Project Summary (2005-2009)

Many chemical compounds introduced into the environment by human activity are suspected of influencing reproductive outcome. Epidemiological evidence suggests that those living in the vicinity of Superfund sites experience adverse pregnancy outcomes such as premature fetal loss and birth, intrauterine growth restriction (ILJGR), and low birth weight. However, little is known about the mechanistic basis of reproductive anomalies. The long-term objective of this work is to understand the impact of co-exposure to genetic and chemical stress on pregnancy outcome and to delineate basic mechanisms of immune programming of toxicant-induced pregnancy disruption. This research project establishes a mouse model to understand how ubiquitous environmental contaminants such as polychlorinated biphenyls (PCBs), given at sub-toxic doses, influence gestation in animals deficient in pregnancy compatible cytokines such as interleukin-10 (IL-10) or in anti-inflammatory immunity as observed in STAT6^-/- mice. Dr. Sharma’s team has recently demonstrated that sub-clinical inflammation when combined during pregnancy with IL-10 deficiency results either in fetal loss or premature birth depending on the gestational age-dependent induction of inflammation. Furthermore, these adverse pregnancy outcomes are uniquely associated with cytotoxic activation of uterine Natural Killer (uNK) cells and/or loss of regulatory T cell subpopulations. The team’s hypothesis is that chemical stress induced by sub-toxic doses of PCBs represents a physiologic counterpart of inflammation that predisposes to adverse pregnancy outcomes when combined with genetic disruptions in pregnancy compatible loci. The objectives of this project address:

1. dose response and time dependence of exposure to PCBs or lipopolysaccharide (IPS) to influence pregnancy outcome in wild type and IL-10^-/- or STAT6^-/- mice,
2. uterine immune cell recruitment, NK cell cytotoxic activation, and trophoblast trafficking in response to PCS or LPS treatment,
3. restoration of pregnancy by IL-10 administration or depletion of NK cells in IL-10^-/- mice exposed to PCBs, and
4. microarray analysis of differentially regulated genes in uteroplacentaltissue from normal and toxicant-induced adverse pregnancy.

Understanding the mechanisms underlying toxicant-induced pregnancy disruption in mice is important for identifying bio-markers of pregnancy associated disorders in humans.