Superfund Research Program
PCB Effects on Uterine Muscle
Project Leader: Rita Loch-Caruso (University of Michigan)
Grant Number: P42ES004911
Funding Period: 1995 - 2006
Regulation of uterine contractility is vital to successful reproduction. During pregnancy, the uterus remains relatively inactive from conception until just prior to the initiation of labor. As the time of delivery approaches, the uterus becomes more active with muscular contractions that increase in frequency, intensity and coordination, eventually forcing the fetus through the birth canal. Fine-tuned control of uterine contractions is important not only for an effective labor at the end of pregnancy, but also for preventing premature labor. Previous research by this laboratory demonstrated that polychlorinated biphenyls (PCBs), a group of widespread, persistent environmental contaminants, stimulate or inhibit contractions in isolated segments of uterus in a congener-specific manner. This project is investigating mechanisms by which PCBs may disrupt the natural termination of pregnancy by altering uterine contractions. In a series of experiments, the researchers discovered that the once common commercial PCB mixture Aroclor 1242 stimulates uterine contraction frequency and alters cellular signal transduction pathways known to be involved in the regulation of contractions in uterine muscle cells. In one set of studies, Aroclor 1242 was shown to increase release of the cellular messenger arachidonic acid in cultured uterine muscle cells. Because Aroclor 1242 inhibits arachidonic acid metabolism to eicosanoids (such as prostaglandins) while increasing release of arachidonic acid, arachidonic acid per se may be critical to the stimulation of uterine contraction. Enzyme inhibition experiments revealed that this activity is likely mediated by the enzyme phospholipase A2. Other experiments showed that Aroclor 1242 activates voltage-operated calcium channels and increases intracellular calcium concentration in uterine muscle cells, a potentially significant finding because calcium is an essential stimulus for initiating uterine muscular contractions. These experiments suggest that Aroclor 1242 may stimulate uterine contraction frequency by a phospholipase A2-dependent, arachidonic acid-mediated activation of voltage-sensitive calcium channels and the subsequent increase of intracellular calcium concentration. PCBs have been associated with shortened gestation length in women in some studies. In laboratory studies with relatively high concentrations, PCBs decreased gestation length and induced spontaneous abortions. The mechanistic understanding acquired in these studies is providing insight into potential reproductive risks that may arise from PCB exposures.