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Murine susceptibility to organophosphorus-induced delayed neuropathy (OPIDN)
B Veronesi1, S Padilla, K Blackmon
1U.S. Environmental Protection Agency, Health Effects Research Laboratory, Research Triangle Park, North Carolina 27711.
Abstract:
This study reports that CD-1 strain mice are neuropathologically and biochemically responsive to acute doses of tri-ortho-cresyl phosphate (TOCP). Young (25-30 g) male and female animals were exposed (po) to a single dose of TOCP (580-3480 mg/kg) and sampled for neurotoxic esterase (NTE) activity at 24 and 44 hr postexposure and for neuropathic damage 14 days later. Biochemically, high intragroup variability existed at the lower doses, and at higher levels of TOCP exposure (i.e., greater than or equal to 1160 mg/kg), mean brain NTE inhibition never exceeded 68%. Hen and mouse brain NTE activity, assayed in vitro for sensitivity to inhibition by tolyl saligenin phosphate (TSP), the active neurotoxic metabolite of TOCP, showed similar IC50 values. Histologically, highly variable spinal cord damage was recorded throughout treatment groups and mean damage scores followed a dose-response pattern with no apparent correlation to threshold (i.e., greater than or equal to 65%) inhibition of brain NTE activity. Topographically, axonal degeneration in the mouse spinal cord predominated in the lateral and ventral columns of the upper cervical cord. Unlike the rat, which displays degeneration in the upper cervical cord's dorsal columns (i.e., gracilis fasciculus) in response to TOCP intoxication, treated mice showed minimal damage to this tract. To examine this discrepancy further, ultrastructural morphometric analysis of axon diameters in the cervical cord was performed in control mice and rats. These results indicated that in both species, the largest diameter (greater than or equal to 4 microns) axons are housed in the ventral columns of the cervical spinal cord, suggesting that axon length and diameter may not be the only criteria underlying fiber tract vulnerability in OPIDN.
Insights
Tri-ortho-cresyl phosphate (TOCP) causes neuropathology in mice, but brain neurotoxic esterase (NTE) inhibition did not correlate with damage severity. Axonal degeneration patterns in mice differ from rats, suggesting complex vulnerability factors.
Area of Science:
- Neuroscience
- Toxicology
- Biochemistry
Background:
- Tri-ortho-cresyl phosphate (TOCP) is an organophosphate known to cause organophosphate-induced delayed neuropathy (OPIDN).
- Understanding the dose-response relationship and specific neuropathological targets of TOCP is crucial for assessing neurotoxic risk.
Purpose of the Study:
- To investigate the neuropathological and biochemical responses of CD-1 strain mice to acute tri-ortho-cresyl phosphate (TOCP) exposure.
- To compare the topographical patterns of axonal degeneration in mice with those observed in rats.
Main Methods:
- CD-1 mice were administered single oral doses of TOCP.
- Neurotoxic esterase (NTE) activity was measured at 24 and 44 hours post-exposure.
- Neuropathological damage was assessed 14 days later, with topographical and ultrastructural analyses of spinal cord axons.
Main Results:
- High variability in NTE inhibition was observed at lower TOCP doses; higher doses (>1160 mg/kg) resulted in <68% mean brain NTE inhibition.
- Spinal cord damage showed high variability and a dose-response pattern, but no clear correlation with NTE inhibition thresholds (>65%).
- Axonal degeneration predominantly occurred in the lateral and ventral columns of the upper cervical cord in mice, differing from the dorsal column degeneration seen in rats.
Conclusions:
- Mouse brain NTE inhibition by TOCP does not directly correlate with the severity of neuropathological damage.
- The distinct topographical pattern of axonal degeneration in mice compared to rats suggests that factors beyond axon length and diameter influence fiber tract vulnerability in OPIDN.