内分泌干扰物对机体脂质代谢的影响及其机制研究进展
Research Progress on Effects of Endocrine Disrupting Chemicals on Lipid Metabolism of Organisms and Underlying Mechanisms
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摘要: 近年来许多动物实验研究表明，内分泌干扰物（endocrine disrupting chemicals，EDCs）暴露除了会损伤生殖、免疫和神经系统等，还能够干扰脂质代谢，增加肥胖、非酒精性脂肪肝和高脂血症等疾病的发病风险。笔者总结了多种EDCs对不同动物模型（哺乳动物、硬骨鱼类、两栖动物）脂质代谢的影响，主要包括促进哺乳动物脂肪细胞分化、脂质蓄积和促进肥胖的表观遗传跨代继承，促进硬骨鱼类脂肪从头合成和脂质蓄积，破坏两栖动物的脂质平衡；并从4个方面综述了EDCs影响脂质代谢的作用机制，包括（1）影响转录因子的表达，从而影响脂质代谢相关酶和蛋白的表达水平；（2）影响调控昼夜节律的时钟基因的活性继而诱导脂质蓄积；（3）影响内源性大麻素和大麻素受体的表达从而改变瘦素或脂肪肝信号神经肽Y的表达；（4）影响表观遗传修饰继而影响脂质代谢相关酶、转录因子和脂肪细胞因子的表达。最后，提出今后研究需关注新型EDCs对脂质代谢的影响，同时应深入研究昼夜节律、内源性大麻素系统和表观遗传修饰等不同途径之间的交叉作用，以更好地了解EDCs通过以上机制影响脂质代谢的过程。Abstract: Recent studies on animal experiments have shown that exposure of endocrine disrupting chemicals (EDCs), in addition to damaging reproductive, immune, and nervous systems, can also interfere with lipid metabolism of organisms and increase the risk of diseases such as obesity, non-alcoholic fatty liver, and hyperlipidemia. This article summarized the effects of various EDCs on lipid metabolism in different animal models. In mammals, EDCs were reported to mainly promote adipocyte differentiation, lipid accumulation and epigenetic transgenerational inheritance of obesity. In teleosts, EDCs were found to promote de novo synthesis and lipid accumulation. In amphibians, EDCs were reported to be able to destroy the balance of lipid metabolism. Moreover, it is reported that EDCs produce the above adverse effects by:(1) affecting expressions of transcription factors and thus interfering with the expression levels of lipid metabolism related enzymes and proteins, (2) disturbing activities of clock genes that regulate circadian rhythm and as such to induce lipid accumulation, (3) changing the expression levels of endogenous cannabinoids and cannabinoid receptors to alter expression levels of leptin or fatty liver signaling neuropeptide Y, and (4) changing epigenetic modifications and then influencing expressions of lipid metabolism related enzymes, transcription factors, and adipokines. In addition, this article proposed that more attention should be paid to the adverse effects produced by new EDCs on animal lipid metabolism, and the interaction between different pathways of circadian rhythm, endocannabinoid system, and epigenetic modifications on lipid metabolism should be further studied, to deepen the understanding towards the mechanisms of EDCs interference on lipid metabolism.
