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 enzymes.
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 microM 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 microM) 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 microM). 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 microM). 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.
Bae
J
J
Toxicology Program, Department of Environmental and Industrial Health, Department of Medicine, The University of Michigan, Ann Arbor, Michigan, USA.
Peters-Golden
M
M
Loch-Caruso
R
R
D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D016718:Arachidonic Acid / Q000378:metabolism*; D001140:Aroclors / Q000633:toxicity*; D044182:Benzylisoquinolines; D015777:Eicosanoids / Q000378:metabolism; D004785:Environmental Pollutants / Q000633:toxicity*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000378:metabolism; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D007537:Isometric Contraction / Q000187:drug effects; D009215:Myometrium / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009281:Naphthalenes / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054467:Phospholipases A2; D011247:Pregnancy; D011753:Pyrones / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013729:Terpenes / Q000494:pharmacology; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors; D014590:Uterine Contraction / Q000187:drug effects*; D014599:Uterus / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism*
D000470:Alkaloids; D000975:Antioxidants; D001140:Aroclors; D044182:Benzylisoquinolines; D015777:Eicosanoids; D004785:Environmental Pollutants; D004791:Enzyme Inhibitors; D007295:Inositol Phosphates; D007527:Isoenzymes; D009281:Naphthalenes; D010726:Phosphodiesterase Inhibitors; D011753:Pyrones; D013729:Terpenes; D016718:Arachidonic Acid; C009438:tetrandrine; C027423:aroclor 1242; C068314:6-(bromomethylene)tetrahydro-3-(1-naphthaleneyl)-2H-pyran-2-one; C045673:manoalide; D010741:Phospholipases A; D054467:Phospholipases A2; D010738:Type C Phospholipases