Brominated Diphenyl Ether-47 Activates Reactive Oxygen-Mediated Inflammatory Pathways in Human First Trimester Extravillous Trophoblasts In Vitro.

Abstract

Polybrominated diphenyl ethers (PBDEs) are widely used flame retardant compounds. Exposure to PBDEs has been linked to adverse pregnancy outcomes in humans including preterm birth, low birth weight and stillbirth. Although underlying mechanisms of adverse birth outcomes are poorly understood, critical roles of impaired trophoblast invasion and placental dysfunction characterized with dysregulated inflammatory pathways have been implicated. The present study examined the hypothesis that brominated diphenyl ether (BDE)-47, one of the most prevalent PBDE congeners, stimulates reactive oxygen-mediated activation of inflammatory pathways in a human first trimester extravillous trophoblast (EVT) cell line, HTR-8/SVneo, and that the antioxidant transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) plays a protective role against BDE-47-induced inflammatory pathways. Our results provide evidence of altered mitochondrial membrane potential, enhanced production of reactive oxygen species (ROS), and enhanced production of the pro-inflammatory interleukin (IL)-6, IL-8, and prostaglandin E2 (PGE2) stimulated by BDE-47 in HTR-8/SVneo cells. The inhibition of stimulated release of IL-6 and PGE2 by antioxidant treatments implicates the involvement of ROS in the regulation of BDE-47-stimulated inflammatory pathways in HTR-8/SVneo cells. In addition, treatment with BDE-47 activated Nrf2-mediated oxidative stress responses as indicated by increased Nrf2 transactivation, differential expression of redox-sensitive genes, and augmented glutathione (GSH) production. Pretreatment with the Nrf2 inducers tert-butyl hydroquinone (tBHQ) or sulforaphane suppressed BDE-47-stimulated IL-6 production and nuclear factor kappa B transactivation in HTR-8/SVneo cells, with stimulated Nrf2 transactivation, intracellular GSH production, and mRNA expression of antioxidant genes compared with non-pretreated controls. The latter findings suggest that Nrf2 may play a protective role against BDE-47-stimulated inflammatory responses. In conclusion, BDE-47, a predominant flame retardant chemical found in human tissues, activates proinflammatory responses in human first trimester EVTs. The present study provides the first experimental data to support a mechanism by which PBDE exposure could contribute to increased risk for adverse birth outcomes. This study demonstrates that a common toxicological effect, oxidative stress, activates inflammatory pathways associated with impaired trophoblast function and placental dysfunction. Furthermore, this research contributes new information for potential interventions to reduce adverse obstetrical outcomes originating from abnormal placental function, with attendant possible economic, societal and public health benefits.