IntroductionEndocrine disrupting chemicals (EDCs) are agents, found either singly or used in mixtures, that disrupt the endocrine system or its production of hormones and may cause adverse effects in the exposed individuals or populations and, in the case of pregnant women, their offspring. It is presumed that maternal thyroid hormones contribute to fetal brain development. The EDCs that could impair maternal thyroid hormone function might result in subtle deficits in neurodevelopmental outcomes in children. Polychlorinated biphenyls (PCBs) are a class of EDCs produced in the past century and are still found in the environment. This dissertation aims to explore, elaborate, and embellish the associations between prenatal exposure to PCBs, the metabolites associated with PCBs, and child cognitive and motor development. The next aim of this dissertation is to explore the associations between prenatal exposure to PCBs, the metabolites associated with PCBs, and maternal thyroid hormones. Five chapters are included in this dissertation: First, an introduction to PCBs and specific aims; second, a systematic review of the literature, including the studies where prenatal exposure to PCBs or the hydroxylated PCB metabolites (OH-PCBs) and their relationship with various domains of children's neurodevelopment were investigated; third, an empirical study of exploring the associations between prenatal exposure to a mixture of PCB, OH-PCBs and children cognitive and motor skills measured in different ages; fourth, an empirical study of investigating the associations between prenatal exposure to a mixture of PCB, OH-PCBs and maternal thyroid hormones with potential for investigating the mediation of possible associations observed in the third chapter by maternal thyroid hormone concentrations; fifth, a discussion of the findings, implications for public health research, and practice and conclusions. Materials and Methods The systematic review included peer-reviewed studies indexed in several repositories (N=71 studies) from the inception of the repositories. This systematic review of the studies measured the PCBs directly in prenatal or immediately after delivery in maternal serum, cord blood, placenta, or breast milk. The empirical studies used the data available on mothers and children from "Child Health and Development Studies." Eleven PCB congeners and five OH-PCB metabolites were measured in the maternal serum post-partum among a random subset of the participants. I used a mixture analysis, Bayesian Kernel Machine Regression (BKMR), and generalized linear models (GLM) to assess the association between concentrations of PCB congeners and OH-PCB metabolites measured three days post-partum and children's cognitive and motor skills scores at age five, and cognitive skills measured at a follow-up at ages 9-11. BKMR and GLM were also used to explore the associations between PCB congeners and OH-PCB metabolites and maternal free thyroxine (FT4) and thyroid-stimulating hormone (TSH). Results The systematic review found that prenatal exposure to PCBs was possibly associated with poor cognitive development and poor attention in early and middle childhood. The evidence regarding motor development, behavior, and other neurodevelopmental outcomes were not conclusive at any stage in childhood. There was an indication for sex-specific associations with worse cognition and attention scores among boys. There was also evidence in individual studies regarding the possible association between prenatal exposure to OH-PCBs and neurodevelopmental outcomes. There were significant differences between the studies in markers of exposure, exposure assessment timing, outcome assessment, and the methodological approaches to assess the association. In the second empirical study, I found that in the crude and adjusted BKMR models among the OH-PCB metabolites, cognitive skills test scores at age five increased with each decile increase in the mixture of OH-PCB metabolites compared to when all of the metabolites were fixed at their 50th percentile among all the children and the boys and girls. These associations were largely driven by OH-PCB153 and OH-PCB146, metabolites associated with the congener PCB153. In the third empirical study, among OH-PCB metabolites attributed to PCB congeners, I observed suggestive evidence for a positive association with maternal FT4, particularly in the highest percentile of exposure to overall OH-PCB metabolites. I did not observe an association between exposure to the mixture of PCB congeners and Maternal FT4 or TSH. Nonetheless, the overall patterns suggested a positive association between exposure to PCB congeners and maternal FT4.No associations of the overall mixture of PCBs and OH-PCB metabolites were observed with maternal TSH concentrations in the BKMR models. Nonetheless, in single metabolite risk estimates, I found that 3’-OH-PCB138 was positively associated with maternal TSH values when the 3’-OH-PCB138 was fixed at its 90th percentile compared to when it was in its 10th percentile, fixing all the other congeners in their 10th, 50th, and 90th percentiles. Finally, there was an indication of a possible antagonistic interaction between 4-OH-PCB107 and 3’-OH-PCB-138 in the association of OH-PCBs with maternal FT4 such that 3’-OH-PCB138 tended to have a positive association with maternal FT4 when 4-OH-PCB107 was fixed in the 90th percentile and tended to have a negative association with maternal FT4 when 4-OH-PCB107 was fixed in their 10th percentile when all the other metabolites were fixed in their median value. Conclusions There were patterns of positive associations of OH-PCB metabolites with the children’s cognitive outcomes and maternal FT4 and maternal TSH. Nonetheless, the observed associations were weak in magnitude, often including the null value. The BKMR allowed me to explore and investigate the interactions between different components of the mixture and the overall mixture effect on the outcomes. My dissertation indicated the necessity of a holistic approach to address the impact of exposure to environmental toxins, specifically due to the detected findings regarding interactions between OH-PCB metabolites.

