Preterm birth (PTB) is a significant health problem that continues to persist even in the face of better clinical care and patient awareness. This condition disproportionately affects African-American women and, even more so, African-American couples (Palomar et al, 2007). Whether endocrine disrupting chemicals in the environment pose a risk for PTB is unknown, but minorities have been shown to be more often exposed to environmental pollutions and toxicants (Silbergeld and Patrick, 2005). Taken together, these seemingly disparate issues suggest a possible role of gene-environment interactions in preterm birth. Using an animal model of developmental TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) exposure, this R21 grant will begin exploring the mechanisms by which early life exposure to this toxicant may alter endocrine control of the reproductive tract inflammatory response, leading to an increased risk of PTB. Specifically, we hypothesize that spontaneous PTB in the absence of overt infection is due to an altered placental/decidual relationship that increases local sensitivity to proinflammatory cytokines resulting in preterm birth. We propose that reduced decidual progesterone sensitivity and increased inflammation within the placenta are biologically linked and control timing of parturition. Although inflammation as a cause of PTB is not a new concept, the possibility that a developmental environmental toxicant exposure of either the female or male partner contributes to the risk of PTB via altered decidual-fetal communication is novel.
In Specific Aim #1 we will largely focus on the female and understanding the potential role of toxicant-induced inflammation in decreasing decidual progesterone receptor (PR) expression and influencing placental cytokine expression which may lead to PTB.
In Specific Aim #2, our focus will shift to the male and the paternal contribution of premature placental inflammation to loss of decidual PR expression and, thus PTB. Although we expect that maternal factors will have the greatest influence on timing of pregnancy, examination of the male in this regard is warranted in light of new studies which suggest placental inflammation may contribute to timing of normal parturition (Houben et al, 2009). Finally, we will explore the possibility that nutritional supplementation with omega-3 fatty acids, which act to reduce systemic inflammation, could be a clinically effective method to extend pregnancy and reduce the PTB rate among all women. Even a modest increase in length of gestation would have a significant beneficial effect on surviving infants and greatly reduce the cost in both health care dollars and lost human potential.
Using an animal model of developmental TCDD exposure, this R21 grant will begin exploring the mechanisms by which an environmental endocrine disruptor alters inflammatory response, leading to an increased risk of PTB. Specifically, we will examine both maternal (decidual) and paternal (placenta) contributions to premature inflammation which may lead to early parturition.
