The UK epidemic of BSE: slow virus or chronic pesticide-initiated modification of the prion protein? Part 1: Mechanisms for a chemically induced pathogenesis/transmissibility.
It is proposed that exposure of the bovine embryo to specific high-dose lipophilic formulations of organophosphate insecticide (containing phthalimide) applied exclusively in the UK during the 1980s/early 1990s was the primary trigger that initiated the UK's bovine spongioform encephalopathy epidemic. Multi-site binding organophosphate toxic metabolites penetrate the fetus, covalently binding with, phosphorylating and ageing serine, tyrosine or histidine active sites on fetal central nervous system prion protein. An abnormal negative charge corrupts prion protein molecular surface, which blocks both proteases and chaperones from accessing their cleavage/bonding sites. This impairs normal degradation and folding of prion protein respectively. Once the abnormally phosphorylated abnormal prion protein isoform agent is initiated, any stress event ensuing in adult life induces a nerve growth factor-mediated synthesis of normal cellular prion protein isoform that aggregates to abnormally phosphorylated abnormal prion protein isoform, thereby becoming 'infected'/transformed into the same; due to the vicious circle of positive feedback invoked by the blocking of a prion protein-specific kinase. Prion protein could therefore serve as a hitherto unrecognized critical link in a chain of delayed neuroexcitotoxic proteins that are triggered off by chronic exposure to specific classes of chemical/metal that 'hit and run' during the vulnerable in utero period, producing spongioform encephalopathy disease years later.
Purdey
M
M
High Barn Farm, Somerset, UK.
D000595:Amino Acid Sequence; D000818:Animals; D002417:Cattle; D004622:Embryo, Mammalian; D016643:Encephalopathy, Bovine Spongiform / Q000453:epidemiology* / Q000635:transmission; D005260:Female; D007306:Insecticides / Q000009:adverse effects* / Q000493:pharmacokinetics; D008954:Models, Biological; D008969:Molecular Sequence Data; D009154:Mutation; D009414:Nerve Growth Factors / Q000502:physiology; D009943:Organophosphorus Compounds; D010766:Phosphorylation; D010797:Phthalimides / Q000009:adverse effects / Q000493:pharmacokinetics; D011247:Pregnancy; D011328:Prions / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D006113:United Kingdom / Q000453:epidemiology
D007306:Insecticides; D009414:Nerve Growth Factors; D009943:Organophosphorus Compounds; D010797:Phthalimides; D011328:Prions; C037431:phthalimide; D011494:Protein Kinases