The focus of this dissertation is the use of aluminum Schiff base compounds, Salen(tBu)AlBr (SAB), in the dealkylation and detection of organophosphates (OPs). Three SAB compounds, Salen(tBu)AlBr (1), Salpen(tBu)AlBr (2), and Salophen(tBu)AlBr (3) were used to dealkylate a variety of trialkyl OPs. These reactions lead to unique organic-soluble aluminum phosphate compounds containing six-coordinate aluminum. Examples include [salen(tBu)AlOP(O)(OCH3)2]n (4), [salen(tBu)AlOP(O)(OCH2CH3)2]n (5), [salen(tBu)AlOP(O)(OPh)2]n (6), [Salophen(tBu)AlOP(O)(OCH3)2 (7), Salpen(tBu)AlOOP(O)(OiPr)2 (8). These compounds are unique examples of polymeric (4, 5, 6 and 7) and dimeric compounds (8) with salenAl units connected by phosphate linkages. The compounds do not decompose in neutral water. This is an advantage in the use of SABs for the deactivation of phosphate esters such as nerve agents. Water-soluble and stable group 13 salen complexes, Salen(SO3Na)MNO3 (M =Al (19), Ga (22)), Salpen(SO3Na)MNO3 (M = Al (20), Ga (23)), and Salophen(SO3Na)M(NO3) (M = Al (21), Ga (24)) were synthesized by using water-soluble Salen(SO3Na) ligand. All the compounds were characterized by various analytical techniques: 1H and 13C NMR, IR, and melting point. One SAB was used to detect the nerve agents (NA). Salen(tBu)Al(Ac), prepared in situ from Salen(tBu)AlBr and NaAc, forms Lewis acid-base adducts with the NAs, GB (sarin) and GD (soman), and the VX hydrolysis product, EMPA, in aqueous solution. The [Salen(tBu)Al(NA)]+ compound is sufficiently stable to allow the identification of the NA with ESI-MS. Molecular ion peak was detected for every compound with little or no fragmentation. The distinctive MS signatures for [Salen(tBu)Al(NA)]+ compounds provide a new technique for identifying NAs in aqueous solution.

Tris(1-chloro-2-propyl) phosphate (TCPP) and tris(1,3-dichloro-2-propyl) phosphate (TDCPP) are added to polyurethane foams in a variety of industrial and consumer products to prevent flame ignition. The gradual release of these flame retardants (FRs) from such products leads to contamination of various abiotic and biotic media, including wild birds. Recent studies demonstrated endocrine-disrupting effects of TCPP and TDCPP, including alteration of circulating thyroid hormone (TH) levels. The TH-pathway is essential for normal growth and development in birds. There are limited data on the toxicological effects of TCPP and TDCPP in avian species and, prior to this work, no study has examined their effects in avian embryos. This M.Sc. thesis investigates the developmental, molecular and biochemical effects of TCPP and TDCPP in chicken (Gallus gallus domesticus) embryos via egg injection studies. TCPP delayed pipping at doses ≥9.24 μg/g, both TCPP and TDCPP reduced embryo growth at the highest dose (51.6 μg TCPP/g and 45 μg TDCPP/g), and TDCPP decreased free plasma thyroxine and gallbladder size at 7.64 μg/g and 45 μg/g, respectively. Real-time reverse transcription polymerase chain reaction was used to measure changes in mRNA levels of hepatic genes that were responsive to these FRs in a previous in vitro study. TCPP dysregulated the expression of TH-responsive genes and xenobiotic metabolizing enzymes (cytochrome P450s; CYPs), whereas TDCPP only affected CYPs. Less than 1% of the administered TCPP or TDCPP was detected in egg contents following 19 days of incubation, indicating extensive metabolism of the parent compounds. DNA microarrays were used to perform a global transcriptional analysis on liver samples from embryos that exhibited adverse effects following TDCPP injection. 47 differentially expressed genes were identified at the 45 μg/g dose. Functional analysis revealed that immune function and lipid and steroid metabolism were major targets of TDCPP toxicity and indicated a state of cholestatic liver/biliary fibrosis. Since the TH-pathway is a key regulator of metabolic homeostasis, its disruption early in development is a potential cause of the observed adverse effects. This thesis demonstrates, for the first time, developmental and endocrine-disrupting effects of TCPP and TDCPP in an avian species and attempts to link phenotypic changes to molecular-level disruptions in hopes to improve the understanding of their modes of action.

