Systemic Toxicity and Specific Ototoxicity of Paraquat

ZHANG Jianhui; DING Dalian; SUN Hong; Richard Salvi

doi:10.3969/j.issn.1672-2922.2017.04.019

Abstract：Paraquat (PQ), one of the most widely used herbicides in the world, is believe to exert its toxic effects on mammalian organisms by generating a large amount of superoxides via redox reactions which in turn cause lipid per-oxidation, mitochondrial degeneration, DNA damage and protein degradation. In the acute poisoning process, PQ initial-ly accumulates in alveolar cells in the lungs presumably because the chemical structure of PQ is similar to polyamine. Clara cells and alveolar type I and II epithelial cells in the lungs contain very strong polyamine transport systems. PQ can also cross the blood-brain barrier and accumulate in dopaminergic neurons by uptake through dopamine transporters making, dopaminergic neurons highly susceptible to PQ neurotoxicity. Consequently, chronic PQ poisoning has been implicated in the pathogenesis of Parkinson's disease. PQ has also been shown to damage sensory hair cells in the co-chlea. The damage is thought to be mediated by increased production of superoxide anions and oxidative stress. Local application of PQ induces a stereotypic pattern of damage which begins at the base of the cochlea and progresses toward the apex, consistent with early high-frequency hearing loss that expands to low frequencies. In PQ damaged cochlear cells, superoxide anions detected by dihydroethidium first appear in the cytoplasm and later condense in the nucleus, suggesting that the damage to cochlear cells is indeed due to the occurrence of superoxide. The free radical damage eventually initiates the cell's self-destruction leading to apoptosis. In contrast to earlier reports, our recent experimental studies indicate that PQ-induced cochlear cell damage first occurs in supporting cells. The destruction of these support cells results in the collapse of support structures of the organ of Corti such that cochlear hair cells become detached and rearranged within the sensory epithelium. Anoikis is a form of programmed cell death that is induced by anchorage-de-pendent cells becoming detached from the surrounding extracellular matrix. The loss of surrounding cells connections induces anoikis. Our new results suggest that the PQ induced damage to hair cells is initiated by anoikis caused by PQ induced damage of supporting cells which releases hair cells from the extracellular matrix. Thus, PQ-induced apoptotic damage to cochlear cells may be induced not only by superoxide induced oxidative stress, but also by"anoikis"due to loss of extracellular matrix linking with surrounding supporting cells.