Xenobiotic-Induced Oxidative Stress

Reactive oxygen (ROS) and nitrogen (RNS) species, such as superoxide anion radical (SO), hydrogen peroxide (H2O2), hydroxyl radical, nitric oxide, peroxynitrite, and others (Figure 4.1), are formed during normal cellular processes and as a result of exposure to toxicants and other stressors. ROS are formed during oxidative phosphorylation as a result of leakage of electrons through the inner mitochondrial membrane. ROS are also formed during steroid synthesis in the ovary and other steroidogenic tissues, as a result of uncoupling of electron transfer from substrate hydroxylation by mitochondrial cytochrome P450 enzymes, producing SO (Hall 1994, Hanukoglu 2006). ROS and RNS play important roles in normal physiology as signaling molecules, but due to their high reactivity, free radical ROS/RNS can damage cellular macromolecules and are, therefore, tightly regulated. Ovulation is an example of a critical ovarian process, which is regulated by ROS. Ovarian levels of ROS rise

4.1 Reactive Oxygen Species and Oxidative Stress .............................................. 71 4.2 Antioxidant Defenses in the Ovary ................................................................ 72 4.3 Evidence for Xenobiotic-Induced Oxidative Stress in Ovarian

Follicle Toxicity .............................................................................................. 74 4.3.1 Antioxidant Depletion......................................................................... 74 4.3.2 Polycyclic Aromatic Hydrocarbons .................................................... 74 4.3.3 Ionizing Radiation .............................................................................. 75 4.3.4 Cyclophosphamide .............................................................................. 76 4.3.5 Methoxychlor ......................................................................................77 4.3.6 Phthalates ............................................................................................ 78 4.3.7 Chromium ........................................................................................... 78

4.4 Evidence for Xenobiotic-Induced Oxidative Stress in Oocyte Toxicity .........80 4.5 Evidence for Xenobiotic-Induced Oxidative Stress in Fetal

Ovary Toxicity ............................................................................................ 81 4.5.1 Polycyclic Aromatic Hydrocarbons .................................................... 81 4.5.2 Ionizing Radiation .............................................................................. 81

4.6 Conclusions ..................................................................................................... 82 References ................................................................................................................ 82

and antioxidant levels fall transiently after the preovulatory gonadotropin surge, and treatment with antioxidants inhibits ovulation (Laloraya et al. 1988, Miyazaki et al. 1991, Sato et al. 1992, Shkolnik et al. 2011). There are numerous redox (reduction/ oxidation) elements in cells, such as redox-sensitive cysteine residues in proteins, which function in cell signaling, macromolecular trafcking, and regulation of physiological processes. These elements are components of redox circuits and networks, which are controlled by two thiol-containing systems, thioredoxins (TXN) and glutathione (GSH) (Jones 2008). These systems are not in thermodynamic equilibrium with one another, and each system exists in separate cytosolic, mitochondrial, and other subcellular compartments (Go and Jones 2008, Hansen et al. 2006). While oxidative stress was previously dened as oxidative damage to lipids, proteins, and nucleic acids by free radicals, the “redox hypothesis” expands the denition of oxidative stress to include disruption of intracellular redox circuits (Jones 2008).