title: Protective effect of nuclear factor E2-related factor 2 on inflammatory cytokine response to brominated diphenyl ether-47 in the HTR-8/SVneo human first trimester extravillous trophoblast cell line.
abstract: Polybrominated diphenyl ethers (PBDEs) are widely used flame retardants, and BDE-47 is a prevalent PBDE congener detected in human tissues. Exposure to PBDEs has been linked to adverse pregnancy outcomes in humans. Although the underlying mechanisms of adverse birth outcomes are poorly understood, critical roles for oxidative stress and inflammation are implicated. The present study investigated antioxidant responses in a human extravillous trophoblast cell line, HTR-8/SVneo, and examined the role of nuclear factor E2-related factor 2 (Nrf2), an antioxidative transcription factor, in BDE-47-induced inflammatory responses in the cells. Treatment of HTR-8/SVneo cells with 5, 10, 15, and 20μM BDE-47 for 24h increased intracellular glutathione (GSH) levels compared to solvent control. Treatment of HTR-8/SVneo cells with 20μM BDE-47 for 24h induced the antioxidant response element (ARE) activity, indicating Nrf2 transactivation by BDE-47 treatment, and resulted in differential expression of redox-sensitive genes compared to solvent control. Pretreatment with tert-butyl hydroquinone (tBHQ) or sulforaphane, known Nrf2 inducers, reduced BDE-47-stimulated IL-6 release with increased ARE reporter activity, reduced nuclear factor kappa B (NF-κB) reporter activity, increased GSH production, and stimulated expression of antioxidant genes compared to non-Nrf2 inducer pretreated groups, suggesting that Nrf2 may play a protective role against BDE-47-mediated inflammatory responses in HTR-8/SVneo cells. These results suggest that Nrf2 activation significantly attenuated BDE-47-induced IL-6 release by augmentation of cellular antioxidative system via upregulation of Nrf2 signaling pathways, and that Nrf2 induction may be a potential therapeutic target to reduce adverse pregnancy outcomes associated with toxicant-induced oxidative stress and inflammation.
authors.affiliation: Department of Environmental Health Sciences, University of Michigan, 1415 Washington Heights, Ann Arbor, MI 48109-2029, USA. Electronic address: heaven@umich.edu.
authors.forename: Hae-Ryung
authors.initials: HR
authors.lastname: Park
authors.affiliation: Department of Environmental Health Sciences, University of Michigan, 1415 Washington Heights, Ann Arbor, MI 48109-2029, USA.
authors.forename: Rita
authors.initials: R
authors.lastname: Loch-Caruso
mesh_terms: D002460:Cell Line; D016207:Cytokines / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005411:Flame Retardants / Q000633:toxicity; D055768:Halogenated Diphenyl Ethers / Q000633:toxicity*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D011247:Pregnancy; D011261:Pregnancy Trimester, First / Q000187:drug effects / Q000378:metabolism*; D020011:Protective Agents / Q000378:metabolism; D014327:Trophoblasts / Q000187:drug effects / Q000378:metabolism*
chemical_list: D016207:Cytokines; D005411:Flame Retardants; D055768:Halogenated Diphenyl Ethers; D018836:Inflammation Mediators; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D020011:Protective Agents; C511295:2,2',4,4'-tetrabromodiphenyl ether
keywords: Antioxidant response; Cytokines; HTR-8/SVneo cells; Human placental cells; Nuclear factor E2-related factor 2 (Nrf2); Polybrominated diphenyl ethers (PBDEs)