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Fertility, smoking and early mammalian development

Institution: University of California, Riverside
Investigator(s): Prudence Talbot, Ph.D.
Award Cycle: 2001 (Cycle 10) Grant #: 10RT-0239 Award: $454,490
Subject Area: General Biomedical Science
Award Type: Research Project Awards

Initial Award Abstract
Active smoking increases the risk of infertility, spontaneous abortion, and ectopic pregnancy (implantation outside of the uterus). These reproductive disorders are of medical importance and have increased in the past several decades. In the United States, as many as 1 in 6 couples may be infertile. Ectopic pregnancy, which is the leading cause of maternal death during the first trimester and which is almost always fatal to the fetus, has quadrupled in the United States since 1970. Our previous work has shown that female reproductive organs (the oviduct and corpus luteum of the ovary) are targets of mainstream (MS) and sidestream (SS) cigarette smoke. The oviduct functions in picking up the oocyte and transport it to the uterus. The corpus luteum develops numerous blood vessels that are essential for distributing the hormones it produces to other organs during pregnancy. Impairment of oviductal function or blood vessel formation in corpora lutea by smoke may cause infertility, spontaneous abortion, and ectopic pregnancy. We propose to isolate and identify the toxicants in smoke that impair functioning of these organs and to examine the mechanism of action of the toxicants on each organ. The hamster is used as a model for the oviductal studies. Blood vessel development is studied using a chick membrane rich in blood vessels, cultured human blood vessel cells, and hamster corpora lutea. Isolation and identification of toxicants: A preliminary screen showed that sidestream gas phase smoke (SSG) is more toxic to oviducts and developing blood vessels than any other type of smoke tested. We have used modern biochemical techniques to identify the chemicals present in our SGG smoke solutions. We are currently screening these chemicals to determine which are toxic in our bioassays. Once the dominant toxicants are identified, we will conduct dose response experiments with individual toxicants to determine which are most detrimental. We will also determine at what concentration each toxicant produces an effect in intact animals, and we will determine if hamsters exposed to smoke have sufficient levels of each toxicant in their serum to account for malfunctioning of the oviduct and corpus luteum. Our data will likely lead to identification of molecules in smoke that are highly toxic to reproductive organs but that are not currently recognized as dangerous. Identification of these toxicants may lead to methods for removing them from smoke. Mechanism of action of SSG toxicants: We showed previously that the least reversible and therefore most damaging mode of action of SSG smoke on the oviduct is to increase adhesion of the oocyte to the surface of the oviduct. This inhibits oocyte pickup and could in human smokers result in ectopic pregnancy. One goal is to identify the adhesion molecules that are targets of SSG smoke using a combination of biochemical techniques and assays developed by us for this purpose. Our second goal is to determine how the genes that regulate blood vessel development are affected by SSG smoke. Cultured human blood vessel cells will be exposed to smoke solutions or the isolated toxicants, and DNA analysis techniques will be used to determine which treatments influence gene expression. Smoking machine experiments with hamsters will determine how inhalation of smoke alters processes regulated by the genes that govern blood vessel development in corpora lutea.

Results from our studies will be made available for educational purposes and may help prevent women of childbearing age from smoking. People are more likely to stop smoking if they know its effects are imminent (childbearing) rather than remote (death). The techniques we have developed to study reproductive toxicology are needed and may become widely used to study other toxicants. The toxicants in smoke, once identified, could be removed from cigarette smoke, thereby decreasing the toxicity of smoke to women unable to stop smoking during their reproductive years. Our results may also lead to more advanced ways to control the effects of smoke on the reproductive organs. Our DNA data will be posted on the Internet for other investigators to use and will be a valuable resource for any scientist studying the effects of smoke on cells. Finally, our studies will benefit other branches of medicine. Results on the oviduct may apply to any organs having ciliated cells and smooth muscle cells, such as the respiratory system. Our studies on the corpus luteum will contribute to the overall understanding of how smoke affects blood vessel development at other sites, such as in wounds, the lining of the uterus, the placenta, and the embryo/fetus. In general, our studies will benefit the long-term reproductive health of our species.

Capillary plexus development in the day 5-day 6 chick chorioallantoic membrane in inhibited by cytochalasin D and suramin.
Periodical: Journal of Experimental Zoology Index Medicus:
Authors: Melkonian G, Munoz N, Chung J, Tong C, Marr R, and Talbot P ART
Yr: 2002 Vol: 292 Nbr: Abs: Pg: 241 - 254

Mainstream and sidestream cigarette smoke inhibit growth and angiogenesis in the day 5 chick chorioallantoic membrane.
Periodical: Toxicological Sciences Index Medicus:
Authors: Melkonian G, Cheung L, Marr R, Tong C, and Talbot P ART
Yr: 0 Vol: Nbr: Abs: Pg:

Reactive carbonyls from tobacco smoke increase arterial endothelial layer injury.
Periodical: American Journal of Physiology, Heart and Circulatory Physiology Index Medicus:
Authors: Mullick AE, McDonald JM, Melkonian G, Talbot P, Pinkerton KE, and Rutledge JC ART
Yr: 2002 Vol: 10 Nbr: 1152 Abs: Pg: 01046

Pyridines in cigarette smoke inhibit hamster oviductal functioning in picomolar doses.
Periodical: Reproductive Toxicology Index Medicus:
Authors: Riveles K, Iv M, Arey J, Talbot P ART
Yr: 2003 Vol: 17 Nbr: Abs: Pg: 191-202

Cell adhesion and fertilization: steps in oocyte transport, spermzona peilucida interactions, and sperm-egg fusion.
Periodical: Biology of Reproduction Index Medicus:
Authors: Talbot P, Sur D, Myles D ART
Yr: 2003 Vol: 68 Nbr: Abs: Pg: 1-9

Identification of pyridine compounds in cigarette s oke solution hat inhibit growth of the chick chorioallantoic membrane.
Periodical: Toxicological Sciences Index Medicus:
Authors: Lin J, Melkonian G, Riveles K, Talbot P ART
Yr: 0 Vol: 69 Nbr: Abs: Pg: 217-225

CD44 and tenascin play critical roles in growth and vascular development of the chick chorioallantoic membrane (CAM) and are targets of cigarette smoke.
Periodical: Anatomy and Embryology Index Medicus:
Authors: Melkonian G, Wang JL, Chung J, Munoz N, Talbot P ART
Yr: 2004 Vol: 208 Nbr: 109-120 Abs: Pg:

Pyrazine derivatives in cigarette smoke inhibit hamster oviductal functioning.
Periodical: Reproductive Biology and Endocrinology Index Medicus:
Authors: Riveles K, Roza R, Arey J, Talbot P ART
Yr: 2004 Vol: 2 Nbr: Abs: Pg: 23

Perivitelline space: does it play a role in blocking polyspermy in mammals?
Periodical: Microscopy Research and Technique Index Medicus:
Authors: Talbot P, Dandekar P ART
Yr: 2003 Vol: 61 Nbr: Abs: Pg: 349-357

Superoxide anion, hydrogen peroxide, and hydroxyl radicals in cigarette smoke inhibit hanster oocyte cumulus complex pickup.
Periodical: Toxicological Sciences Index Medicus:
Authors: Gieseke C, Pederson R, Talbot P ART
Yr: 2005 Vol: 84 Nbr: S-1 Abs: Pg: 1115

Reactive oxygen species in cigarette smokme inhibit hamster oocyte cumulus complex pickup.
Periodical: Molecular Biology of the Cell Index Medicus:
Authors: Gieseke C, Pederson R, Talbot P ART
Yr: 2004 Vol: 14 Nbr: Abs: Pg: L279