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Diamanti-Kandarakis E, Bourguignon J P, Giudice L C, et al. Endocrine-disrupting chemicals:An Endocrine Society scientific statement[J]. Endocrine Reviews, 2009, 30(4):293-342 李文梅, 俞捷, 杨静, 等. 肥胖与环境内分泌干扰物暴露的关系及机制[J]. 重庆医学, 2017, 46(24):3425-3427 Dongiovanni P, Valenti L. Genetics of nonalcoholic fatty liver disease[J]. Metabolism:Clinical and Experimental, 2016, 65(8):1026-1037 Bastos Sales L, Kamstra J H, Cenijn P H, et al. Effects of endocrine disrupting chemicals on in vitro global DNA methylation and adipocyte differentiation[J]. Toxicology in Vitro, 2013, 27(6):1634-1643 Grün F, Watanabe H, Zamanian Z, et al. Endocrine-disrupting organotin compounds are potent inducers of adipogenesis in vertebrates[J]. Molecular Endocrinology, 2006, 20(9):2141-2155 Chamorro-García R, Shoucri B M, Willner S, et al. Effects of perinatal exposure to dibutyltin chloride on fat and glucose metabolism in mice, and molecular mechanisms, in vitro[J]. Environmental Health Perspectives, 2018, 126(5):057006 Kanayama T, Kobayashi N, Mamiya S, et al. Organotin compounds promote adipocyte differentiation as agonists of the peroxisome proliferator-activated receptor gamma/retinoid X receptor pathway[J]. Molecular Pharmacology, 2005, 67(3):766-774 Ariemma F, D'Esposito V, Liguoro D, et al. Low-dose bisphenol-A impairs adipogenesis and generates dysfunctional 3T3-L1 adipocytes[J]. PLoS One, 2016, 11(3):e0150762 Kamstra J H, Hruba E, Blumberg B, et al. Transcriptional and epigenetic mechanisms underlying enhanced in vitro adipocyte differentiation by the brominated flame retardant BDE-47[J]. Environmental Science & Technology, 2014, 48(7):4110-4119 Inadera H, Shimomura A. Environmental chemical tributyltin augments adipocyte differentiation[J]. Toxicology Letters, 2005, 159(3):226-234 Bertuloso B D, Podratz P L, Merlo E, et al. Tributyltin chloride leads to adiposity and impairs metabolic functions in the rat liver and pancreas[J]. Toxicology Letters, 2015, 235(1):45-59 Yan Z H, Zhang H J, Maher C, et al. Prenatal polycyclic aromatic hydrocarbon, adiposity, peroxisome proliferator-activated receptor (PPAR) γ methylation in offspring, grand-offspring mice[J]. PLoS One, 2014, 9(10):e110706 Zhang W, Shen X Y, Zhang W W, et al. The effects of di 2-ethyl hexyl phthalate (DEHP) on cellular lipid accumulation in HepG2 cells and its potential mechanisms in the molecular level[J]. Toxicology Mechanisms and Methods, 2017, 27(4):245-252 Brulport A, Le Corre L, Chagnon M C. Chronic exposure of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces an obesogenic effect in C57BL/6J mice fed a high fat diet[J]. Toxicology, 2017, 390:43-52 Martella A, Silvestri C, Maradonna F, et al. Bisphenol A induces fatty liver by an endocannabinoid-mediated positive feedback loop[J]. Endocrinology, 2016, 157(5):1751-1763 Wang C, Yue S Q, Hao Z L, et al. Pubertal exposure to the endocrine disruptor mono-2-ethylhexyl ester at body burden level caused cholesterol imbalance in mice[J]. Environmental Pollution, 2019, 244:657-666 Hao Z L, Zhang Z J, Lu D Z, et al. Organophosphorus flame retardants impair intracellular lipid metabolic function in human hepatocellular cells[J]. Chemical Research in Toxicology, 2019, 32(6):1250-1258 Yu J, Yang X S, Yang X F, et al. Nonylphenol aggravates non-alcoholic fatty liver disease in high sucrose-high fat diet-treated rats[J]. Scientific Reports, 2018, 8(1):3232 Skinner M K, Manikkam M, Tracey R, et al. Ancestral dichlorodiphenyltrichloroethane (DDT) exposure promotes epigenetic transgenerational inheritance of obesity[J]. BMC Medicine, 2013, 11:228 Manikkam M, Haque M M, Guerrero-Bosagna C, et al. Pesticide methoxychlor promotes the epigenetic transgenerational inheritance of adult-onset disease through the female germline[J]. PLoS One, 