Studies on the putative interactions between the organophosphorus insecticide Phosmet and recombinant mouse PrP and its implication in the BSE epidemic.
It has been suggested that exposure of cattle to the ectoparasiticide Phosmet in the 1980s caused a conformational change in the cellular prion protein (PrP(C)) to form the BSE prion (PrP(SC)), which initiated the epidemic of bovine spongiform encephalopathy (BSE). Recombinant mouse cellular prion (r[mouse]PrP(C)) was exposed to the organophosphorus pesticide Phosmet in vitro and the conformation of the prion before and after exposure was monitored using circular dichroism (CD) spectroscopy, utilizing synchrotron radiation at the Council for the Central Laboratory of the Research Councils (CLRC) facilities at Daresbury, UK. Metabolites of Phosmet, generated in situ by rat microsomes, were investigated in the same way, to determine whether they might initiate the conformational change due to their high chemical reactivity. Our studies showed that exposure of r[mouse]PrP(C) to Phosmet or microsomes-generated metabolites of Phosmet did not result in the conformational change in the protein from alpha-helix to beta-pleated sheet that is characteristic of the PrP(C) to PrP(SC) conversion and, therefore, Phosmet is very unlikely to have initiated the BSE epidemic by a simple direct mechanism of conformational change in the prion protein.
Shaw
I
I
Centre for Toxicology, University of Central Lancashire, Preston, UK. ian.shaw@esr.cri.nz
Berry
C
C
Lane
E
E
Fitzmaurice
P
P
Clarke
D
D
Holden
A
A
D000818:Animals; D002417:Cattle; D002942:Circular Dichroism; D016643:Encephalopathy, Bovine Spongiform / Q000209:etiology*; D007306:Insecticides / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D008861:Microsomes / Q000378:metabolism; D010706:Phosmet / Q000494:pharmacology*; D011328:Prions / Q000737:chemistry*; D011487:Protein Conformation / Q000187:drug effects; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry
D007306:Insecticides; D011328:Prions; D011994:Recombinant Proteins; D010706:Phosmet