title: Hexabromocyclododecane exposure induces cardiac hypertrophy and arrhythmia by inhibiting miR-1 expression via up-regulation of the homeobox gene Nkx2.5.
abstract: Hexabromocyclododecane (HBCD) is one of the most widely used brominated flame retardants. Although studies have reported that HBCD can cause a wide range of toxic effects on animals including humans, limited information can be found about its cardiac toxicity. In the present study, zebrafish embryos were exposed to HBCD at low concentrations of 0, 2, 20 and 200 nM. The results showed that HBCD exposure could induce cardiac hypertrophy and increased deposition of collagen. In addition, disordered calcium (Ca(2+)) handling was observed in H9C2 rat cardiomyocyte cells exposed to HBCD. Using small RNA sequencing and real-time quantitative PCR, HBCD exposure was shown to induce significant changes in the miRNA expression profile associated with the cardiovascular system. Further findings indicated that miR-1, which was depressed by Nkx2.5, might play a fundamental role in mediating cardiac hypertrophy and arrhythmia via its target genes Mef2a and Irx5 after HBCD treatment. HBCD exposure induced an arrhythmogenic disorder, which was triggered by the imbalance of Ryr2, Serca2a and Ncx1 expression, inducing Ca(2+) overload in the sarcoplasmic reticulum and high Ca(2+)-ATPase activities in the H9C2 cells.
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China.
authors.forename: Meifang
authors.initials: M
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China.
authors.forename: Di
authors.initials: D
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China; State Key Laboratory of Marine Environmental Science, Xiamen University, Xiamen, Fujian 361005, China.
authors.forename: Chonggang
authors.initials: C
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China.
authors.forename: Zhizhun
authors.initials: Z
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Marine Environmental Science, Xiamen University, Xiamen, Fujian 361005, China.
authors.forename: Bowen
authors.initials: B
authors.lastname: Li
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China; State Key Laboratory of Marine Environmental Science, Xiamen University, Xiamen, Fujian 361005, China. Electronic address: zuozhenghong@xmu.edu.cn.
authors.forename: Zhenghong
authors.initials: Z
authors.lastname: Zuo
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced*; D006332:Cardiomegaly / Q000139:chemically induced*; D006321:Heart / Q000187:drug effects*; D006842:Hydrocarbons, Brominated / Q000633:toxicity*; D035683:MicroRNAs / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D015027:Zebrafish
chemical_list: D006842:Hydrocarbons, Brominated; D035683:MicroRNAs; C000589536:Mirn1 microRNA, zebrafish; C089796:hexabromocyclododecane
keywords: Arrhythmia; Cardiac hypertrophy; HBCD; Nkx2.5; miR-1