Stimulation of pregnant rat uterine contraction by the polychlorinated biphenyl (PCB) mixture aroclor 1242 may be mediated by arachidonic acid release through activation of phospholipase A(2) enzymes

The polychlorinated biphenyl (PCB) mixture Aroclor 1242 (A1242) increases f requency of contractions of pregnant rat uteri, suggesting a possible mecha nism for decreased gestational age and increased spontaneous abortion in wo men and animals exposed to PCBs, In the present study, we hypothesized that A1242-induced stimulation of uterine contraction is mediated by arachidoni c acid released by phospholipase A(2) (PLA(2)) enzymes. Isometric uterine c ontraction was measured in longitudinal uterine strips isolated from gestat ion day 10 rat. Pretreatment of uterine strips with the PLA(2) inhibitor (E )-6-(bromomethylene)tetrahydro-3-(1 -naphthalenyl)-2H-pyran-2-one (HELSS) o r manoalide, or an inhibitor of the G protein of PLA(2), isotetrandrine, co mpletely prevented the increase of contractile frequency induced by 50 mu M A1242. However, the phospholipase C inhibitors 2-nitro-4-carboxyphenyl-N,N -diphenylcarbamate (NCDC) and neomycin were unable to block stimulation of uterine contraction by A1242. In accordance, A1242 (100 mu M) did not relea se inositol phosphates from myo[H-3]inositol-labeled myometrial cells, wher eas myometrial cells prelabeled with [H-3]arachidonic acid released arachid onic acid in a concentration- and time-dependent manner after exposure to A 1242 (10-100 mu M). A1242 significantly stimulated arachidonic acid release in the absence of extracellular calcium, although the release was attenuat ed. Analysis of the eicosanoids released by A1242 indicated that only 0.83% of released [H-3]arachidonic acid was metabolized to eicosanoids and 99.07 % remained as free arachidonate. Uterine contraction increased in strips ex posed to exogenous arachidonic acid (1-100 mu M). This study suggests that A1242 stimulates contraction in pregnant rat uterus by a mechanism involvin g PLA(2)-mediated arachidonic acid release, and that arachidonic acid, rath er than eicosanoids, may mediate A1242 uterotonic action in the uterus.