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The three isomers of dichlorobenzene (DCB) exhibit marked differences in hepatotoxicity following intraperitoneal (ip) administration in male F-344 rats. Plasma GPT activity, measured 24 hours post exposure, was elevated to approximately 4080 units/ml following a 1.8 mmol/kg dose of o-DCB. Conversely, n-DCB produced only a moderate elevation (306 units/ml) following a 4.5 mmol/kg dose, while p-DCB produced no elevation in GPT activity at this dose (24 units/ml). Ultra-structurally, o- and m-DCB induced elevations in GPT activity were associated with a centrilobular pattern of hepatic necrosis. The role of cytochrome P-450 mediated bioactivation in DCB-induced hepatotoxicity was demonstrated by elevated GPT activities following an otherwise nontoxic 0.9 mmol/kg dose of either o- or m-DCB in phenobarbital pretreated animals (16770 and 21540 units/ml, respectively). The paraisomer of DCB showed no induction of toxicity with phenobarbital pretreatment. Hepatic glutathione (GSH) concentrations were reduced 0.5, 3 and 5 hours after a 1.8 mmol/kg dose of either o- or m-DCB, a dose which produces hepatotoxicity only for o-DCB. Pretreatment of animals with phorone depleted hepatic GSH to 15% of control levels within two hours; subsequent ip administration of either o- or m-DCB (1.8 mmol/kg) produced approximately equivalent elevations in GPT activity for both isomers (5749 ± 648 and 4732 ± 857 units/ml, respectively). In vitro incubations of o- and m-DCB with GSH and rat liver cytosolic fraction, suggested that GSH may bind m-DCB without prior bioactivation, thereby reducing the hepatotoxicity of this isomer relative to the more toxic ortho isomer. The interactive hepatotoxicity of the dichlorobenzenes with carbon tetrachloride (CCl₄) was also investigated. Concomitant ip injection of CCl₄ (1.0 mmol/kg) and o-DCB (2.7 mmol/kg) produced a marked inhibition of o-DCB hepatotoxicity, as measured by GPT activity (approximately 200 units/ml vs. 7450 units/ml for o-DCB alone). The mechanism of this inhibition of o-DCB hepatotoxicity was shown to be a reduction in the cytochrome P-450 mediated bioactivation of o-DCB, by CCl₄. A similar inhibition of o-DCB hepatotoxicity was seen following administration of CCl₄ as a pretreatment, via the drinking water. Concomitant ip administration of CCl₄ with either m- or p-DCB also produced a reduction in the metabolism of the dichlorobenzene.

Exposure to polycyclic aromatic hydrocarbons such as benzo[a]pyrene (B[a]P) has been determined to be a risk factor for various forms of human cancer. PAH DNA adducts have been shown to cause mutations, but carcinogenesis is also accompanied by alterations in gene expression. Inhibiting individual cytochrome P450s could clarify the interaction of P450s and other enzymes in the activation of polycyclic aromatic hydrocarbons to DNA binding intermediates. Phosphorodiamidate morpholino oligomers (PMOs), a class of antisense agents were targeted against cytochrome P450 1A1 (CYP1A1) and cytochrome P450 1B1 (CYP1BI). No significant inhibition of enzyme activity or expression was observed with any PMO used as measured by ethoxyresorufin-O-deethylase (EROD) activity and immunoblots. It was demonstrated that BPDE may react with PMOs in vitro, and PMOs may be segregated in lysosomes, blocking their efficacy. Nonspecific effects by the PMO on CYP1A1 activity were observed. These observations indicate multiple confounding effects in the use of PMOs for this purpose. Many of the genes regulated by histone deacetylases are involved in proliferation, cell function, and differentiation, and HDAC inhibitors are of great interest in cancer research. To probe epigenetic regulation of CYP1A1, MCF-7 cells were treated with two HDAC inhibitors, suberoylanilide hydroxamic acid (SAHA) and trichostatin A (TSA). SARA and TSA increased EROD activity and in RT-PCR. SARA and TSA reduced B[a]P induced CYP1A1 and CYP1B1 mRNA levels. B[a]P DNA binding was not significantly altered by SAHA or TSA treatment. To assay global protein expression changes after treatment with PAR, MCF-7 cells were treated with B[a]P, DB{a,1]P, coal tar extract (SRM 1597) and diesel exhaust extract (SRM 1975), Proteins were separated by two-dimensional electrophoresis, and analyzed using PDQuest. Spots of interest were excised and identified by matrix assisted laser desorption/ionization time of flight time of flight mass spectroscopy. Alterations in expression of heat shock proteins, cytoskeletal proteins, DNA associated proteins, and glycolytic and mitochondrial proteins were observed. Universally increased expression was observed for tubulin alpha and myosin light chain alkali, cyclophilin B, heterogeneous nuclear riboprotein B1, and alpha enolase. Additional proteins exhibiting change in expression included histone H2A.1, heat shock protein 70-2, galectin-3, nucleoside diphosphate kinase, ATP synthase, and electron transfer flavoprotein. / Graduation date: 2004

by Jian Wang. / Thesis (Ph.D.)--Chinese University of Hong Kong, 1996. / Includes bibliographical references (p. 154-171). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web.

