Carbon disulfide neurotoxicity in rats: IV. Increased mRNA expression of low-affinity nerve growth factor receptor--a sensitive and early indicator of PNS damage.
Expression of the low-affinity nerve growth factor receptor (NGF-R) in the peripheral nervous system is regulated by Schwann cell-axonal contact. Steady-state mRNA levels for NGF-R are very low in the mature peripheral nervous system, but are markedly upregulated in sciatic nerve during both primary demyelination (tellurium exposure) and secondary demyelination (Wallerian degeneration). Upregulation also occurs in various subdegenerative axonopathy models where there is axonal atrophy, suggesting its usefulness as a marker for subtle perturbations in normal axon-Schwann cell interactions (Roberson et al., Mol Brain Res 1995; 28:231-238). To further test this hypothesis, we examined NGF-R mRNA expression in sciatic nerves of rats exposed to carbon disulfide (CS2), a toxicant known to cause a distal axonopathy. Adult rats were exposed to CS2 gas (50, 500, or 800 ppm, 6 hr/day, 5 days/wk) for 2-13 weeks. RNA was isolated from sciatic nerves and levels of mRNA for NGF-R determined by Northern blot analysis. NGF-R mRNA expression increased in a dose- and time-dependent manner. Message levels were already increased after 2 wks of exposure to 800 ppm CS2, and increased further with continued exposure. Morphological alterations were not apparent in the sciatic nerve, even at the highest dosage levels with the longest exposure times. Upregulation of NGF-R mRNA is thus an indicator of subtle alterations in the normal axon-Schwann cell relationship and provides a sensitive measure of CS2 neurotoxicity. Assay of this marker may also be useful as a rapid and very sensitive general screen for other compounds which are potentially toxic to the peripheral nervous system.
Toews
A D
AD
Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill 27599, USA.
Harry
G J
GJ
Lowrey
K B
KB
Morgan
D L
DL
Sills
R C
RC
D000280:Administration, Inhalation; D000818:Animals; D015415:Biomarkers / Q000032:analysis; D002246:Carbon Disulfide / Q000008:administration & dosage / Q000633:toxicity*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D017933:Peripheral Nervous System / Q000378:metabolism* / Q000473:pathology*; D012333:RNA, Messenger / Q000096:biosynthesis* / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D017475:Receptors, Nerve Growth Factor / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics; D012584:Sciatic Nerve / Q000187:drug effects / Q000473:pathology; D013979:Tibial Nerve / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure
D015415:Biomarkers; D012333:RNA, Messenger; D017475:Receptors, Nerve Growth Factor; D002246:Carbon Disulfide