Relationship of the acylation of membrane esterases and proteins to the teratogenic action of organophosphorus insecticides and eserine in developing hen eggs.

The yolk sac membrane from hen eggs contains esterases that hydrolyze phenyl phenylacetate OpPA) and are sensitive to inhibition, both in vitro and in vivo, by many organophosphorus compounds and by eserine. These esterases are the principal proteins in the membrane which are phosphorylated by 3H-diisopropyl phosphorofluoridate. Inhibition of this mixture of PPA-hydrolyzing esterases in viuo does not correlate with the induction of teratogenesis because they react with both teratogenic and non-teratogenic acylating agents. However, electrophoresis studies indicate that inhibiti~ in vivo of one or more separable components making up a very small proportion of the total membrane esterase mixture occurs with teratogenlc but not with non-teratogenic treatment schedutes. Thus, dialkyiphospho~lation or methylcarbamoylation of this reactive membrane component(s) in viva may initiate a sequence of events leading to embryonic abnormalities. This postulated mode of action is analogous to that proposed earlier by British workers in the production of delayed neurotoxicity by some organophosphorus compounds. SOME organophosphorus insecticides and methylcarbamates are teratogenic when injected into hen eggs before or within the first few days of incubation.l-r2t or when administered to mammals.12-‘6 Chemical structure-teratogenic activity correlations and biochemical studies made with hen eggs establish that: (a) a wide variety of compounds are teratogenic;l-i 2 t (b) the acetylcholine~holinesterase components of the cholinergic system of the embryo are probably not involved:2*s (c) nicotinamide and nicotinamide-adenine dinucleotidecofactors diminish the abnormalities;1-3*8*10* t l and (d) some teratogens impair membrane permeability,2 Many organophosphorus compounds also produce delayed neurotoxicity in hens. The mechanism of this neurotoxicity may depend on the reaction of the organophosphate with a specific nerve membrane protein which is readily phosphorylated by &isopropyl phosphorofluoridate (DFP) and which hydrolyzes phenyl phenylacetate (PPA). The esteratic activity of this protein is sensitive to inhibition by neurotoxic but not by non-neurotoxic organophosphorus compounds.17-21 Possibly, the acylation of a similar protein in the yolk sac membrane would lead to nutritional deficiencies in the embryo and differential inhibition of embryonic development, thus causing the teratogenic effects noted with organophosphorus compounds and methylcarbamates. * Present address: Department of Clinical Pharmacology, Royal Postgraduate Medical School, London W12, England. t W. Landauer, personal communication.