Polyaromatic hydrocarbons (PAHs) are contaminants synthesized through incomplete combustion of carbon based substances. PAHs are known to be photodynamic and toxicity increases exponentially when in contact with ultraviolet radiation (UV). The effect of UV absent recovery periods and potential for latent toxicity during photo-induced toxicity are previously unknown and are not included within the toxicity model. Results of equal interval tests further support the current reciprocity model as a good indicator of PAH photo-induced toxicity. Interval test results also indicate a possible presence of time-dependent toxicity and recovery thresholds and should be included into toxicity risk assessments. Moreover, results of latent effects assays show that latent mortality is a significant response to PAH photo-induced toxicity and should be included into toxicity risk assessments. The present research demonstrates that UV exposure time rate is a significant driving force of PAH photo-induced toxicity.

The prenatal period of development is uniquely susceptible to lasting harmful health effects from exposure to environmental toxicants. Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental pollutants which have a wide variety of associated health effects, including impaired neurodevelopment when exposure occurs in-utero. While a handful of mechanisms have been implicated in PAH neurodevelopmental toxicity, none fully resolve the intricate biological processes that contribute to these outcomes. Mitochondria are increasingly being studied as sensitive targets of many environmental toxicants including PAHs. Despite the known mitochondrial sensitivity to PAHs, and the role of mitochondrial functions in neurodevelopment, little research has been done to evaluate mitochondrial dysfunction as mechanism of PAH neurodevelopmental toxicity. The work of this dissertation seeks to investigate a number of questions on this topic using a wide variety of techniques. We study exposure sources of individual PAHs, the relationship between prenatal PAH exposure constituents and mitochondrial functional outcomes and mitochondrial DNA copy number (mtDNAcn) in multiple biospecimens, including windows of exposure. We employ both epidemiological and experimental techniques, leveraging the advantages of one approach against the weakness of another to draw robust conclusions. Chapter 2 begins by comprehensively studying the demographic and behavioral variables predictive of personal PAH exposure. We combined a significant amount of personal exposure data collected using silicone wristbands with prenatal questionnaires to identify variables most predictive of both exposure to individual PAH compounds and total exposure. This work revealed complex relationships between multiple parameters in the prediction of each individual PAH. We found demographic and socioeconomic variables to be the most common predictors of exposure, followed by behavior variables. This work provides the foundation to identify pathways to reduce exposure and protecting the most vulnerable populations. In chapter 3, we describe two epidemiological studies conducted in Northern Manhattan birth cohorts. The first study uses data from the Columbia Center for Children’s Environmental Health (CCCEH) Fair Start cohort. We measured mitochondrial DNA copy number (mtDNAcn) in umbilical cord tissue, a novel biospecimen with unique utility due to its ease of acquisition and homogenous cellular composition. We measured individual exposure to 63 PAH compounds using silicone wristband samplers and analyze this data using both individual models and quantile G computation to estimate the overall mixture effect. We identified three compounds associated with mtDNAcn in individual models, and a positive association