BPA-induced DNA hypermethylation of the master mitochondrial gene PGC-1α contributes to cardiomyopathy in male rats

被引：44

作者：

Jiang, Ying

Xia, Wei

Yang, Jie

Zhu, Yingshuang

Chang, Huailong

Liu, Juan

Huo, Wenqian

Xu, Bing

Chen, Xi

Li, Yuanyuan ^{[1
]}

Xu, Shunqing ^{[1
]}

机构：

[1] Huazhong Univ Sci & Technol, Tongji Med Coll, Sch Publ Hlth, Key Lab Environm & Hlth,Minist Educ, Wuhan 430030, Peoples R China

来源：

TOXICOLOGY | 2015年 / 329卷

基金：

中国国家自然科学基金; 国家教育部博士点专项基金资助;

关键词：

Bisphenol A; Cardiomyopathy; DNA methylation; Mitochondrial dysfunction; PGC-1; alpha;

D O I：

10.1016/j.tox.2015.01.001

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Implication of environmental endocrine disruptors, such as bisphenol A (BPA), on the development of cardiopathy has been poorly investigated. The aim of the study was to investigate the effects of long-term exposure to BPA at the reference dose on the myocardium of rats, and the underlying mechanisms. Male rats received corn oil or 50 mu g/kg/day of BPA since delactation. At 24 and 48 weeks (wk), cardiac function and mitochondrial function were examined. The mRNA expression and the methylation status of PCG-1 alpha, a major regulator of mitochondrial biogenesis in cardiac muscle, were also tested. At 48 wk, BPA-exposed rats displayed cardiomyopathy, characterized by myocardium hypertrophy, cardiomyocyte enlargement, and impairment of cardiac function. At 24 wk, significantly reduced ATP production, dissipated mitochondrial membrane potential (psi m) and declined mitochondrial respiratory complex (MRC) activity in cardiomyocytes were observed in BPA-exposed rats compared with the control rats, indicating a decrease in mitochondrial function occurs before the development of cardiomyopathy. Additionally, BPA exposure decreased the expression of PGC-1 alpha and induced hypermethylation of PGC-1 alpha a in heart tissue in 24- and 48-week-old rats. The change in methylation of PGC-1 alpha was observed more pronounced in BPA-exposed rats at 48 wk. Overall, long-term BPA exposure induces cardiomyopathy in male rats, and the underling mechanism may involve the impairment of cardiac mitochondrial function and the disturbance of methylation of PGC-1 alpha. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

引用

页码：21 / 31

页数：11

共 73 条

[1]

Aboul Ezz H.S., Khadrawy Y.A., Mourad I.M., The effect of bisphenol A on some oxidative stress parameters and acetylcholinesterase activity in the heart of male albino rats, Cytotechnology, (2013)

[2]

Adami H.O., Berry S.C., Breckenridge C.B., Smith L.L., Swenberg J.A., Trichopoulos D., Weiss N.S., Pastoor T.P., Toxicology and epidemiology: improving the science with a framework for combining toxicological and epidemiological evidence to establish causal inference, Toxicol. Sci., 122, pp. 223-234, (2011)

[3]

Ahuja P., Zhao P., Angelis E., Ruan H., Korge P., Olson A., Wang Y., Jin E.S., Jeffrey F.M., Portman M., Maclellan W.R., Myc controls transcriptional regulation of cardiac metabolism and mitochondrial biogenesis in response to pathological stress in mice, J. Clin. Invest., 120, pp. 1494-1505, (2010)

[4]

Ahuja P., Wanagat J., Wang Z., Wang Y., Liem D.A., Ping P., Antoshechkin I.A., Margulies K.B., Maclellan W.R., Divergent mitochondrial biogenesis responses in human cardiomyopathy, Circulation, 127, pp. 1957-1967, (2013)

[5]

Arany Z., He H., Lin J., Hoyer K., Handschin C., Toka O., Ahmad F., Matsui T., Chin S., Wu P.H., Rybkin I.I., Shelton J.M., Manieri M., Cinti S., Schoen F.J., Bassel-Duby R., Rosenzweig A., Ingwall J.S., Spiegelman B.M., Transcriptional coactivator PGC-1 alpha controls the energy state and contractile function of cardiac muscle, Cell Metab., 1, pp. 259-271, (2005)

[6]

Arany Z., Novikov M., Chin S., Ma Y., Rosenzweig A., Spiegelman B.M., Transverse aortic constriction leads to accelerated heart failure in mice lacking PPAR-gamma coactivator 1alpha, Proc. Natl. Acad. Sci. U. S. A., 103, pp. 10086-10091, (2006)

[7]

Bae S., Kim J.H., Lim Y.H., Park H.Y., Hong Y.C., Associations of bisphenol A exposure with heart rate variability and blood pressure, Hypertension, 60, pp. 786-793, (2012)

[8]

Barres R., Osler M.E., Yan J., Rune A., Fritz T., Caidahl K., Krook A., Zierath J.R., Non-CpG methylation of the PGC-1alpha promoter through DNMT3B controls mitochondrial density, Cell Metab., 10, pp. 189-198, (2009)

[9]

Bayeva M., Gheorghiade M., Ardehali H., Mitochondria as a therapeutic target in heart failure, J. Am. Coll. Cardiol., 61, pp. 599-610, (2013)

[10]

Billia F., Hauck L., Konecny F., Rao V., Shen J., Mak T.W., PTEN-inducible kinase 1 (PINK1)/Park6 is indispensable for normal heart function, Proc. Natl. Acad. Sci. U. S. A., 108, pp. 9572-9577, (2011)

← 1 2 3 4 5 6 7 8 →