Arsenic-induced neurotoxicity in relation to toxicokinetics: effects on sciatic nerve proteins.
In our previous study in rats acutely exposed to As, we observed an effect of As on neurofilaments in the sciatic nerve. This study deals with the effects of inorganic As in Wistar rats on the cytoskeletal protein composition of the sciatic nerve after subchronic intoxication. Sodium meta-arsenite (NaAsO2) dissolved in phosphate-buffered saline (PBS) was administered daily in doses of 0, 3 and 10 mg/kg body weight/day (n=9 rats/group) by intragastric route for 4, 8 and 12 week periods. Toxicokinetic measurements revealed a saturation of blood As in the 3- and 10-mg/kg dose groups at approximately 14 microg/ml, with an increase in renal clearance of As at increasing doses. After exsanguination, sciatic nerves were excised and the protein composition was analyzed. Analysis of the sciatic nerves showed compositional changes in their proteins. Protein expression of neurofilament Medium (NF-M) and High (NF-H) was unchanged. Neurofilament protein Low (NF-L) expression was reduced, while mu- and m-calpain protein expression was increased, both in a dose/time pattern. Furthermore, NF-H protein was hypophosphorylated, while NF-L and microtubule-associated protein tau (MAP-tau) proteins were (hyper)-phosphorylated. In conclusion, we show that expression of mu- and m-calpain protein is increased by exposure to As, possibly leading to increased NF-L degradation. In addition, hyperphosphorylation of NF-L and MAP-tau by As also contribute to destabilization and disruption of the cytoskeletal framework, which eventually may lead to axonal degeneration.
Vahidnia
A
A
Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, L1-P Albinusdreef 2, Postbox 9600, 2300 RC Leiden, The Netherlands. ali.vahidnia@gmail.com
Romijn
F
F
van der Voet
G B
GB
de Wolff
F A
FA
D000818:Animals; D018053:Arsenites / Q000493:pharmacokinetics* / Q000633:toxicity* / Q000652:urine; D001835:Body Weight / Q000187:drug effects; D002154:Calpain / Q000096:biosynthesis; D008297:Male; D016900:Neurofilament Proteins / Q000096:biosynthesis / Q000378:metabolism*; D009498:Neurotoxins / Q000493:pharmacokinetics* / Q000633:toxicity* / Q000652:urine; D017933:Peripheral Nervous System / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D012584:Sciatic Nerve / Q000187:drug effects* / Q000378:metabolism*; D017670:Sodium Compounds / Q000493:pharmacokinetics* / Q000633:toxicity* / Q000652:urine; D014018:Tissue Distribution
D018053:Arsenites; D016900:Neurofilament Proteins; D009498:Neurotoxins; D017670:Sodium Compounds; C017947:sodium arsenite; D002154:Calpain