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Science

High Dose

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Scientific papers - High Dose

Medical Hypotheses (1998) 50, 91-111 ©Harcourt Brace & Co. Ltd 1998

High-dose exposure to systemic phosmet insecticide modifies the phosphatidylinositol anchor on the prion protein: the origins of new variant transmissible spongiform encephalopathies?

Mark PURDEY

High Barn Farm, Elworthy, Taunton, Somerset, TA43PX, UK

Abstract - 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.

Received 13 May 1997 Accepted 12 June 1997

Introduction

The aetiology of the familial and sporadic types of prion disease, such as sporadic Creutzfeldt-Jakob(CJD) and scrapie, is considered to hinge, in part, upon a diverse range of abnormal isoforms of a host encoded glycoprotein called prion protein (PrP) (1). On the other hand, BSE and 'new variant' CJD (nvCJD) are characterized by one uniform isoform of abnormally modified PrP (1), which suggests the presence of some hitherto unidentified common environmental trigger factor that was initially introduced into the bovine environment at some point during the late 1970s/early 1980s.

Further research continues to support the hypothesis (2) that. the UK's exclusive mode of compulsory high-dose usage of a systemic formulation of phosmet (N-mercaptomethyl-phthalimide, S-00-dimethyl phosphorodithioate) insecticide directly upon cattle for warble fly eradication during the late 1970s/1980s, coupled to the recycling of bioconcentrated phosmet in the tallow fraction of cattlefeed, was the primary trigger that initiated the abnormally modified prion protein, causing the onset and spread of the UK's 160,000 -case BSE epidemic.

CNS penetration by systemic organophosphorus compounds

Organophosphorus (OP) warble fly treatments (such as phosmet) are manufactured in a lipophilic, 'systemic' formulation that enables the active ingredients to penetrate through the hide and internal body membranes, permeating the whole internal environment of the bovine so as to exterminate any warble parasite present. The OP was applied in a 'pour-on' solvent-based oil solution, applied along the back of the head and the entire length of the spinal column.

Cattle very occasionally developed a paraplegic syndrome as an acute abnormal reaction to OP warblecide treatment (3,4). This was usually caused by an anaphylactic-type reaction to the dead warble larvae that had been intoxicated by OP whilst congregating in the epidural fat of the spinal cord during the later stages of their annual life cycle. Such complications following use of OP warblecides were largely avoided because treatment during the winter months was prohibited - the stage of the life cycle when warbles could sometimes be found inside the spinal canal.

The fatal intoxication of warbles in the spinal canal following treatment with recommended doses of systemic OP warblecides demonstrates that 0Ps are penetrating the phospholipid membranes in the spinal canal at a dose which is lethal to the warble.

'Toxic phospholipid membrane bank' - the infectious vehicle in transmissible spongiform encephalopathies.

Phosmet and various other 0Ps are well recognized to bind and concentrate in the phospholipid phase/ liposomes of neuronal membranes in the CNS (5,6) causing an alteration in the charge of the polar heads of the affected phospholipids. This disrupts the overall structure, function and activity of these membranes with 'knock-on' effects on the allosteric behaviour/folding of their membrane-associated proteins; such as PrP. Interestingly, PrP is found anchored/conjugated to the same types of phospholipid (7), phosphatidylinositol (P1), in the nerve membranes which are targeted by phosmet, and PrP is recognized to form phospholipid-protein complexes in liposornes (7) found in the membranes of select tracts in the CNS.

Thus, intoxication of the organism with a toxic membrane bank of phosmet-modified phospholipids is subsequently capable of 'infecting' any membrane associated proteins - such as PrP - that conjugate onto them.

If phosmet does indeed initiate the 'infectious' new variant PrP, then the 'systemic' route of chemical entry after its delivery along the spinal column/ headline perhaps explains why brain titrations/tissue assays in clinical cases of BSE have detected infectivity exclusively in brain and cervical spinal cord (8 [p. 64]). By contrast, in scrapie and chronic wasting disease (CWD) (the prion disease found in cervidae), infectivity originates in the tissues of the gut and lymphoreticular system and then travels to the CNS over a 2 year period - suggesting the causal agent enters via the oral route in scrapie/CWD.

It could also be suggested that phosmet will only covalently modify and unleash pathogenic consequences of multireplication in a specific subtype of PrP which is expressed exclusively within the CNS and implicated in the aetiology of nvCJD and BSE (1); this explains why the residues of phosmet, which are complexed with the lipid/fat fractions of meat and bone meal (MBM) and are recycled back into the cow via the oral route, still fail to modify the cellular prion protein (PrPc) subtypes that are expressed in spleen and the lymphatic system.

Furthermore, the specific CNS P1s to which phosmet initially complexes following exposure to systemic pour-on treatment, may well demonstrate specificity towards conjugation with PrPc subtypes that are exclusively expressed in CNS cell lines; this explains why any phosmet-phospholipid complexes that are recycled back into the bovine as residual contaminants in MBM feed are only able to covalently conjugate with the PrP subtypes implicated in BSE/nvCJD and exclusively confined to the CNS.

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