High-dose exposure to systemic phosmet insecticide modifies the phosphatidylinositol anchor on the prion protein: the origins of new variant transmissible spongiform encephalopathies?
Compulsory exposure of the UK bovine to exclusively high biannual doses of a 'systemic' pour-on formulation of an organo-phthalimido-phosphorus warblecide, phosmet, during the 1980s (combined with exposure to the lipid-bound residues of 'bioconcentrated' phosmet recycled back via the intensive feeding of meat and bone meal), initiated the 'new strain' modification of the CNS prion protein (PrP) causing the UK's bovine spongiform encephalopathy (BSE) epidemic. A lipophilic solution of phosmet was poured along the bovine's spinal column, whence it penetrated and concentrated in phospholipids of the CNS membranes, covalently modifying endogenous phosphorylation sites on phosphatidylinositols (PIs) etc., forming a 'toxic membrane bank' of abnormally modified lipids that 'infect' any membrane proteins (such as PrP) that are programmed to conjugate onto them for anchorage to the membrane. Thus, phosmet invokes a primary covalent modification on PrP's PI anchor which, in turn, invokes an overall diverse disturbance upon CNS phosphoinositide second messenger feed back cycle, calcium homeostasis and essential free radicals; thus initiating a self-perpetuating cascade of abnormally phosphorylated PI-PrP that invokes a secondary electrostatic and allosteric disturbance on the main body of PrP impairing tertiary folding. Chaperone stress proteins conjugate onto misfolded PrP blocking its sites of proteolytic cleavage. Fresh epidemiological evidence is presented and experimental evidence referenced that adds support to a multifactorial hypothesis which proposes that BSE is a hitherto unrecognized and previously unmanifested class of subtle chronic phosmet-induced delayed neuro-excitotoxicity in the susceptible bovine.
Purdey
M
M
High Barn Farm, Elworthy, Taunton, Somerset, UK.
D000818:Animals; D001665:Binding Sites; D002417:Cattle; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism; D007562:Creutzfeldt-Jakob Syndrome / Q000209:etiology; D016643:Encephalopathy, Bovine Spongiform / Q000453:epidemiology / Q000209:etiology* / Q000635:transmission; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007306:Insecticides / Q000493:pharmacokinetics / Q000633:toxicity*; D008297:Male; D008563:Membrane Lipids / Q000737:chemistry / Q000378:metabolism; D008954:Models, Biological; D010706:Phosmet / Q000493:pharmacokinetics / Q000633:toxicity*; D010716:Phosphatidylinositols / Q000737:chemistry / Q000378:metabolism; D010766:Phosphorylation; D011328:Prions / Q000737:chemistry* / Q000187:drug effects* / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D006113:United Kingdom / Q000453:epidemiology
D007306:Insecticides; D008563:Membrane Lipids; D010716:Phosphatidylinositols; D011328:Prions; D010706:Phosmet