between the mixture of 19 compounds and mtDNAcn. In the second study we expanded upon previous analyses in the CCCEH Mothers and Newborns cohort which had demonstrated an association between summed-total prenatal exposure to 8 carcinogenic PAHs and scores on the Bayley Scale of Infant Development-II at age 3. We used measures of mtDNAcn in umbilical cord blood to evaluate the role of mitochondrial toxicity in PAH neurodevelopment and improved upon prior studies by including adjustment for cell type composition. We utilized both traditional linear model approaches as well as quantile G computation to evaluate the mixture both as a sum-total and using newly developed mixture methods. We determined that while prenatal PAH exposure was negatively associated with umbilical cord blood mtDNAcn using mixtures methods mtDNAcn was not associated with neurodevelopment. The bidirectional effect of prenatal PAH exposure on mtDNAcn between these two studies reveals the complexity of mtDNAcn as a biomarker and the need for more direct measures of mitochondrial functions in the study of PAH neurodevelopmental toxicity. Chapter 4 seeks to complement the epidemiological research with an experimental system. Using mouse preimplantation embryos, we measured the effect of exposure to an environmentally relevant mixture of PAHs on morphological development, superoxide production, mitochondria membrane potential, and mtDNAcn. We found exposure to low levels of a PAH mixture from days 2.5-3.5 post fertilization caused a significant decrease in healthy embryo morphology and a reduction in mtDNAcn. PAH exposure increased mitochondrial membrane potential under several dosing regimens while the effect on superoxide levels was variable and potentially mediated by changes in mitochondrial mass. As a whole these results indicate mitochondrial dysfunction as a result of low-level PAH exposure during the earliest periods of development with a window of heightened susceptibility immediately prior to implantation. In chapter 5 we evaluate the relative mitochondrial potency of the 8 commonly studied carcinogenic PAHs and an environmental relevant mixture of those 8 compounds. Using human umbilical cord mesenchymal stem cells, we specifically study these effects in the context of prenatal development. Superoxide production, mitochondrial membrane potential, mitochondrial mass, cell death and mtDNAcn was quantified at 9 doses for each exposure. This data was used to fit dose response curves and determine relative potency of each exposure/outcome endpoint. We identified benzo[k]fluoranthene and chrysene among the most toxic compounds analyzed and noted differences between relative mitochondrial toxicity and carcinogenicity of these constituents emphasizing the need for continued research into the non-cancer endpoints of PAH exposure. With the intentional comparable exposures and outcomes utilized in these studies comes the opportunity to make connections and draw conclusions across chapters to arrive at four major conclusion: (1) Demographic variables, not behavior, are most predictive of exposure to many PAH compounds (2) prenatal PAH exposure affects multiple measures of mitochondrial functions, (3) there is variability in the susceptibility during early development, and (4) the developmental mitochondrial toxicity of previously studied PAH compounds does not follow the same patterns of relative potency seen in carcinogenesis. This work provides significant insight into the impact of prenatal PAH exposure on mitochondrial functions while highlighting critical areas for further research. More studies are needed to fully understand the mechanisms and long-term effects of PAH exposure on early development, as well as to identify effective interventions to mitigate these risks.

