Disturbance of the Dlk1-Dio3 imprinted domain may underlie placental Dio3 suppression and extracellular thyroid hormone disturbance in placenta-derived JEG-3 cells following decabromodiphenyl ether (BDE209) exposure. (30th June 2021)

• Record Type: Journal Article
• Authors: Qin, Chang; Cheng, Ying; Shang, Xiaona; Wang, Ruijun; Wang, Ruonan; Hao, Xiaoji; Li, Sisi; Wang, Ye; Li, Yachen; Liu, Xiaohui; Shao, Jing
• Is Part Of: Toxicology. Volume 458(2021)
• Publication Date: 2021-06-30
• Subjects: BDE209 decabromodiphenyl ether -- PBDEs polybrominated diphenyl ethers -- POPs persistent organic pollutants -- TH thyroid hormone -- T4 tetraiodothyronine -- T3 triiodothyronine -- TSH thyroid stimulating hormone -- Dio3 type III iodothyronine deiodinase -- Dlk1 delta-like homolog 1 -- miRNA short endogenous noncoding RNAs (microRNA) -- DMRs differentially methylated regions -- IG-DMR intergenic differential methylation region -- MEG3-DMR maternally expressed gene 3 promotor differential methylation region -- CGI CpG island -- JEG-3 human choriocarcinoma-derived cells -- RT-qPCR quantitative real-time polymerase chain reaction -- DMSO dimethyl sulfoxide -- MTT 3-4, 5-dimethylthiazole-2-yl)-2, 5-diphenyltetrazolium bromide -- 5-Aza 5-Azaine-2'-deoxycytidine -- HPT axis hypothalamus-pituitary-thyroid axis -- TRH thyrotropin-releasing hormone; Decabromodiphenyl ether (BDE209) -- Placenta-derived cells -- Type III iodothyronine deiodinase (Dio3) -- Dlk1-Dio3 imprinted domain -- MicroRNAs (miRNAs) -- Differentially methylated regions (DMRs); Toxicology -- Periodicals; Chemicals -- Physiological effect -- Periodicals; 615.9005
• DOI: 10.1016/j.tox.2021.152837
• Languages: English
• ISSNs: 0300-483X

Abstract

Highlights: BDE209 down-regulated placental Dio3 and interfered extracellular TH in JEG-3 cells. BDE209 suppressed miRNAs in the miR379/656 cluster of the DLk1-Dio3 in JEG-3 cells. BDE209 changed DNA methylation imprints at the paternal IG-DMR and MEG3-DMR in JEG-3 cells. Demethylation of genomic DNA offset BDE209-mediated Dio3 disruption in JEG-3 cells. Abstract: Decabromodiphenyl ether (BDE209) has been widely used as a flame retardant in the past four decades, leading to human health consequences, especially neurological impairments. Our previous in vivo studies have suggested that developmental neurotoxicity in offspring may be the result of BDE209-induced placental type III iodothyronine deiodinase (Dio3) disturbance and consequent thyroid hormone (TH) instability. Dio3 is paternally imprinted gene, and its balanced expression is crucial in directing normal development and growth. In this study, we used placenta-derived cells to investigate how BDE209 affected Dio3 expression through interfering imprinting mechanisms in the delta-like homolog 1 (Dlk1)-Dio3 imprinted region. Gene chip analysis and RT-qPCR identified miR409-3p, miR410-5p, miR494-3p, miR668-3p and miR889-5p as potential candidates involved in Dio3 deregulation. The sodium bisulfite-clonal sequencing revealed the BDE209 affect methylation status of two differentially methylated regions (DMRs), intergenic-DMR (IG-DMR) and maternally expressed gene 3-DMR (MEG3-DMR). Our data indicate that placental Dio3 may be a potential molecular target for future study of BDE209 developmental toxicity. In particular, miRNAs, IG-DMR and MEG3-DMR in the Dlk1-Dio3 imprinted locus may be informative in directing studies in TH disturbance and developmental toxicity induced by in utero exposure to environmental persistent organic pollutants (POPs), and those candidate miRNAs may prove to be convenient and noninvasive biomarkers for future large-scale population studies.