| Polychlorinated biphenyls (PCBs) are widespread environmental contaminants that were first manufactured for commercial use as mixture of isomers (congeners). Epidemiological studies have linked PCB exposures with decreased gestation length in women and spontaneous abortion in non-human primates. This dissertation examines structure-activity relationships of PCB congeners and the mechanisms by which ortho-substituted polychlorinated biphenyls (PCBs) increase the frequency of contractions in pregnant rat uterus. The examined hypotheses were that: (1) microbial dechlorination converts the PCB mixture Aroclor 1260 to an uterotonic mixture by increasing the relative abundance of stimulatory congeners, (2) ortho-substitution was required for uterotonic activity of PCBs whereas the uterotonic activity of simple ortho-substituted PCBs was augmented by para -substitution, and (3) uterotonic activity of ortho -substituted PCBs was mediated through inhibition of potassium channels. Using standard muscle bath procedures, changes in the oscillatory contractions of uterine strips were monitored after exposure to PCBs in vitro. PCB-stimulated uterine contraction in relation to chlorine content and position was evaluated using the non-uterotonic PCB mixture Aroclor 1260, the dechlorinated Aroclor 1260 mixture HR1260, ortho- and/or para-substituted tri-, di-, and mono-chlorinated biphenyls (CBs), and nonchlorinated biphenyl (BP). A role for potassium channels was examined using specific inhibitors of the channels. In addition, a role for phospholipase A2 (PLA 2) and protein kinase C (PKC) was explored using specific PLA2 and PKC inhibitors to examine upstream regulation on potassium channels by these enzymes. The results showed that the presence of chlorine in a biphenyl ring was necessary to induce uterotonic effects of PCBs, in which prominent increases of contraction frequency by ortho-substituted PCBs with two or one chlorine were characteristic. Additionally, the uterotonic activity was augmented by chlorine substitution at the para-position. The order of potency in regard to uterine activity was: 2,4' -CB > 2,4-CB > 2,2'-CB and 4,4' -CB > BP. However, the ortho-substituted PCB-stimulated uterine contraction was independent of PLA2, PKC, and potassium channel activation. Future studies are required to explain the details of the mechanisms and to determine whether a specific ion channel controls stimulation of uterine contraction frequency by the ortho-substituted PCBs. |