Hydrocarbon solvents are widely used in the production of paints, adhesives, dyes, polymers, plastics, textiles, printing inks, agricultural products and pharmaceuticals. While the neuropathic potential of aliphatic solvents was shown in the 1970s, little is known about the neuropathic potential of aromatic solvents. The present study examines such solvents, 1,2-diethylbenzene (DEB) and its metabolite 1,2-diacetylbenzene (DAB), to determine (a) the neuropathological evidence for peripheral neuropathy in rodents treated with 1,2-DAB, (b) the neurochemical basis for the neurotoxic properties of this compound, and (c) the structural requirements for nerve fiber damage. The properties of 1,2-DAB and 2,5- hexanedione (HD) are also compared. A key finding of this thesis is that 1,2-DAB induces a 2,5-HD-like pattern of nerve damage of motor and sensory axons with focal swellings containing neurofilaments. Whereas nerve damage begins distally in 2,5-HD intoxication, with 1,2-DAB treatment axonal swellings begin intraspinally and in the proximal ventral roots of motor nerve fibers. A second key finding is the reactivity of 1,2-DAB with amino acids, notably lysine, a property that is shared with 2,5-HD. 1,2-DAB and 2,5-HD react with amino acids and proteins to form blue and yellow chromophores, respectively. Relative to 2,5-HD, 1,2-DAB is three orders of magnitude more reactive in forming high-molecular-weight species. 1,2-DAB treatment of spinal cord slices in vitro and intact sciatic nerve in vivo showed that neurofilament proteins react more readily than beta-tubulin. The heavy and medium subunits of neurofilament protein were more reactive than the light subunit. The reactivity of these four axonal proteins was in proportion to their lysine content. These data are consistent with selective accumulation of neurofilaments in giant axonal swellings. In summary, these studies have shown a relationship between the chromogenic and neuropathic properties of two gamma-diketones, one aliphatic (2,5-HD) the other aromatic (1,2-DAB). These studies are relevant to occupational and public health for at least two reasons. First, urinary chromogens generated by neuropathic aliphatic and aromatic hydrocarbons could serve as biological markers of exposure to solvents with neuropathic potential, and second, other chromogenic solvents (such as tetralin) should be considered for neuropathic potential. / Graduation date: 2002

Orientador: Fosca Pedini Pereira Leite / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Biologia / Made available in DSpace on 2018-08-14T00:36:25Z (GMT). No. of bitstreams: 1 Pavani_Lilian_M.pdf: 1390022 bytes, checksum: 43df8a085a06d86b5eadaf092c0fbf14 (MD5) Previous issue date: 2009 / Resumo: Na região do Canal de São Sebastião, onde opera o maior terminal petrolífero do Brasil, há extensos bancos de algas pardas do gênero Sargassum e anfípodes associados, mas também existem hidrocarbonetos alifáticos e aromáticos de petróleo na água e no sedimento. Sabese que os anfípodes são eficientes bioindicadores de qualidade ambiental, assim como as algas são importantes bioacumuladores. Avaliou-se a presença de hidrocarbonetos em Sargassum e buscou-se relacionar suas concentrações com distâncias crescentes a partir do terminal, tanto ao norte quanto ao sul da Ilha de São Sebastião. Essas concentrações e distâncias também foram utilizadas para verificar a estruturação das comunidades de anfípodes do fital de Sargassum. Essa avaliação foi feita para anfípodes, abordando-se a composição de grupos tróficos e de espécies. Não foi constatada relação entre as distâncias e concentrações de hidrocarbonetos presentes nas algas e na estruturação das comunidades de anfípodes em nenhuma das abordagens. No entanto, notou-se correspondência entre elas, o que indica que a identificação em famílias para o estabelecimento de grupos tróficos pode ser eficiente numa avaliação ambiental mais rápida. Também se obteve importante informação em relação à fauna de anfípodes do litoral do Estado de São Paulo, uma vez que ainda não havia estudos na Ilha de São