Estrogen-regulated synthesis of vitellogenin (Vg), a yolk-protein precursor required for reproduction, was monitored to explore the potential antiestrogenic effects of the coplanar polychlorinated biphenyl (PCB), 3,3',4,4',5,5'-hexachlorobiphenyl (3,4,5-HCB), in juvenile rainbow trout (Oncorhynchus mykiss). The effects of 17β-estradiol on 3,4,5-HCB induction of cytochrome P4501A (CYP1A) were also examined. Trout were injected with 3,4,5-HCB (0.25, 2.5, 25, 50, or 100 mg/kg) or a vehicle control, and after 10 weeks, they were sampled or injected with 17β-estradiol (0.1 mg/kg). Markers of vitellogenesis, such as liver somatic index, hepatic estrogen- binding sites, and plasma Vg concentrations, in 17β-estradiol-treated fish were not affected by 3,4,5-HCB. Maximal induction of CYP1A protein and mRNA occurred at doses above 2.5 mg/kg, and 17β-estradiol reduced CYP1A protein content at a single dose (0.25 mg 3,4,5-HCB/kg). Ethoxyresorufin-O-deethylase (EROD) activity was induced by 3,4,5-HCB doses of between 0.25 and 2.5 mg/kg, but induction was reduced at higher doses, indicating that 3,4,5-HCB suppressed CYP1A catalytic activity. In 3,4,5-HCB/17β-estradiol-treated fish, plasma estradiol was significantly reduced at 100 mg 3,4,5-HCB/kg, but the depression was not associated with CYP1A induction or with other antiestrogenic effects. Although CYP1A was induced, 3,4,5-HCB did not interfere with vitellogenesis, which suggests that the PCB congener is not a potent antiestrogen in rainbow trout.

For more than 50 years, heavy metal exposure during pre- or post-natal ontogeny has been known to produce long-lived hyperactivity in rodents. Global brain injury produced by neonatal hypoxia also produced hyperactivity, as did (mainly) hippocampal injury produced by ontogenetic exposure to X-rays, and (mainly) cerebellar injury produced by the ontogenetic treatments with the antimitotic agent methylazoxymethanol or with polychlorinated biphenyls (PCBs). More recently, ontogenetic exposure to nicotine has been implicated in childhood hyperactivity. Because attention deficits most often accompany the hyperactivity, all of the above treatments have been used as models of attention deficit hyperactivity disorder (ADHD). However, the causation of childhood hyperactivity remains unknown. Neonatal 6-OHDA-induced dopaminergic denervation of rodent forebrain also produces hyperactivity - and this model, or variations of it, remain the most widely-used animal model of ADHD. In all models, amphetamine (AMPH) and methylphenidate (MPH), standard treatments of childhood ADHD, typically attenuate the hyperactivity and/or attention deficit. On the basis of genetic models and the noted animal models, monoaminergic phenotypes appear to most-closely attend the behavioral dysfunctions, notably dopaminergic, noradrenergic and serotoninergic systems in forebrain (basal ganglia, nucleus accumbens, prefrontal cortex). This paper describes the various pharmacological models of ADHD and attempts to ascribe a neuronal phenotype with specific brain regions that may be associated with ADHD.

Thesis (MTech (Chemistry))--Cape Peninsula University of Technology, 2012. / Polychlorinated biphenyls (PCBs) are known harmful chemicals which require urgent remediation, monitoring and assessment in the environment. The predominant current methods used to analyze PCBs involve expertise and are cost intensive. Most of these methods are chromatographic based techniques which are difficult to sustain in Africa due to the expensive nature of the instrument, costly running expenses and skilled labour required. These limitations face Africans, who are the most affected by the presence of PCBs in their environment as a result of improper disposal and usage of these compounds.

