Prematurity, postmaturity and poor labor progression significantly contribute to perinatal morbidity and other adverse birth outcomes. Despite a relatively high incidence of such complications, the potential effects of environmental contaminants on parturition are largely unknown. The development of labor is associated with gap junction formation and cyclic elevations of intracellular Ca2+ ([Ca2+]i) in the myometrium. Elevated [Ca2+]i is necessary for contraction of individual muscle cells. It has been suggested that gap junctions between uterine muscle cells allow direct intercellular communication of depolarizing signals, thereby improving propagation and synchronization of uterine contractions. Our laboratory has found that the insecticide, lindane (gamma- hexachlorocyclohexane), abolished gap junctional communication in cell cultures of rat uterine smooth muscle cells. Furthermore, we observed that a rapid rise in [Ca2+]i followed addition of lindane to the cells, and subsequent experiments showed that an IP3-sensitive pool was the source of Ca2+. However, further experiments suggested that increased [Ca2+]i was independent of the inhibitory effect of lindane on gap junctional communication. The hypothesis of this proposal is that lindane inhibition of gap junctional communication relaxes uterine muscle and interferes with parturition. Additionally, mechanisms of lindane modification of Ca2+ homeostasis will be investigated. Should the gap junction hypothesis be shown to be untenable, the Ca2+ experiments may provide the basis for the alternate hypothesis that lindane-induced changes in Ca2+ homeostasis initiate relaxation of the uterus.
The specific aims of the proposal are to: l) Characterize lindane's effects on parturition in rats; 2) Characterize lindane inhibition of rat uterine contractility in vitro; 3) Evaluate mechanisms whereby lindane inhibits gap junctional communication; 4) Evaluate the relationship between lindane-induced inhibition of gap junctional communication and uterine contractility in vitro; 5) Analyze whether inhibition of gap junctional communication in uterine muscle contributes to lindane's observed effects on parturition; and 6) Investigate mechanisms of lindane-induced Ca2+ release from intracellular stores. Identification of the mechanism of lindane inhibition of gap junctional communication should facilitate understanding of the toxicant effects of this pesticide, not only in the reproductive system, but perhaps in other tissues as well. Furthermore, studies of lindane's mechanism of relaxation of uterine contractility may provide insight for new therapeutic approaches to preterm labor.
