Premature birth is a major cause of perinatal mortality and illness in the United States, and delayed or failed labor often requires surgical intervention. These examples emphasize the importance of timely initiation of labor, and the potentially adverse outcomes which may result from interference with uterine function. The onset of labor is accompanied by a dramatic increase in the area and incidence of gap junctions in the myometrium. Gap junctions are the membrane structures believed to mediate direct cell-to-cell transfer of small compounds. These junctions allow rapid transmission of small inorganic ions which propagate action potentials and synchronize contractions of myometrial cells during labor. Many substances, including toxicants, drugs and hormones, are known to affect the formation and function of these junctions in various tissues, and these actions may underline certain physiological and pathological responses. Cell cultures have not been used previously to asses the impact of substances on uterine junctional communication, nor have environmental toxicants been evaluated for potential effects on myometrial cell- cell communication. The hypothesis of the proposed research is that environmental toxicants, drugs, and certain physiological substances may alter cell-cell communication among myometrial cells, and that these effects may be mediated by calcium, cAMP, pH and/or protein phosphorylation. Assuming that communicating junctions are necessary for the onset of labor, this research may improve management of labor, thereby allowing for safer and more successful pregnancy outcome.
The specific aims of the proposed research are to: (1) establish protocols to measure cell-cell communication in myometrial cultures; (2) evaluate the uterine cell line, SK-UT-1, for inhibition of cell-cell communication by substances known to inhibit myometrial gap junction formation, labor or cell-to-cell communication in other cell/test systems; (3) establish cell lines of rat and human myometrium; if this is not possible, then establish procedures for in vitro maintenance of uterine strips from rats and humans; (4) evaluate myometrial cultures for intrinsic levels of cell-cell communication; (5) evaluate potentially hazardous substances, drugs and certain physiological substances for their ability to alter cell-cell communication; (6) investigate mechanisms of modulation of junctional communication in myometrial cultures, focusing on protein phosphorylation, calcium, pH and cAMP involvement.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29ES004424-03
Application #
3465203
Study Section
Reproductive Endocrinology Study Section (REN)
Project Start
1987-09-01
Project End
1992-08-31
Budget Start
1989-09-01
Budget End
1990-08-31
Support Year
3
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Type
Schools of Public Health
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Loch-Caruso, R; Galvez, M M; Brant, K et al. (2004) Cell and toxicant specific phosphorylation of conexin43: effects of lindane and TPA on rat myometrial and WB-F344 liver cell gap junctions. Cell Biol Toxicol 20:147-69
Criswell, K A; Loch-Caruso, R (1999) Lindane-induced inhibition of spontaneous contractions of pregnant rat uterus. Reprod Toxicol 13:481-90
Marty, M S; Loch-Caruso, R (1998) 2-Methoxyethanol inhibits gap junctional communication in rat myometrial myocytes. Cell Biol Toxicol 14:199-210
Criswell, K A; Loch-Caruso, R; Stuenkel, E L (1995) Lindane inhibition of gap junctional communication in myometrial myocytes is partially dependent on phosphoinositide-generated second messengers. Toxicol Appl Pharmacol 130:280-93
Juberg, D R; Stuenkel, E L; Loch-Caruso, R (1995) Dde chlorinated insecticide 1,1-dichloro-2,2-bis(4-chlorophenyl)ethane (p,p'-DDD) increases intracellular calcium in rat myometrial smooth muscle cells. Toxicol Appl Pharmacol 135:147-55
Criswell, K A; Loch-Caruso, R (1995) Lindane-induced elimination of gap junctional communication in rat uterine myocytes is mediated by an arachidonic acid-sensitive cAMP-independent mechanism. Toxicol Appl Pharmacol 135:127-38
Criswell, K A; Stuenkel, E L; Loch-Caruso, R (1994) Lindane increases intracellular calcium in rat myometrial smooth muscle cells through modulation of inositol 1,4,5-trisphosphate-sensitive stores. J Pharmacol Exp Ther 270:1015-24
Watts, S W; Tsai, M L; Loch-Caruso, R et al. (1994) Gap junctional communication and vascular smooth muscle reactivity: use of tetraethylammonium chloride. J Vasc Res 31:307-13
Marty, M S; Loch-Caruso, R (1993) Nickel-induced increases in gap junctional communication in the uterine cell line SK-UT-1. In Vitro Cell Dev Biol 29A:215-20
Corcos, I A; Meese, E U; Loch-Caruso, R (1993) Human connexin43 gene locus, GJA1, sublocalized to band 6q21-->q23.2. Cytogenet Cell Genet 64:31-2

Showing the most recent 10 out of 18 publications