| Increased understanding of how 2,2'-DCB alters uterine contractions may contribute to improved assessment of the potential risks of 2,2'-DCB and possibly other PCBs to pregnant women and their offspring. The overall object of this dissertation is to understand the mechanism(s) by which 2,2'-dichlorobiphenyl (2,2'-DCB) decreases amplitude and synchronization of rat uterine contractions. 2,2'-DCB was selected as a model ortho-substituted non-coplanar PCB congener whose mechanism for adverse effects is different from coplanar PCB congeners.; I hypothesized that 2,2'-DCB-induced decrease in amplitude and synchronization of uterine contractions results from oxidative stress-dependent inhibition of myometrial gap junctions via kinase-mediated phosphorylation of Cx43. The specific aims were to determine whether: (1) 2,2'-DCB decreases amplitude and synchronization of uterine contractions via inhibition of myometrial gap junctions due to kinase-mediated phosphorylation of Cx43, and (2) 2,2'-DCB-induced modification of uterine contractions is through oxidative stress-initiated kinase-mediated inhibition of myometrial gap junctions.; Under specific aim one, it was concluded that: (1) 2,2'-DCB (100 muM) inhibited rat myometrial gap junctions by evidence of decreased Lucifer yellow dye transfer; (2) 2,2'-DCB-induced inhibition of rat myometrial gap junctions was through MAPK-mediated phosphorylation of Cx43 evidenced by reversal of 2,2'-DCB-induced decreased dye transfer by cotreatment with PD98059, increased intensity of pCx43(S255) on western blot after exposure to 100 muM 2,2'-DCB, and 2,2'-DCB-induced increase in phosphorylation of ERK; and (3) the MAPK signaling pathway is the mechanism for 2,2'-DCB-induced modification of uterine contractions as evidenced by reversal of 2,2'-DCB-induced phosphorylation of Cx43 and modification of rat uterine contractions by cotreatment with PD98059. Under specific aim two, it was concluded that: (1) oxidative stress is likely induced by 2,2'-DCB in the pregnant rat uterus as indicated by lowered total SOD activity and increased superoxide anion generation in uterine tissue exposed to 100 muM 2,2'-DCB; (2) oxidative stress is involved in 2,2'-DCB-induced modification of uterine contractions as evidenced by the reversal of 2,2'-DCB-induced modification of uterine contractions by antioxidants; (3) oxidative stress is not involved in 2,2'-DCB-induced signaling pathway for inhibition of myometrial gap junctions as evidenced by failure of cotreatment with deferoxamine mesylate or SOD to change dye transfer and western blot of pCx43(S255) and pERK. |