Tris(1-chloro-2-propyl) phosphate (TCPP) and tris(1,3-dichloro-2-propyl) phosphate (TDCPP) are added to polyurethane foams in a variety of industrial and consumer products to prevent flame ignition. The gradual release of these flame retardants (FRs) from such products leads to contamination of various abiotic and biotic media, including wild birds. Recent studies demonstrated endocrine-disrupting effects of TCPP and TDCPP, including alteration of circulating thyroid hormone (TH) levels. The TH-pathway is essential for normal growth and development in birds. There are limited data on the toxicological effects of TCPP and TDCPP in avian species and, prior to this work, no study has examined their effects in avian embryos. This M.Sc. thesis investigates the developmental, molecular and biochemical effects of TCPP and TDCPP in chicken (Gallus gallus domesticus) embryos via egg injection studies. TCPP delayed pipping at doses ≥9.24 μg/g, both TCPP and TDCPP reduced embryo growth at the highest dose (51.6 μg TCPP/g and 45 μg TDCPP/g), and TDCPP decreased free plasma thyroxine and gallbladder size at 7.64 μg/g and 45 μg/g, respectively. Real-time reverse transcription polymerase chain reaction was used to measure changes in mRNA levels of hepatic genes that were responsive to these FRs in a previous in vitro study. TCPP dysregulated the expression of TH-responsive genes and xenobiotic metabolizing enzymes (cytochrome P450s; CYPs), whereas TDCPP only affected CYPs. Less than 1% of the administered TCPP or TDCPP was detected in egg contents following 19 days of incubation, indicating extensive metabolism of the parent compounds. DNA microarrays were used to perform a global transcriptional analysis on liver samples from embryos that exhibited adverse effects following TDCPP injection. 47 differentially expressed genes were identified at the 45 μg/g dose. Functional analysis revealed that immune function and lipid and steroid metabolism were major targets of TDCPP toxicity and indicated a state of cholestatic liver/biliary fibrosis. Since the TH-pathway is a key regulator of metabolic homeostasis, its disruption early in development is a potential cause of the observed adverse effects. This thesis demonstrates, for the first time, developmental and endocrine-disrupting effects of TCPP and TDCPP in an avian species and attempts to link phenotypic changes to molecular-level disruptions in hopes to improve the understanding of their modes of action.

Organophosphates are neurotoxic compounds that inhibit acetylcholinesterase producing excess cholinergic stimulation. This produces various toxic signs including excitotoxic neuronal damage. Oximes can be used as a treatment for organophosphate poisoning by reactivating inhibited acetylcholinesterase. Traditional oximes do not penetrate the blood-brain barrier, limiting protection of the central nervous system. Novel, brain-penetrating oximes have the potential to protect the brain from organophosphate induced damage. Adult male rats were used to examine the ability of model organophosphates to produce neuropathology and the ability of novel oximes to prevent this damage. Additionally, adult male rats were used to examine changes in gene expression of the MAP kinase system resultant of treatment with model organophosphates and novel oximes. Results of these experiments support that the model organophosphates can be used to study neurodegeneration, the novel oximes may prevent neurodegeneration, and both organophosphates and novel oximes affect expression of MAP kinase genes.

