Neuropathological changes in rat brain following oral administration of 2-chloropropionic acid.
The agrochemical intermediate, L-2-Chloropropionic acid (L-2-CPA) and D-2-chloropropionic acid (D-CPA), when administered separately by oral gavage to rats, produced extensive cerebellar granule cell necrosis (> 80%) characterised by varying degrees of nuclear condensation and nuclear karyorrhexis. In contrast a few necrotic Purkinje cells (< 5%) were observed. Purkinje cell damage consisted of cytoplasmic and nuclear shrinkage and hyperchromasia. Karyorrhexis was not seen in Purkinje cells. Extensive vacuolation (edema) was present both in the cerebellar granular layer and Purkinje cell layer. Astrogliosis (hypertrophy and hyperplasia) was seen at lesion sites and activity was recognised by positive glial fibrillary acidic protein (GFAP) staining. Proliferative activity of astrocytes at lesion sites was confirmed by positive proliferating cell nuclear antigen (PCNA) immunostaining. Astrogliosis was focused exclusively in the necrotic granule cell layer. A single oral dose of 750 mg/kg of either stereoisomer or three consecutive daily doses of 250mg/kg L-2-CPA. produced the lesion. Cerebellar water content increased with time in parallel with the edematous response noted by neuropathological examination. The earliest onset of the lesion was observed at 36 hours appearing more extensive at 48 and 72 hours post-dosing. No other major neuropathological changes were detected in the brain, spinal cord, spinal ganglia, Gasserian ganglia, peripheral nerves and voluntary muscle following L-2-CPA administration. In conclusion, both stereoisomers of CPA were found to be selective neurotoxicants of the rat central nervous system.
Simpson
M G
MG
Zeneca Central Toxicology Laboratory and Safety of Medicines, Alderley Park, Macclesfield, Cheshire, England.
Wyatt
I
I
Jones
H B
HB
Gyte
A J
AJ
Widdowson
P S
PS
Lock
E A
EA
D000284:Administration, Oral; D000818:Animals; D001834:Body Water / Q000737:chemistry; D001921:Brain / Q000187:drug effects / Q000473:pathology; D001923:Brain Chemistry; D002531:Cerebellum / Q000187:drug effects* / Q000473:pathology; D006843:Hydrocarbons, Chlorinated; D008297:Male; D009336:Necrosis; D011422:Propionates / Q000633:toxicity*; D051381:Rats; D013237:Stereoisomerism; D013997:Time Factors
D006843:Hydrocarbons, Chlorinated; D011422:Propionates; C021974:2-chloropropionic acid