Vol. 289, Issue 2, 1112-1120, May 1999

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 A₂ Enzymes¹

Jeehyeon Bae, Marc Peters-Golden and Rita Loch-Caruso

Toxicology Program, Department of Environmental and Industrial Health (J.B., R.L-C.), and Division of Pulmonary and Critical Care Medicine, Department of Medicine (M.P-G.), The University of Michigan, Ann Arbor, Michigan

The polychlorinated biphenyl (PCB) mixture Aroclor 1242 (A1242) increases frequency of contractions of pregnant rat uteri, suggesting a possible mechanism for decreased gestational age and increased spontaneous abortion in women and animals exposed to PCBs. In the present study, we hypothesized that A1242-induced stimulation of uterine contraction is mediated by arachidonic acid released by phospholipase A₂ (PLA₂) enzymes. Isometric uterine contraction was measured in longitudinal uterine strips isolated from gestation day 10 rat. Pretreatment of uterine strips with the PLA₂ inhibitor (E)-6-(bromomethylene)tetrahydro-3-(1-naphthalenyl)-2H-pyran-2-one (HELSS) or manoalide, or an inhibitor of the G protein of PLA₂, isotetrandrine, completely prevented the increase of contractile frequency induced by 50 µM 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 µM) did not release inositol phosphates from myo-[³H]inositol-labeled myometrial cells, whereas myometrial cells prelabeled with [³H]arachidonic acid released arachidonic acid in a concentration- and time-dependent manner after exposure to A1242 (10-100 µM). A1242 significantly stimulated arachidonic acid release in the absence of extracellular calcium, although the release was attenuated. Analysis of the eicosanoids released by A1242 indicated that only 0.83% of released [³H]arachidonic acid was metabolized to eicosanoids and 99.07% remained as free arachidonate. Uterine contraction increased in strips exposed to exogenous arachidonic acid (1-100 µM). This study suggests that A1242 stimulates contraction in pregnant rat uterus by a mechanism involving PLA₂-mediated arachidonic acid release, and that arachidonic acid, rather than eicosanoids, may mediate A1242 uterotonic action in the uterus.