Cardiovascular effects of lead and mercury and their mixtures in rats
Cardiovascular diseases are the major cause of death worldwide. It is a group of diseases, which affect the heart, the vasculature and the brain. Lifestyle and metabolic risk factors are major contributors to cardiovascular ill-health. In addition to these risk factors, a growing number of scientific studies show that some environmental pollutants, e.g. lead and mercury, can adversely affect cardiovascular health. Despite the increasing amount of knowledge from human and animal studies, cardiovascular effects of lead, mercury species or their mixtures are not well understood. It is also unknown if safe exposure thresholds for these metals exist or the underlying mechanisms of action for the elicitation of cardiovascular toxicity. The first set of studies had the objectives to elucidate the range of effects of single exposure to lead, inorganic mercury or methylmercury on the cardiovascular system. Therefore, male Wistar rats were exposed to a broad range of doses of lead, inorganic mercury or methylmercury for four weeks through the drinking water. Cardiovascular health of the rats was assessed by measuring the blood pressure and the cardiac electrical activity after four weeks of exposure, while the heart function and blood flow in the carotid artery was measured at baseline and at the end of the exposure duration. The study showed that all three metals differ in their effects on the cardiovascular system. Lead showed bi-phasic dose-response curves for several cardiovascular end-points. No cardiovascular effects were observed for inorganic mercury, while methylmercury showed linear dose-response curves. Based on these results, safe levels of exposure for lead and methylmercury were derived. The second study applied the same experimental design as the previous study in order to investigate the cardiovascular effects of combined exposures to lead, inorganic mercury and methylmercury. The mixture ratios were based on reference and exposure values published in the scientific literature. The adverse cardiovascular effects, which were observed for single exposures were reversed for the mixtures indicating antagonism. In contrast to single exposures, mixtures negatively affected the electrical activity of the heart (synergism), which could lead to arrhythmias and heart failure. The third set of studies focused on the exploration of oxidative stress, kidney function and damage, and global DNA methylation as potential mechanisms of action for the development of elevated blood pressure. Results for lead showed an increase in oxidative stress but not mercury. While only lead was associated with kidney damage, only inorganic mercury was related to altered global DNA methylation. Methylmercury appears to elevate blood pressure through a not investigated mechanism. Therefore, oxidative stress and kidney damage seem to be associated with elevated blood pressure but not global DNA methylation. Overall, the research presented in this thesis shows that lead, inorganic mercury and methylmercury and their mixtures have the ability to adversely affect the cardiovascular system. However, each metal affected the cardiovascular system differently and surprisingly, mixtures showed antagonism or synergism depending on the examined end-point, which was reflected in the results of the mechanistic study. As health problems of the cardiovascular system, e.g. hypertension, occur mainly in the adult population and in particular the elderly, cardiovascular effects should be considered as an important end-point for this age group in addition to neurodevelopmental effects in children.
DegreeDoctor of Philosophy (Ph.D.)
SupervisorWeber, Lynn P.; Siciliano, Steven D.
CommitteeJanz, David; Wickstrom, Mark; Richardson, Mark; Krone, Patrick
Copyright DateApril 2015