Khalil Ahmed, Parker Mikhail, Mpanga Richard, Cevik Sebnem E, Thorburn Cassandra, Suvorov Alexander
Department of Environmental Health Sciences, School of Public Health and Health Sciences, University of Massachusetts Amherst, Amherst, Massachusetts 01003.
Medical Biotechnology Department, Genetic Engineering and Biotechnology Research Institute, City of Scientific Research and Technological Applications, Alexandria 21934, Egypt.
J Endocr Soc. 2017 Mar 14;1(4):323-344. doi: 10.1210/js.2016-1011. eCollection 2017 Apr 1.
Polybrominated diphenyl ethers (PBDEs) were used as flame-retardant additives in a wide range of polymers. The generations born when environmental concentrations of PBDEs reached their maximum account in the United States for one-fifth of the total population. We hypothesized that exposure to PBDEs during sensitive developmental windows might result in long-lasting changes in liver metabolism. The present study was based on experiments with CD-1 mice and human hepatocellular carcinoma cells (human hepatoma cell line, HepG2). Pregnant mice were exposed to 0.2 mg/kg 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) from gestation day 8 until postnatal day 21. The metabolic health-related outcomes were analyzed on postnatal day 21 and postnatal week 20 in male offspring. Several groups of metabolic genes, including ribosomal and mitochondrial genes, were significantly upregulated in the liver at both points. Genes regulated via mechanistic target of rapamycin (mTOR) pathway, the gatekeeper of metabolic homeostasis, were whether up- or downregulated at both measurement points. On postnatal day 21, but not week 20, both mTOR complexes in the liver were activated, as measured by phosphorylation of their targets. mTOR complexes were also activated by BDE-47 in HepG2 cells . The following changes were observed at week 20: a decreased number of polyploid hepatocytes, suppressed cytoplasmic S6K1, twofold greater blood insulin-like growth factor-1 and triglycerides, and 2.5-fold lower expression of fatty acid uptake membrane receptor CD36 in liver tissue. Thus, perinatal exposure to environmentally relevant doses of BDE-47 in laboratory mice results in long-lasting changes in liver physiology. Our evidence suggests involvement of the mTOR pathway in the observed metabolic programming of the liver.
多溴二苯醚（PBDEs）曾作为阻燃添加剂被广泛应用于各类聚合物中。在美国，PBDEs环境浓度达到峰值时出生的人群占总人口的五分之一。我们推测，在敏感发育窗口期接触PBDEs可能会导致肝脏代谢发生持久变化。本研究基于对CD - 1小鼠和人肝癌细胞（人肝癌细胞系HepG2）的实验。怀孕小鼠从妊娠第8天至出生后第21天暴露于0.2 mg/kg的2,2',4,4'-四溴二苯醚（BDE - 47）。在出生后第21天和出生后第20周对雄性后代的代谢健康相关指标进行分析。包括核糖体和线粒体基因在内的几组代谢基因在这两个时间点的肝脏中均显著上调。通过雷帕霉素作用机制靶点（mTOR）途径调控的基因，即代谢稳态的守门人，在两个测量点均有上调或下调。在出生后第21天，而非第20周，肝脏中的两种mTOR复合物被激活，这通过其靶点的磷酸化来衡量。在HepG2细胞中，BDE - 47也激活了mTOR复合物。在第20周观察到以下变化：多倍体肝细胞数量减少、细胞质S6K1受抑制、血液中胰岛素样生长因子-1和甘油三酯增加两倍，以及肝脏组织中脂肪酸摄取膜受体CD36的表达降低2.5倍。因此，围产期在实验室小鼠中暴露于环境相关剂量的BDE - 47会导致肝脏生理发生持久变化。我们的证据表明mTOR途径参与了所观察到的肝脏代谢编程。
