Journal
TOXICOLOGICAL SCIENCES
Volume 180, Issue 2, Pages 342-355Publisher
OXFORD UNIV PRESS
DOI: 10.1093/toxsci/kfaa193
Keywords
dorsal root ganglion; calpain; tributyltin; mitochondrial dynamics
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Funding
- William Jewell College Department of Biology and Oxbridge Research
- Monte Harmon endowed chair funds
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Research found that TBT induces axon degeneration and cell death in peripheral neurons by increasing cytosolic and mitochondrial calcium levels, disrupting mitochondrial dynamics, reducing cellular ATP levels, and activating calpains as key execution factors.
Tributyltin (TBT) remains a global health concern. The primary route of human exposure to TBT is either through ingestion or skin absorption, but TBT's effects on the peripheral nervous system have still not been investigated. Therefore, we exposed in vitro sensory dorsal root ganglion (DRG) neurons to TBT at a concentration of 50-200 nM, which is similar to the observed concentrations of TBT in human blood samples. We observed that TBT causes extensive axon degeneration and neuronal death in the DRG neurons. Furthermore, we discovered that TBT causes an increase in both cytosolic and mitochondrial calcium levels, disrupts mitochondrial dynamics, decreases neuronal ATP levels, and leads to the activation of calpains. Additional experiments demonstrated that inhibition of calpain activation prevented TBT-induced fragmentation of neuronal cytoskeletal proteins and neuronal cell death. Thus, we conclude that calpain activation is the key executioner of TBT-induced peripheral neurodegeneration.
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