and in CS and PRL concentrations was similar. An acute exposure to PCB and tumor resulted in an increase in circulating CS concentration and a decrease in circulating PRL concentrations. These changes may contribute to PCB-induced immunosuppressioin. / Graduation date:1992

Persistent Organic Pollutants (POPs), such as Polychlorinated Biphenyls (PCBs) or Hexachlorobenzene (HCB), released into water system. They will adsorb to particles, and incorporate into sediments. Thus the concentrations of PCBs and HCB in surface sediments provide information on recent contaminations. Besides, organisms in marine environment are influenced by the concentration in sediments, and so as the food chain. This study investigated the concentrations and characteristics of PCBs and HCB in surficial sediments of Kao-Ping Chi Estuary and nearby areas. The concentrations of PCBs and HCB in sediments were ranged from 1.432 to 6.681 (ng/g dry wt), and from 0.151 to 8.109 (ng/g dry wt¡^¡Awith an average of 3.219 and 1.978, respectively. Both of PCBs and HCB did not exceed the concentrations suggested by several sediment quality guidelines (SQGs). Compared with studies in other countries, the sediments in Kao-Ping coastal areas were more polluted by HCB. Neither PCBs nor HCB could correlate well with mean particle size or total organic carbon (TOC). The Toxic equivalents (TEQ) of dioxin-like PCBs and HCB were ranged from 0.014 to 0.061 pg-TEQ/g, and from 0.015 to 0.811 pg-TEQ/g, respectively. Using Principal Component Analysis, four possible principal components were found. These four principal components could account for 89.29% of the total variance. The first principal component was composed of highly chlorinated PCBs. The second principal component was composed of particle mean size and TOC. And the third and the fourth principal component were composed of di-, tri- PCBs and HCB. According to the factor score plot, the sample stations in this study could be divided into four groups. The first group was the stations that near the shore. The second group which contained stations were 4Km offshore. The third group contained stations with highly chlorinated PCBs. And the fourth group only contained one stations, D16. It was possible that there were other sources influenced station D16. In conclusion, the pollution in the surficial sediments was influenced by the distances from the pollutant sources and the particle size affected by tidal effect.