Possible mechanisms by which an estrogenic polychlorobiphenyl alters oscillatory contractions of pregnant uteri.

Abstract

Many studies show that exposure to polychlorinated biphenyls (PCBs) are associated with prematurity and prolonged gestation. The diverse effects of PCBs on parturition are explained partially because PCBs were produced and measured as mixtures of PCB congeners. One of the PCB congeners, 4-hydroxy-2$\sp\prime$,4$\sp\prime$,6$\sp\prime$- trichlorobiphenyl(40HTCB), exerts a uterotrophic effect and competitive binding affinity for estrogen receptors, indicating that 40HTCB is estrogenic. Estrogens exert dual effects on uterine contractions which play a major role during parturition. A high concentration of estrogen immediately decreases uterine contractions. In contrast, 24 to 48 hours of exposure to a low concentration of estrogen increases contractions of pregnant uteri in response to oxytocin. Therefore, the general hypothesis of this thesis is that the estrogenic PCB 40HTCB alters uterine contractions via two different mechanisms. The immediate exposure to 40HTCB decreases spontaneous contractions through a nonestrogen receptor-mediated pathway, and a 42-h exposure to 40HTCB increases the oscillatory contractile response of pregnant uteri to oxytocin through an estrogen receptor-mediated pathway. To test this hypothesis, four aims were proposed: (1) to examine the acute effect of 40HTCB on spontaneous uterine contractions and to compare this response to other PCB congeners, (2) to explore the possible involvement of gap junctions in uterine relaxation by estrogenic compounds following acute exposure, (3) to assess the changes of oscillatory contractile responses to oxytocin after 20- to 42-h exposure to 4OHTCB, and (4) to investigate the possible involvement of estrogen receptors in the alterations of the oscillatory contractile response to oxytocin after a 42-h exposure to estrogenic compounds. Our findings demonstrated that (1) the reduction of intercellular communication is associated with the acute inhibition of spontaneous uterine contractions by 4OHTCB and (2) the increase of oxytocin-induced oscillatory contractions by a 42-h incubation with 4OHTCB is reversed by an estrogen receptor antagonist. As such, the data suggest that the estrogenic PCB 4OHTCB alters the functions of pregnant uteri through non-estrogen or estrogen receptor mediated-pathways depending on the duration and the concentration of exposure.