Superfund Research Program
PCB Effects on Uterine Muscle
Project Leader: Rita Loch-Caruso (University of Michigan)
Grant Number: P42ES004911
Funding Period: 1995 - 2006
Polychlorinated biphenyls (PCBs) are widespread environmental contaminants. Previous epidemiologic and laboratory animal studies indicate that some PCBs alter gestation length, suggesting that PCBs modify uterine muscle (myometrial) contractility. Additionally, PCBs accumulate in the uterus during pregnancy, suggesting that the uterus may be a direct target of PCB action. Because parturition requires the development of coordinated, forceful, phasic uterine contractions, this project is investigating how PCBs alter uterine muscle contraction. More specifically, this study aims to elucidate structure-activity relationships and signal transduction mechanisms for PCB-induced alteration of uterine muscle contraction.
A previous study with six PCB congeners showed that acute exposure to PCBs with chlorine substitution at the ortho position and four or fewer chlorines increased uterine contraction frequency. In experiments with an extended series of ortho-substituted chlorinated biphenyls (CBs) having three or fewer chlorines, chlorine substitution in the ortho position was required for stimulation of uterine contraction frequency by biphenyls containing one or two chlorines. In ortho-substituted trichlorinated biphenyls, chlorine substitution at the meta position inhibited uterotonic activity. Dichlorobiphenyls with ortho substitution of one phenyl ring stimulated contraction frequency if the other ring had a chlorine substitution at the para position, whereas 4,4'-CB had no significant effect on oscillatory uterine contractions. Studies failed to demonstrate significant membrane depolarization by 2,4'-CB using the membrane potential dye DiBAC4(3), suggesting that stimulation of uterine contraction frequency is not related to significant increase of membrane excitability.
Additional studies showed that the nonchlorinated biphenyl, 2'-CB and 2,2'-CB promoted desynchronization of uterine contractions, characterized by irregular contraction frequency and amplitude. 2,2'-CB was used as a model PCB in subsequent experiments investigating mechanisms of uterine desynchronization. Contraction desynchronization was reversed by antioxidants, suggesting a role for oxidative stress in 2,2'-CB-induced desynchronization of uterine contractions. Because gap junctions coordinate uterine contractions, current studies are investigating inhibition of myometrial gap junctions as an intermediate cell response linking oxidative stress and desynchronization of uterine contractions.
Previous studies in this project showed that PCBs activate phospholipase A2 (PLA2) to release arachidonic acid from myometrial membrane phospholipids. Arachidonic acid serves as the precursor to eicosanoids that can modulate uterine contraction. Because 2,2',4,6-CB was shown by others to significantly activate PLA2 in non-uterine cells, this congener was used as a model PCB in initial investigations of PCB actions on phospholipases in pregnant myometrium. A significant increase in frequency of uterine contractions was observed in gestation day (GD) 20 strips, but not GD10 strips, treated with 2,2',4,6-CB compared to solvent control. Pretreatment with an iPLA2 inhibitor reversed 2,2',4,6-CB induced stimulation of contraction frequency in GD20 uterine strips, whereas a sPLA2 inhibitor had no significant effect. These results suggest that changes in uterine expression and/or activity of iPLA2 contribute to the gestation day-dependent sensitivity to 2,2',4,6-CB-induced stimulation of contraction frequency. Current experiments are extending these studies to include the environmentally relevant PCB congener 2,4,5,2',4',5'-CB and to investigate effects on PLA2 expression.
The results from these experiments suggest a scientific basis for previous reports that PCBs alter parturition by showing that PCBs modify uterine muscle contractility.