New Model Leading to Preterm Delivery: Role of Exposure to Environmental Toxins

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DESCRIPTION (provided by applicant): Preterm birth is a major cause of neonatal morbidity and mortality and childhood neurological disability particularly in infants born less than 28 weeks gestation. Despite significant advances in the care of pregnant mothers, the incidence of preterm labor is on the rise. There is growing recognition that cytokines and inflammatory mediators, in particular, prostaglandins, present at the maternal-fetal interface, play a fundamental role in regulating labor. Of particular importance is the anti-inflammatory cytokine, interleukin-10 (IL-10) which functions to inhibit the pro-inflammatory anti-fetal immune responses in the placental micro-environment that initiate labor. We speculate that in the presence of subclinical infection, decreases in IL-10 lead to an exaggerated inflammatory reaction that drives the local immune system at the maternal-fetal interface towards anti-fetal responses and preterm labor. Mechanisms underlying suppression of IL-10 in the placenta are unknown. TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) is a persistent environmental pollutant, generated as a manufacturing byproduct of waste incineration, and is found as a contaminant in pesticide mixtures. Epidemiologic studies have suggested a strong association between maternal exposure to TCDD and preterm birth. TCDD is known to modulate immune responses and we have demonstrated that it blocks placental IL-10 production. We hypothesize that intrauterine exposure to TCDD leads to down regulation of IL-10 and/or up regulation of pro-inflammatory cytokines that can trigger preterm labor in the setting of low grade infection. To test this hypothesis, studies are planned to: (1) compare cytokines produced by human placentas from preterm, normal second trimester, and term labor samples; (2) Analyze the role of IL-10 in regulating placental prostaglandin production in preterm when compared to normal second trimester and term labor samples; (3) characterize the effects of TCDD on placental cytokines expression and activity, and (4) Determine if TCDD increases susceptibility to preterm delivery in infection-induced preterm labor in mice. PUBLIC HEALTH RELEVANCE: The studies described in this application will improve our understanding of the molecular pathogenesis of preterm labor and the role of exposure to environmental toxicants on this pathologic process. These findings will be useful in studies aimed at identifying more effective prevention and treatment strategies for preterm labor.