Early differential induction of C-jun in the central nervous system of hens treated with diisopropylphosphorofluoridate (DFP).
Diisopropyl phosphorofluoridate (DFP) produces organophosphorus-ester induced delayed neurotoxicity (OPIDN) in the hen, human and other sensitive species. We studied the effect of a single dose of DFP (1.7 mg/kg/sc) on the expression of c-jun, which is one of the heterodimerizing ITFs (Inducible Transcriptional Factors) of the AP-1 family. The hens were sacrificed at different time points ie 0.25, .0.50, 1 and 2 hrs. Total RNA was extracted from the following brain regions: cerebrum, cerebellum, brainstem, midbrain and as well as spinal cord. Northern blots prepared using standard protocols were hybridized with c-jun as well as b-actin and 18S RNA cDNA (control) probes. The results indicate differential regulation of c-jun levels which may be due to the activation of both cholinergic and non-cholinergic pathways of CNS, besides changing roles of c-jun (as mediator of degeneration or regeneration) depending on heterodimerization with other ITFs. In the highly susceptible tissues like brainstem and spinal cord c-jun transcript levels increased at 15 minutes and continued to increase gradually till it reached the maximum at 2 hrs. Overall spinal cord showed the maximum levels of c-jun induction (207%) at 2 hrs time point of all the CNS tissues. The enhancement of cholinergic transmisson by the inhibition of cholinestrase may be responsible for the gradual increase mediated by neural and vascular factors. In contrast, less susceptible tissue, cerebellum showed almost immediate induction to high level of (179%) at 15 minutes and the levels stayed more or less the same until it peaked to 185% at 2 hrs. Relatively low abundance of cholinergic neurons and high number of sensitized specialized cell types like Bergman glia and Purkinje cells may be responsible for the immediate higher induction. Non-susceptible tissue cerebrum did not show any changes in the c-jun levels. In midbrain the induction pattern was very similar to that of brainstem. This differential induction pattern of c-jun encomposing the differences in the quantity and time course was directly proportionate to the degree of susceptibility and cellular heterogeneity of different regions of CNS. The significant increase in c-jun levels along with our earlier observation on the increased c-fos levels indicate that AP-1 family of genes may be one of the IEGs involved in the long term changes which eventually lead to OPIDN.
Damodaran
T V
TV
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27708, USA.
Rahman
A A
AA
Abou-Donia
M B
MB
D000818:Animals; D001921:Brain / Q000378:metabolism; D001933:Brain Stem / Q000378:metabolism; D002531:Cerebellum / Q000378:metabolism; D002645:Chickens; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D007531:Isoflurophate / Q000494:pharmacology*; D008636:Mesencephalon / Q000378:metabolism; D009498:Neurotoxins / Q000494:pharmacology*; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism
D009498:Neurotoxins; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D007531:Isoflurophate