Functional neurotoxicity of arsenic and manganese as environmental agents and the possible protective role of natural antioxidants

Abstract

SUMMARYOxidative stress apparently plays a major role in the effect of several toxicants, including heavy metals, of environmental or occupational origin. It means inequilibrium between metabolic reactions producing reactive oxygen and nitrogen species (ROS and RNS), and the capacity of enzymatic and non-enzymatic reactions to neutralize these. In itself, oxidative stress is a side effect of oxidative energy production, which can be caused by exposure to a number of environmental xenobiotics, metals and others. Non-neutralized ROS and other radicals damage the nervous system, liver, kidneys etc. Free radicals are more and more held responsible for various chronic non-communicable diseases, and for aging. The central and peripheral nervous system is prone to oxidative damage, due to highly active mitochondrial energy production, to abundance of (unsaturated) structural lipids, and to low antioxidant defence capacity in the brain; and ROS may constitute the final common pathway for several neurotoxicants because oxidative damage to membrane lipids may lead to alterations of the membrane-bound functions crucial to the functioning of neurons. In the present thesis, the relationships of neurotoxicity, oxidative stress and antioxidant protection are investigated in case of two heavy metals with public health importance, arsenic (As) and manganese (Mn). Arsenic used to have numerous practical applications most of which have been discontinued because of the health risks. Its modern applications e.g. in semiconductors, are apparently safe. Increased presence of As in certain rocks may lead to human exposure by As emissions from mining and smelting non-ferrous metal ores or from burning coal with higher As content, but most importantly via drinking water. The problem of As in drinking water has been quite serious in several regions. According to WHO, As is among the ten most important chemicals of major public health concern. Arsenic occurs in various oxidation states in inorganic or organic compounds. Inorganic arsenite (As III ) is more toxic that arsenate (As V ), and most of the organic arsenicals are practically nontoxic. Arsenite strongly binds to the -SH group of proteins, inactivating various enzymes including those in the citrate cycle and terminal oxidation, depleting ATP pool and promoting the generation of ROS in the cells. It also increases oxidative stress by depleting reduced glutathione and thioredoxin. The consequences of chronic exposure to inorganic arsenic include nervous system damage. Electrophysiological data on As neurotoxicity are scarce, but in As-exposed workers altered EEG, visual evoked potentials, and peripheral nerve activity were detected, together with signs of oxidative stress. Manganese (Mn) can have the oxidation states -3 to 7+, indicating its propensity to redox reactions. Mn and its compounds have numerous technical applications (steelmaking, welding, nanotechnology etc). It is an essential trace element, required for normal brain function, and acting as cofactor for several enzyme...