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Title:Toxicity mechanism of anthropogenic water contaminants: drinking water disinfection by-products (haloacetic acids) and particle associated contaminants from sealcoats (polyaromatic hydrocarbons) in lake sediments
Author(s):Azra Dad
Director of Research:Plewa, Michael J
Doctoral Committee Chair(s):Plewa, Michael J
Doctoral Committee Member(s):Werth, Charles J; Rayburn, A. Lane; Flaws, Jodi
Department / Program:Crop Sciences
Discipline:Crop Sciences
Degree Granting Institution:University of Illinois at Urbana-Champaign
Degree:Ph.D.
Genre:Dissertation
Subject(s):Genotoxic
Disinfection by-products
Abstract:Drinking water disinfection was one of the major public health accomplishments of 20th century. Water disinfection helps in reducing waterborne diseases like typhoid fever, cholera, and hepatitis A. However, chemical water disinfection also produces unwanted toxic chemicals, known as water disinfection by-products (DBPs). Most of the DBPs are cytotoxic, neurotoxic, genotoxic, mutagenic, carcinogenic and teratogenic but the toxicity mechanism is not completely understood. Therefore, the objectives of this dissertation were to i) understand the toxicity mechanisms and identify the molecular targets of all the regulated and non-regulated haloacetic acids (HAAs) water DBPs, ii) to differentiate among the toxicity mechanisms of mono-, di-, and triHAAs, iii) to evaluate the toxicity potential of chlorinated and chloraminated wastewater effluents, and iv) to evaluate the mutagenicity potential of the particle associated contaminants such as polyaromatic hydrocarbons (PAHs) associated with coal tar and soot, extracted from lake core sediments. Studies based on the toxicity mechanism of HAAs water DBPs demonstrated that monoHAAs were the strongest inhibitors of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) where, di-, and triHAAs were weaker inhibitors. MonoHAAs greatly reduced the ATP contents of the cells. Unlike monoHAAs, triHAAs increased the cellular ATP levels as compared to the negative controls. Exogenous pyruvate supplementation rescued cells from monoHAA-induced DNA damage and ATP depletion. These results confirmed that monoHAA-induced genotoxicity was due to GAPDH inhibition. HAAs not only affected the GAPDH kinetics and disturbed the cellular energy homeostasis but also increased pyruvate dehydrogenase complex (PDC) activity. Increased PDC activity by monoHAAs was due to changes in metabolite ratios e.g., ATP/ADP, and NADH/NAD ratio but the increase induced by di-, and triHAAs was due to the inhibition of pyruvate dehydrogenase kinase (PDK). Results demonstrated that HAA-induced toxicity is due to disruption in cellular energy homeostasis. This research demonstrated that there was a difference among the HAA-induced toxicity mechanisms and their molecular targets. MonoHAAs had an indirect effect on mitochondrial metabolism by inhibiting GAPDH, affecting the generation of pyruvate, inducing oxidative stress and reducing the final output of mitochondria in the form of ATP. Among monoHAAs, the rank order of toxicity was iodoacetic acid > bromoacetic acid >> chloroacetic acid (IAA > BAA >> CAA). This toxicity pattern was directly correlated with the inhibition of GAPDH kinetics, ATP depletion, and PDC activation. Whereas, di- and triHAAs induced toxicity by directly affecting mitochondrial metabolism by PDK inhibition, which led to PDC activation. The toxicity potential of chlorinated and chloraminated wastewater effluents extracted with XAD-8 and XAD-4 resins was evaluated. For chlorinated water, the organic extracts eluted from XAD-8 were more cytotoxic than that of the chloraminated wastewater extracts. However, the XAD-4 extracts of the chlorinated wastewaters and chloraminated wastewaters did not show any significance difference. Unlike the cytotoxicity analyses, the chloraminated wastewater XAD-8 extracts showed a higher genotoxic effect in mammalian cells than the XAD-4 extracts. Thus the major cytotoxicity and genotoxicity components in wastewater effluents were associated with hydrophobic acid fractions as compared to the transphilic acid fractions. The mutagenicity evaluation of the coal tar and soot associated polyaromatic hydrocarbons (PAHs) from lake sediments demonstrated that the coal tar and soot extracts were not direct acting mutagens but needed S9 microsomal activation. It was also found that coal tar extracts induced a higher rate of base pair substitution mutations as compared to the induction of frameshift mutations. Soot extracts induced a relatively higher rate of frameshift mutations as compared to the coal tar extract frameshift mutation rate.
Issue Date:2016-11-07
Type:Thesis
URI:http://hdl.handle.net/2142/95445
Rights Information:Copyright 2016 Azra Dad
Date Available in IDEALS:2017-03-01
Date Deposited:2016-12


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