Sebastião e a fauna de ilhas do estado ainda é pouco conhecida / Abstract: In the São Sebastião Channel region, where operates the greatest Brazilian petroliferous terminal, there are extensive banks of the brown seaweed Sargassum with many associated amphipods, but also polyciclic aromatic hydrocarbons and aliphatic hydrocarbons, which are present both in sedment and water. The amphipods are known to be efficient bioindicators of environmental quality, as well as the seaweed are important bioacumulators. The presence of hydrocarbons in Sargassum and its relationship with increasing distances from the terminal, both north and south of the São Sebastião Island, was evaluated. These concentrations and distances were also used to verify the structure of amphipod communities associated to Sargassum . This evaluation was made for amphipods identified in trofic groups and in species. There was no significant relationship between distances from the terminal and concentrations of hydrocarbons in the seaweed or the estructure of the amphipod communities. However, correspondence between the aproachs (trofic groups and species) was noticed, which indicates that the identification in families for the establishment of trofic groups can be efficient in a faster ambient evaluation. Also, important information related to amphipods of the São Paulo State coast was achieved, as far as the fauna of São Sebastião Island was first studied and the islands fauna of the State are still little known / Mestrado / Ecologia / Mestre em Ecologia

Lai Ho-yan. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1999. / Includes bibliographical references (leaves 104-122). / Abstracts in English and Chinese. / ACKNOWLEDGEMENT --- p.I / ABSTRACT (ENGLISH) --- p.II / ABSTRACT (CHINESE) --- p.IV / TABLE OF CONTENT --- p.VI / LIST OF FIGURES --- p.IX / LIST OF TABLES --- p.V / INTRODUCTION --- p.1 / Chapter 1.1 --- Background --- p.1 / Chapter 1.2 --- Sources of oil pollution --- p.1 / Chapter 1.3 --- Composition of oil --- p.4 / Chapter 1.4 --- Fate of oil in the environment --- p.6 / Chapter 1.5 --- Toxic effect of oil on marine ecosystem --- p.8 / Chapter 1.5.1 --- Acute toxicity --- p.8 / Chapter 1.5.2 --- Chronic toxicity --- p.9 / Chapter 1.5.3 --- Carcinogenicity of oil --- p.11 / Chapter 1.6 --- The origins of ecotoxicology --- p.12 / Chapter 1.7 --- Need for ecotoxicity tests --- p.13 / Chapter 1.8 --- Testings in ecotoxicology --- p.15 / OBJECTIVES --- p.17 / MATERIALS AND METHODS --- p.18 / Chapter 1. --- Collection of oily wastes samples --- p.18 / Chapter 2. --- Preparation of samples --- p.18 / Chapter 2.1 --- Water-soluble fraction --- p.19 / Chapter 2.2 --- Polycyclic aromatic hydrocarbon fraction --- p.20 / Chapter 2.2.1 --- Supercritical fluid extraction --- p.20 / Chapter 2.2.2 --- Silica gel chromatography --- p.22 / Chapter 2.2.3 --- Sample concentration --- p.22 / Chapter 3. --- Chemical analyses of oily wastes --- p.26 / Chapter 3.1 --- Determination of heavy metal concentration in oily waste samples --- p.26 / Chapter 3.1.1 --- Nitric acid-perchloric acid digestion --- p.26 / Chapter 3.1.2 --- Inductively coupled plasma-emission spectrometric analysis --- p.26 / Chapter 3.2 --- Determination of polycyclic aromatic hydrocarbon concentration in oily waste samples --- p.28 / Chapter 3.2.1 --- Determination of polycyclic aromatic hydrocarbon concentration in water- soluble fraction --- p.28 / Chapter a. --- Liquid-liquid extraction --- p.28 / Chapter b. --- Gas chromatography-mass spectrometric analysis of water-soluble fraction --- p.29 / Chapter 3.2.2 --- Determination of polycyclic aromatic hydrocarbon concentration in crude oily waste samples --- p.32 / Chapter a. --- Supercritical fluid extraction and silica gel column chromatography --- p.32 / Chapter b. --- Gas chromatography-mass spectrometric analysis of polycyclic aromatic hydrocarbon fraction --- p.33 / Chapter 4 --- ecotoxicological studies of oily wastes --- p.34 / Chapter 4.1 --- Toxicity tests and sample preparation --- p.34 / Chapter 4.2 --- Ecotoxicological studies of water