Thesis (M. Eng. in Ocean Engineering)--Joint Program in Oceanography/Applied Ocean Science and Engineering (Massachusetts Institute of Technology, Dept. of Mechanical Engineering; and the Woods Hole Oceanographic Institution), 1999. / Includes bibliographical references (leaves 97-103). / by Rachel H. Levine. / M.Eng.in Ocean Engineering

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This research is part of an effort to develop non-mammalian surrogate immunoessays with the earth worm Lumbricus terrestris to assess immunotoxic potential of xenobiotics to mammals. The objective was to determine if earthworm immunoessays, namely E- and S- rosette formation and phagocytosis, are sensitive to a known mammalian immunotoxin, the PCB Arclor 1254. Results are presented in terms of PCB exposure and tissue concentrations during uptake/depuration.

As technology advances, a need for non-metal, conductive materials has arisen for several types of applications. Lithographic techniques are helpful to develop some of these applications. Such techniques require materials that are insulating and become conductive after irradiated. Composites of polyaniline in its emeraldine base form (PANI-EB) doped with photo-acid generators (PAG) become conductive upon photo-irradiation. This increase in conductivity is due to the protonation of PANI-EB. Such materials may be utilized to fabricate conducting patterns by photo-irradiation; however, the conductivity obtained by direct irradiation of PANI-EB/PAG composites is normally quite low (<10-3 S/cm) due to aggregation of highly loaded PAG. In this work, poly(ethylene glycol) (PEG), a proton transfer polymer, was added to PANI-EB/PAG. Results showed the addition of low molecular weight (MW) (550) PEG significantly enhanced the photo-induced conductivity to a level comparable to that of PANI-salt synthesized by oxidizing aniline in the presence of an acid. High MW (8000) PEG is less effective than PEG 550, and composites of PANI-EB and N-PEG-PANI showed conductivity as high as 102 S/cm after treatment with HCl vapor. The photo-induced conductivity of the N-PEG-PANI/PANI-EB/PAG composite reached 10-2-10-1 S/cm. Polychlorinated biphenyls (PCBs) are a class of chemicals with 209 different congeners, some of which are known carcinogens, and are persistent organic pollutants in the environment. After its synthesis, it was seen as a phenomenal additive in a multitude of different applications leading to the wide spread use of PCBs and a need for a safe, effective, and inexpensive remediation technique. While it is known that magnesium can degrade PCBs, the mechanism of this reaction was not well-understood. In order for magnesium to be broadly used as a remediation tool, it is necessary to fully understand how the reaction is taking place and if the PCBs are able to be fully dechlorinated into biphenyl. This research focuses on the hydrodechlorination of PCBs with zero-valent magnesium in acidified ethanol. The degradation pathways of 2, 2', 3, 5, 5', 6- hexachlorobiphenyl were investigated to determine the identity of the daughter PCBs produced, how and if they continue to be dechlorinated into biphenyl. The proton source for this hydrodehalogenation reaction was also studied using both deuterated solvent and acid to give more detail to the mechanism of this reaction.

For centuries chemists have sought to improve humankind’s quality of life and address many of society’s most pressing needs through the development of chemical processes and synthesis of new compounds, often with phenomenal results. Unfortunately, there also are many examples where these chemicals have had unintended, detrimental consequences that are not apparent until years or decades after their initial use. There are numerous halogenated molecules in this category that are globally dispersed, resistant to natural degradation processes, bioaccumulative, and toxic to living organisms. Chemicals such as these are classified as persistent organic pollutants (POPs), and due to their negative environmental and health effects, they require safe, effective, and inexpensive means of remediation. This research focuses on the development and optimization of a reaction matrix capable of reductively dehalogenating several POPs. Initial experiments determined that powdered magnesium and 1% V/V acetic acid in absolute ethanol was the most effective system for degrading polychlorinated biphenyl (PCB), an extraordinarily recalcitrant environmental contaminant. Further studies showed that this matrix also was capable of degrading polychlorinated dibenzo-p-dioxins (PCDDs), polybrominated diphenyl ethers (PBDEs), and four organochlorine pesticides (OCPs); dieldrin, heptachlor, heptachlor epoxide, and chlordane. During this phase of testing, field samples contaminated with chlordane were washed with ethanol and this ethanol/chlordane solution was degraded using the same reaction matrix, thereby demonstrating this technology’s potential for “real-world” remediation projects. Finally, a set of experiments designed to provide some insight into the mechanism of dechlorination seems to indicate that two distinct processes are necessary for degradation to occur. First, the passivated iv outer layer of the magnesium must be removed in order to expose the zero-valent magnesium core. Next, an electron is transferred from the magnesium to the target molecule, causing the cleavage of the halide bond and the subsequent abstraction of either a hydrogen or proton from a solvent molecule. It is anticipated that an understanding of these fundamental chemical processes will allow this system to be tailored to a wide range of complex environmental media