UC Davis

Exposure to various exogenous factors which could arise from environmental toxicants and contaminants poses both acute and chronic adverse effects on human health. The heart and liver is most susceptible to toxic effects of these exogenous factors due to several structural and functional characteristics – the liver is involved in the metabolism and detoxification of xenobiotics. Their common modes of action include the activation of the mitochondrial dysfunction-reactive oxygen species, lipid metabolites dysfunction, and induction of inflammation. Prometryn is a triazine herbicide that is relatively persistent in waters, soil and even in air near its production or application sites, and has been detected at a concentration of 3-6.1 µg/L in different rivers and lakes in Europe. Previous studies have shown that other triazine herbicide was found at levels as high as 21 ppb in groundwater, 42 ppb in surface waters, 102 ppb in river basins in agricultural areas, and up to 224 ppb in Midwestern U.S. streams during the summer of 1996. Triazine concentrations of up to 108 μg/L have been reported in North America rivers [15]. In addition, all triazine herbicides and their degradation products are persistent in the environment, especially in air and water, and these pesticides can damage human cardiac and immune systems and endanger the health of humans, animals, and plants. Ibuprofen is a propionic acid derivative. It is the most common over-the-counter NSAID used to treat mild to moderate pain and inflammation in arthritis, primary dysmenorrhea, headache, and many other disorders due to their potent analgesic, anti-inflammatory, and antipyretic effects. Ibuprofen is a major medicine in the Essential Drugs List of the World Health Organization. Due to the prevalent and widespread use around the world, ibuprofen enters into the water system through human pharmaceutical use. The toxicity and concentration of ibuprofen in wastewater treatment plants (WTPs) and water bodies are increasing day by day due to increased rate of consumption due to population pressure. This might pose a hazardous impact on the environment due to its bioactive nature. This is becoming ubiquitous to water bodies because it cannot be effectively removed by conventional water treatment methods. Ibuprofen has been linked to increased cardiovascular risk and hepatotoxicity. This dissertation describes research methodologies and findings that were explored to elucidate the molecular mechanisms and signaling pathways that are involved in prometryn and ibuprofen-induced cardiotoxicity and hepatotoxicity using cells and mice. We also focused on sex-differences between male and female mice whilst studying ibuprofen induced cardiotoxicity. More precisely, Chapter 1 discusses the role of oxidative stress in pesticide-induced toxicity. Chapter 2 focuses on the metabolism of ibuprofen, route of contamination in the environment, its toxicity and ibuprofen effects on cardiovascular health. Chapter 3 illuminates that mitochondrial and proteasome dysfunction occurred in the hearts of mice treated with triazine herbicide prometryn. Thereby providing a better explanation into the mechanism involved in pesticide-induced cardiotoxicity. Chapter 4 further focuses on prometryn mechanism of hepatotoxicity by showing that this xenobiotic altered epoxide hydrolase activity and increases cytochrome P450 metabolites in murine livers via lipidomic profiling. Chapter 5 elucidates that ibuprofen effect on hearts are drastically different in male and female mice. Overall, this dissertation shows results which support that prometryn and ibuprofen which have been found at several alarming concentrations in the environment all around the world are capable of inducing cardiotoxicity and hepatotoxicity. We also delineate some of the molecular mechanisms and signaling pathways by which these occurs in cardiac cells, liver cells and mice.