soluble fraction --- p.34 / Chapter 4.2.1 --- "Growth inhibition test on a marine alga, Chlorella pyrenoidosa CU-2" --- p.34 / Chapter 4.2.2 --- "Survival test on a marine amphipod, Elasmopus rapax" --- p.39 / Chapter 4.2.3 --- "Survival test on a marine fish, Ambassis gymnocephalus" --- p.41 / Chapter 4.2.4 --- Microtox® test --- p.43 / Chapter 4.3. --- Ecotoxicological studies of polycyclic aromatic hydrocarbon fraction --- p.45 / Chapter 4.3.1 --- "Growth inhibition test on a marine alga, Chlorella pyrenoidosa CU-2" --- p.45 / Chapter 4.3.2 --- "Survival test on a amphipod, Parhyale plumulosa" --- p.45 / Chapter 4.3.3 --- "Survival test on the fish, Sparus sarba" --- p.47 / Chapter 4.3.4 --- Microtox® test --- p.49 / Chapter 5. --- Statistical analyses of chemical and ecotoxicological analyses --- p.50 / RESULTS --- p.51 / Chapter 1. --- Chemical analyses of oily wastes --- p.51 / Chapter 1.1 --- Inductively coupled plasma-emission spectrometric analysis --- p.51 / Chapter 1.1.1 --- Heavy metal concentration in crude oily wastes --- p.51 / Chapter 1.1.2 --- Heavy metal concentration in water-soluble fraction --- p.51 / Chapter 1.1.3 --- Heavy metal concentration in ploy cyclic aromatic hydrocarbon fraction --- p.54 / Chapter 1.2 --- Gas chromatography- mass spectrometry analysis --- p.54 / Chapter 1.2.1 --- Polycyclic aromatic hydrocarbon concentration in crude oily wastes --- p.54 / Chapter 1.2.2 --- Polycyclic aromatic hydrocarbons concentration in water-soluble fraction --- p.59 / Chapter 1.2.3 --- Polycyclic aromatic hydrocarbons concentration in polycyclic aromatic hydrocarbon fraction --- p.61 / Chapter 2. --- Ecotoxicological studies of oily wastes --- p.63 / Chapter 2.1 --- Ecotoxicological studies of water-souble fraction --- p.63 / Chapter 2.1.1 --- Growth inhibition test on Chlorella pyrenoidosa CU-2 --- p.63 / Chapter 2.1.2 --- Survival test on Elasmopous rapax --- p.63 / Chapter 2.1.3 --- Survival test on Ambassis gymnocephalus --- p.67 / Chapter 2.1.4 --- Microtox® test --- p.67 / Chapter 2.2 --- Ecotoxicological studies of polycyclic aromatic hydrocarbon fraction --- p.70 / Chapter 2.2.1 --- Growth inhibition test on Chlorella pyrenoidosa CU-2 --- p.70 / Chapter 2.2.2 --- Survival test on Parhyale plumulosa --- p.70 / Chapter 2.2.3 --- Survival test on Sparus sarba --- p.74 / Chapter 2.2.4 --- Microtox® test --- p.74 / Chapter 3. --- Statistical analyses of chemical and ecotoxicological studies --- p.77 / Chapter 3.1 --- Statistical analyses of studies on water-soluble fraction --- p.77 / Chapter 3.1.1 --- Correlation between heavy metal concentration in water-soluble fraction and toxicity tests --- p.77 / Chapter 3.1.2 --- Correlation between concentration of total polycyclic aromatic hydrocarbon in water-soluble fraction and toxicity tests --- p.80 / Chapter 3.1.3 --- Correlation among acute toxicity tests --- p.80 / Chapter 3.2 --- Statistical analyses of polycyclic aromatic hydrocarbon fraction --- p.84 / Chapter 3.2.1 --- Correlation between heavy metal level and toxicity tests --- p.84 / Chapter 3.2.2 --- Correlation between total polycyclic aromatic hydrocarbon concentration in polycyclic aromatic hydrocarbon fraction and toxicity tests --- p.84 / Chapter 3.2.3 --- Correlation between four acute toxicity tests --- p.88 / DISCUSSION --- p.91 / Chapter 1 --- Chemical analyses of oily wastes --- p.91 / Chapter 1.1 --- Inductively coupled plasma-emission spectrometric analysis --- p.91 / Chapter 1.2 --- Gas chromatography-mass spectrometry analysis --- p.93 / Chapter 2. --- ecotoxicological studies of oily wastes --- p.95 / Chapter 2.1 --- Growth inhibition test on Chlorella pyrenoidosa CU-2 --- p.95 / Chapter 2.2 --- Survival tests on Elasmopus rapax and Parhyale plumulosa --- p.96 / Chapter 2.3 --- Survival test on Ambassis gymnocephalus and Sparus sarba --- p.97 / Chapter 2.4 --- Microtox® test --- p.98 / Chapter 3 --- Statistical analyses of chemical and ecotoxicological analyses --- p.99 / Chapter 4. --- statistical analyses between acute toxicity tests --- p.101 / CONCLUSION --- p.102 / REFERENCES --- p.104