A study of the effects of p,p′-DDE and other related chlorinated hydrocarbons on inhibition of platelet aggregation

Abstract

A series of chlorinated hydrocarbons of interest in environmental toxicology were investigated concerning their effects on human platelet aggregation. Most potent in inhibiting platelet aggregation were p,p′-DDE and Arochlor 1242. Aggregation induced by arachidonic acid (1 mM) was more sensitive to inhibition by p,p′-DDE than was aggregation induced by ADP (10 ΜM). The former was completely inhibited by p,p′-DDE at a concentration of 1×10⁻⁴M, whereas there was only a 31% inhibition of the latter. Addition of Ca²⁺ (1 mM) blocked the inhibitory effect of p,p′-DDE on aggregation induced by both arachidonic acid and ADP. Calmodulin (1 Μg/ml) blocked the inhibitory effect of p,p′-DDE on aggregation induced by arachidonic acid but not that induced by ADP. The calmodulin inhibitory drugs trifluoperazine and calmidazolium had no effect at all or only a weak effect (−14%), respectively, on platelet aggregation. Increasing the concentrations of p,p′-DDE and Arochlor 1242 caused a delay in the onset of aggregation induced by the addition of arachidonic acid. The synthesis of thromboxane B₂ and other prostaglandins in platelet membranes was dose-dependently reduced by p,p′-DDE. The structurally closely related isomers o,p′-DDE and p,p′-DDT did not significantly inhibit arachidonic acid-induced platelet aggregation or thromboxane B₂ synthesis. It is concluded that p,p′-DDE and Arochlor 1242 inhibited platelet aggregation by inhibiting platelet cyclooxygenase activity.