The Human Gestational Membranes as a Site of Polybrominated Diphenyl Ether Toxicity.

Abstract

Preterm birth is a major public health concern impacting one in eight babies born in the U.S.A. Although a precise cause for preterm birth cannot be established in most cases, one of the most promising predictors of preterm birth is inflammation of the extra-placental gestational membranes. Gestational membrane production of pro-inflammatory cytokines has been shown to initiate term parturition pathways and is thought to play a role in preterm parturition as well. Pregnant woman are exposed to a wide array of environmental pollutants, but few have been investigated epidemiologically for association with preterm birth and none have been satisfactorily investigated mechanistically. Polybrominated diphenyl ethers (PBDEs) are emerging toxicants of concern that have received limited attention regarding potential risks to human health and birth outcomes. Preliminary research suggests that PBDEs may stimulate the gestational membranes to secrete pro-inflammatory cytokines in vitro. This dissertation tests the hypothesis that polybrominated diphenyl ethers bioaccumulate in the human gestational compartment and stimulate cytokine secretion from human gestational membranes. Total PBDE levels were measured in the human gestational membranes and found at levels of 17.4±3.9 pg/g tissue (5.6±1.3 ng/g lipid). Human amniotic fluid levels were 3795±1592 pg/ml fluid (404±126 ng/g lipid). Congener-specific profiles for the 21 congeners measured identified only tri- through hexa-BDEs in gestational membranes. In contrast, tri- through deca-BDE congeners were found in amniotic fluid. To assess stimulation of inflammatory responses in human gestational membranes, two tissue culture systems were compared for cytokine release into the culture medium: a biopsy punch explant culture system and a transwell mounted explant culture system. Although lipopolysacharide stimulated a robust increase of interleukins-1β, 6, 8, 10 and tumor necrosis factor-α in both systems, with an amplified release of interleukins-6, 8 and 10 in the punch culture system, no increase in cytokine release was observed in response to PBDE stimulation. This is the first report of PBDE accumulation in the human gestational membranes, providing a basis for future investigations of toxic action in this tissue and the first to suggest amniotic fluid as a significant route of PBDE exposure for both the gestational membranes and the developing fetus.