Abstract
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.
Footnotes
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Send reprint requests to: Dr. Rita Loch-Caruso, Toxicology Program, Department of Environmental and Industrial Health, The University of Michigan, 1420 Washington Heights, Room M6112, Ann Arbor, MI 48109-2029. E-mail: rlc{at}umich.edu
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↵1 This research was conducted as partial fulfillment of the requirements of the doctoral dissertation of J. Bae, and was supported by an National Institutes of Health (NIH) Grant to R. Loch-Caruso (P42-ES04911) with additional support provided by the Laboratory Animal Core of the Center for the Study of Reproduction at the University of Michigan (NIH P30-HD18258). Portions of this work were presented at the 37th Annual Meeting of the Society of Toxicology, Seattle, WA, March 1–5, 1998 (Toxicol Sci 42:102, 1998).
- Abbreviations:
- A1242
- Aroclor 1242
- BCS
- bovine calf serum
- carbachol
- carbamylcholine chloride
- CMF-PBS
- calcium/magnesium-free PBS
- DMSO
- dimethyl sulfoxide
- HELSS
- (E)-6-(bromomethylene)tetrahydro-3-(1-naphthalenyl)-2H-pyran-2-one
- HETE
- hydroxyeicosatetraenoic acid
- 12-HHT
- 12-hydroxyheptadecatrienoic acid
- PG
- prostaglandin
- 6-k-PGF1α
- 6-keto-PGF1α
- LT
- leukotriene
- NCDC
- 2-nitro-4-carboxyphenyl-N,N-diphenylcarbamate
- PCB
- polychlorinated biphenyl
- PLA2
- phospholipase A2
- PLC
- phospholipase C
- PLD
- phospholipase D
- TXB2
- thromboxane B2
- Received June 17, 1998.
- Accepted December 30, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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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
