title: New insights into cytotoxicity induced by microcystin-LR, estradiol, and ractopamine with mathematical models: Individual and combined effects.
abstract: Humans are most likely to be exposed to microcystins (MCs) combined with other water pollutants rather than to individual compounds through the consumption of contaminated drinking water or through recreational activities, such as swimming. However, the combined effects of MC-LR, estradiol (EST), and ractopamine (RAC) have not been extensively researched. The goal of this study was to investigate the combined effects of these compounds. For this purpose, cytotoxicity was evaluated in HepG2 cells treated with single or combined doses of MC-LR, EST, and RAC based on concentration addition (CA), independent action (IA), and Chou-Talalay's combination-index (CI) methods. Singly applied MC-LR and EST induced HepG2 cellular proliferation at low-concentration levels (1 × 10-12-1 × 10-9M), and decreased viability at higher doses of exposure (1 × 10-9-1 × 10-6M). Exposure to binary or ternary mixtures of MC-LR, EST, and RAC exhibited synergistic effects at high concentrations, irrespective of the models used. In contrast, antagonism was observed for the mixture of MC-LR and EST at relatively low concentrations. A synergistic effect on reactive oxygen species (ROS) generation was observed for the combined drugs at high concentrations. Additionally, the ratio of apoptotic cells was increased more by the combined drugs than the single drugs, consistent with the inhibition of cell viability. The ROS increase after treatment with the combined drugs may enhance cytotoxicity and subsequently lead to cell apoptosis. Given the interactions between MC-LR, EST, and RAC, government regulatory standards for MC-LR should consider the toxicological interactions between MC-LR and other environment pollutions.
authors: State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Synergetic Innovation Center of Food Safety and Quality Control of Jiangsu Province, Jiangnan University, Wuxi, Jiangsu 214122, China.
authors: Min
authors: M
authors: Ma
authors: State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Synergetic Innovation Center of Food Safety and Quality Control of Jiangsu Province, Jiangnan University, Wuxi, Jiangsu 214122, China.
authors: Fuwei
authors: F
authors: Pi
authors: State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Synergetic Innovation Center of Food Safety and Quality Control of Jiangsu Province, Jiangnan University, Wuxi, Jiangsu 214122, China; Department of Environmental Health Science, University of Georgia, Athens, GA 30602, USA.
authors: Jiasheng
authors: J
authors: Wang
authors: State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Synergetic Innovation Center of Food Safety and Quality Control of Jiangsu Province, Jiangnan University, Wuxi, Jiangsu 214122, China.
authors: Jian
authors: J
authors: Ji
authors: State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Synergetic Innovation Center of Food Safety and Quality Control of Jiangsu Province, Jiangnan University, Wuxi, Jiangsu 214122, China. Electronic address: sxlzyz@jiangnan.edu.cn.
authors: Xiulan
authors: X
authors: Sun
mesh_terms: D017304:Annexin A5 / Q000737:chemistry; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D004958:Estradiol / Q000633:toxicity*; D016650:Fluorescein-5-isothiocyanate / Q000737:chemistry; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D008387:Marine Toxins; D052998:Microcystins / Q000633:toxicity*; D008962:Models, Theoretical; D010627:Phenethylamines / Q000633:toxicity*; D017382:Reactive Oxygen Species / Q000737:chemistry; D014873:Water Pollutants / Q000633:toxicity*
chemical_list: D017304:Annexin A5; D008387:Marine Toxins; D052998:Microcystins; D010627:Phenethylamines; D017382:Reactive Oxygen Species; D014873:Water Pollutants; D004958:Estradiol; C060897:ractopamine; C057862:cyanoginosin LR; D016650:Fluorescein-5-isothiocyanate
keywords: Combination index; Combined effect; Concentration addition; Estradiol; Independent addition; Microcystin-LR; Ractopamine