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Acute Exposure to Triethyltin Produces Depolarization in Peripheral Nerves of Adult Male Rats
Citation:
Jung, G., E. Pitzer, K. McDaniel, AND D. Herr. Acute Exposure to Triethyltin Produces Depolarization in Peripheral Nerves of Adult Male Rats. Society of Toxicology, San Diego, California, March 27 - 31, 2022.
Impact/Purpose:
This is the first study using nerve excitability techniques to test a positive control compound, Trietyltin, which resulted in large neurophysiological changes without observing overt behavioral effects. These adverse physiological changes will be correlated with proteomic alterations in the development of adverse outcome pathways. This study supports the CSS 20.4 research goals.
Description:
Triethyltin (TET) is a neurotoxicant known to induce myelin edema in both the central (CNS) and peripheral (PNS) nervous system. Some studies conclude that PNS alterations occur later and require higher dosages when compared to CNS changes. However, evaluation of the acute effects of TET on peripheral nerve function is less extensive. Behavioral and neurophysiological dysfunctions that occur before changes in myelin are detected may indicate that the PNS is targeted sooner and at lower exposures than previously believed. Nerve excitability (NE) testing is a non-invasive technique that measures the activity of ion channels, energy-dependent pumps, and other processes involved in maintaining nerve membrane potential. The NE techniques have been used in human clinical and animal in vivo studies to evaluate the mechanisms behind a variety of neurological conditions. In this study, adult male Long-Evans rats (PND 52-60) were treated with a single dose of 0, 3.0, 4.4, or 6.5 mg/kg TET (p.o.; 5% ethanol vehicle). The high dose was determined based on pilot data that indicated mild gait abnormalities. Nerve excitability testing on peripheral motor and sensory nerves was conducted 3 days post-dose. Stimulation of the nerves involved applying depolarizing or hyperpolarizing pulses of varying durations and magnitudes, then a test stimulus resulting in a 40% maximal amplitude target. Different polarizing currents activate different ion channels, and changes in the current of the test stimulus required to produce the target amplitude reflect alterations in nerve excitability. Measurements of motor nerve activity were derived from compound muscle action potentials (CMAPs); stimulation was applied to the sciatic/tibial nerves and muscular responses were recorded at the foot. Mixed nerve action potentials (MNAPs) reflected activity of motor and sensory nerves; stimulation was applied to tail caudal nerves and responses were recorded at the base of the tail. Results from the NE data indicated that motor and mixed nerves of TET treated animals were more excitable, possibly from partial depolarization. CMAP and MNAP recordings in the tests involving long depolarizing and hyperpolarizing pulses suggested threshold changes may be due to altered K+ conduction. CMAP changes were greater than in MNAPs, indicating that larger motor axons were affected more than mixed nerve axons. These results support that TET may target peripheral nerves, and PNS dysfunctions may be detected independently from CNS alterations. This abstract does not reflect EPA policy.