Effects of novel brominated flame retardant TBPH and its metabolite TBMEHP on human vascular endothelial cells: Implication for human health risks.
As a replacement for polybrominated diphenyl ethers, bis-(2-ethylhexyl) tetrabromophthalate (TBPH) is widely used as a novel flame retardant and has been detected in many environmental matrix including human blood. TBPH can be metabolized into mono-(2-ethyhexyl) tetrabromophthalate (TBMEHP) by carboxylesterase. However, their adverse effects on human vascular endothelium and their potential impacts on human cardiovascular disease are unknown. In this study, their adverse effects and associated molecular mechanisms on human vascular endothelial cells (HUVECs) were investigated. A concentration-dependent inhibition on HUVECs' viability and growth was observed for TBMEHP but not for TBPH. TBMEHP induced a marked G0/G1cell cycle arrest and robust cell apoptosis at 1μg/mL by inducing expression of p53, GADD45α and cyclin dependent kinase (CDK) inhibitors (p21and p27) while suppressing the expression of cyclin D1, CDK2, CDK6, and Bcl-2. Unlike TBMEHP, TBPH caused early apoptosis after G2/M phase arrest only at 10μg/mL via up-regulation of p21 and down-regulation of CDK2 and CDK4. TBMEHP decreased mitochondrial membrane potential and increased caspase-3 activity at 1μg/mL, suggesting that activation of p53 and mitochondrial pathway were involved in the cell apoptosis. The data showed that TBPH and TBMEHP induced different cell cycle arrest and apoptosis through different molecular mechanisms with much higher toxicity for TBMEHP. Our study implies that the metabolites of TBPH, possibly other novel brominated flame retardants, may be of potential concern for human cardiovascular disease.
State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing 210046, People's Republic of China.
Ping
P
Xiang
State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing 210046, People's Republic of China.
Rong-Yan
RY
Liu
State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing 210046, People's Republic of China.
Hong-Jie
HJ
Sun
The State Key Laboratory of Pharmaceutical Biotechnology, College of Life Science, Nanjing University, Nanjing 210046, People's Republic of China.
Yun-Wen
YW
Yang
State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing 210046, People's Republic of China. Electronic address: lizzycui@nju.edu.cn.
Xin-Yi
XY
Cui
State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing 210046, People's Republic of China; Soil and Water Science Department, University of Florida, Gainesville, FL 32611, United States. Electronic address: lqma@ufl.edu.
Lena Q
LQ
Ma
D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000235:genetics; D002478:Cells, Cultured; D005411:Flame Retardants / Q000633:toxicity*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009687:Nuclear Proteins / Q000235:genetics; D010795:Phthalic Acids / Q000633:toxicity*; D018570:Risk Assessment; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D000097642:GADD45 Proteins
D053148:Caspase 3; D018797:Cell Cycle Proteins; D005411:Flame Retardants; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D010795:Phthalic Acids; D016159:Tumor Suppressor Protein p53; C439070:GADD45A protein, human; D000097642:GADD45 Proteins; C576262:bis(2-ethylhexyl) 2,3,4,5-tetrabromophthalate
Apoptosis; Cardiovascular disease; Cell cycle arrest; Human vascular endothelial cells; Mitochondrial pathway