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In an electrochemical sensor, the sensing performance is mainly dependent on the mass transport of the analyte towards the working electrode-electrolyte interface and working electrode properties. Carbon nanomaterials like carbon nanotubes are widely employed to modify the working electrode properties for sensitive detection. A simulation model is formulated to investigate the effects of modifying a planar bare electrode with carbon nanotubes on electrochemical detection of fenitrothion (FT, an organophosphate). The model revealed that porous electrodes caused the change in mass transport regime and influenced FT’s electrochemical response. The results aided in understanding the influence of the porous electrode on analyte detection and thus assisted in the fabrication of an ultrasensitive electrochemical sensor. Simulation supported synthesis of a highly sensitive ink to produce highly porous and electrocatalytic electrodes. Activated carbon (AC) possesses high porosity and surface area, but they suffer from lower electrical conductivity. To enhance their conductivity, AC was co-doped with nitrogen and sulfur. Multiwalled carbon nanotubes were incorporated to further improve their porosity and electrocatalytic properties. The synthesized nitrogen-sulfur co-doped activated carbon coated multiwalled carbon nanotube (NS-AC-MWCNT) ink produced highly porous electrocatalytic electrodes. The sensor revealed a 4.9 nM limit of detection (LOD) under optimized conditions. However, it failed to overcome the enzymatic sensors’ performances. The ultrasensitive performance was achieved by incorporating a detecting agent in the ink that instilled analyte capture ability. Metal oxides like ZrO2, MnO2, and MgO possessed affinity towards organophosphate (fenitrothion), heavy-metal ion (lead), and nutrient (nitrite). Metal oxides were modified with 3,4-dihydroxylbenzaldehyde (DHBA) – Chitosan (CHIT) to produce well dispersed and uniformly coated stable electrodes. The ZrO2-DHBA-CHIT/NS-AC-MWCNT sensor achieved a remarkable limit of detection of 1.69 nM for FT. The sensor's performance exceeded the enzymatic-based sensors. The commonly found chemical interferents had negligible interference. The sensor produced reliable and satisfactory performance in lake and tap water. The MnO2-DHBA-CHIT/NS-AC-MWCNT/GCE and MgO-DHBA-CHIT/NS-AC-MWCNT/GCE sensors produced an enormous improvement in the sensor performance compared to unmodified electrodes for lead and nitrite detection. The preliminary results on detecting other pollutants like lead and nitrite showed the importance of the methodology in providing a platform for a new class of metal oxide-based sensors. / Thesis / Doctor of Philosophy (PhD) / The growing population and rapid industrial development are affecting the water quality worldwide. The major water pollutants are organophosphates, heavy metal ions, and nutrients. These water pollutants are harmful, and their bioaccumulation poses a major health concern. In the USA alone, water quality issues are predicted to cost $210 billion annually. Therefore, sensors to detect water pollutants are developed to monitor their environmental footprints. Electrochemical sensors are popularly used to detect water pollutants owing to their low-cost and high sensitivity. The objective of this dissertation was to fabricate highly sensitive and specific electrochemical sensors to detect organophosphate (e.g., fenitrothion, FT), heavy metal ion (e.g., lead), and nutrient (e.g., nitrite). The sensors were fabricated with ink based on nanomaterials like carbon nanotubes and detecting agents like metal oxides. The fabricated sensors achieved very high sensitivity and specificity and can detect water pollutants in lake and tap water.

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Organophosphates are insecticides which result in acute adverse signs when exposed at toxic doses by animals and lead to death if left untreated. The current treatment for organophosphate toxicity includes atropine and the federally approved oxime 2-PAM. However, 2-PAM is not very effective at crossing the blood brain barrier which results in prolonged inactivation of acetylcholinesterase, which is the primary target of organophosphates, in the brain even after administration. The novel oximes, Oxime 15 and Oxime 20, are able to cross the blood brain barrier and reactivate the inhibited acetylcholinesterase. In this experiment with six animal species frequently used in toxicity studies, they were proven to be just as effective and sometimes better than 2-PAM at reactivating acetylcholinesterase or butyrylcholinesterase inhibited by paraoxon, chlorpyrifos-oxon, phorate-oxon, or dicrotophos. The detoxication enzymes butyrylcholinesterase, carboxylesterase, and paraoxonase were also studied as potential influences of the toxicity of the organophosphates in these different species.