The overall objective of this research is to understand how polychlorinated biphenyls (PCBs) alter uterine contraction, in order to improve knowledge of the potential risks of PCBs to pregnant women and their offspring. PCB exposure is associated with decreased gestation length in women. In animals, PCBs increase, decrease or have no effect on gestation length depending on the congener or mixture. The mechanism(s) that mediate PCB effects on parturition are unknown. This proposal is to study selected PCBs that exhibit acute stimulatory or inhibitory activity in the pregnant uterus. Also, estrogenic PCBs will be studied for long-term effects on uterine activity. We propose the following hypotheses and specific aims: (1) Uterotonic PCBs inhibit K+ channels and thereby depolarize the cell membrane, which then activates voltage-operates calcium channels to promote increased intracellular calcium concentration and contractions using patch clamp procedures and fluorescence detection of intracellular probes. (2) Uterotonic PCBs stimulate contraction frequency by selectively acting on a subpopulation of uterine smooth muscle cells that may be the pacemarkers of the uterus.
This aim will isolate cells and uterine tissues that are deficient in pacemaker-like cells to investigate selective PCB actions on ion channel activities. Cell isolation and dissection strategies will be used to separate putative pacemarker and non-pacemaker cells and tissue from rat uterus. Mutant mice deficient in pacemaker cells of the intestine will be used a potential source of uteri deficient in uterine pacemakers. (3) Inhibitory PCBs decrease the force the promote desynchronization of uterine contractions of uterine contractions by oxidative stress-mediated inhibition of myometrial gap junctions.
This aim will use biochemical and histochemical approaches to measure PCB-induced generation of oxidative stress, superoxide, and oxidation of gap junction proteins. (4) Estrogenic PCBs promote uterine contraction with long-term exposure by increasing expression of oxytocin receptors and gap junctions through an estrogen receptor-dependent mechanism.
This aim will measure by western blot PCB-induced changes in abundance of oxytocin receptors and gap junction proteins. PCBs are wide spread environmental contaminants to which pregnant women may be exposed. By increasing our understanding of PCB actions in the pregnant uterus, the results from these experiments will contribute to improved assessment of risk to pregnant women and may explain previous reports that PCBs alter parturition.
Showing the most recent 10 out of 417 publications