2014, 9(7):e102091 Manikkam M, Tracey R, Guerrero-Bosagna C, et al. Plastics derived endocrine disruptors (BPA, DEHP and DBP) induce epigenetic transgenerational inheritance of obesity, reproductive disease and sperm epimutations[J]. PLoS One, 2013, 8(1):e55387 Lyssimachou A, Santos J G, André A, et al. The mammalian "obesogen" tributyltin targets hepatic triglyceride accumulation and the transcriptional regulation of lipid metabolism in the liver and brain of zebrafish[J]. PLoS One, 2015, 10(12):e0143911 Migliarini B, Piccinetti C C, Martella A, et al. Perspectives on endocrine disruptor effects on metabolic sensors[J]. General and Comparative Endocrinology, 2011, 170(3):416-423 Santangeli S, Notarstefano V, Maradonna F, et al. Effects of diethylene glycol dibenzoate and bisphenol A on the lipid metabolism of Danio rerio[J]. Science of the Total Environment, 2018, 636:641-655 Forner-Piquer I, Mylonas C C, Calduch-Giner J, et al. Endocrine disruptors in the diet of male Sparus aurata:Modulation of the endocannabinoid system at the hepatic and central level by di-isononyl phthalate and bisphenol A[J]. Environment International, 2018, 119:54-65 Lutfi E, Riera-Heredia N, Córdoba M, et al. Tributyltin and triphenyltin exposure promotes in vitro adipogenic differentiation but alters the adipocyte phenotype in rainbow trout[J]. Aquatic Toxicology, 2017, 188:148-158 Fong H C H, Ho J C H, Cheung A H Y, et al. Developmental toxicity of the common UV filter, benophenone-2, in zebrafish embryos[J]. Chemosphere, 2016, 164:413-420 Wang W W, Zhang X N, Qin J Y, et al. Long-term bisphenol S exposure induces fat accumulation in liver of adult male zebrafish (Danio rerio) and slows yolk lipid consumption in F1 offspring[J]. Chemosphere, 2019, 221:500-510 Forner-Piquer I, Santangeli S, Maradonna F, et al. Role of bisphenol A on the endocannabinoid system at central and peripheral levels:Effects on adult female zebrafish[J]. Chemosphere, 2018, 205:118-125 Forner-Piquer I, Maradonna F, Gioacchini G, et al. Dose-specific effects of di-isononyl phthalate on the endocannabinoid system and on liver of female zebrafish[J]. Endocrinology, 2017, 158(10):3462-3476 Lin J B, Wang C H, Liu J F, et al. Up-stream mechanisms for up-regulation of miR-125b from triclosan exposure to zebrafish (Danio rerio)[J]. Aquatic Toxicology, 2017, 193:256-267 Traversi I, Gioacchini G, Scorolli A, et al. Alkylphenolic contaminants in the diet:Sparus aurata juveniles hepatic response[J]. General and Comparative Endocrinology, 2014, 205:185-196 Maradonna F, Nozzi V, Dalla Valle L, et al. A developmental hepatotoxicity study of dietary bisphenol A in Sparus aurata juveniles[J]. Comparative Biochemistry and Physiology Toxicology & Pharmacology:CBP, 2014, 166:1-13 Maradonna F, Nozzi V, Santangeli S, et al. Xenobiotic-contaminated diets affect hepatic lipid metabolism:Implications for liver steatosis in Sparus aurata juveniles[J]. Aquatic Toxicology, 2015, 167:257-264 Kim B M, Jo Y J, Lee N, et al. Bisphenol A induces a distinct transcriptome profile in the male fish of the marine medaka Oryzias javanicus[J]. BioChip Journal, 2018, 12(1):25-37 Carnevali O, Notarstefano V, Olivotto I, et al. Dietary administration of EDC mixtures:A focus on fish lipid metabolism[J]. Aquatic Toxicology, 2017, 185:95-104 Huff M, da Silveira W A, Carnevali O, et al. Systems analysis of the liver transcriptome in adult male zebrafish exposed to the plasticizer (2-ethylhexyl) phthalate (DEHP)[J]. Scientific Reports, 2018, 8(1):2118 Qin J Y, Ru S G, Wang W W, et al. Long-term bisphenol S exposure aggravates non-alcoholic fatty liver by regulating lipid metabolism and inducing endoplasmic reticulum stress response with activation of unfolded protein response in male zebrafish[J]. Environmental Pollution, 2020, 263:114535 Sun L M, Ling Y H, Jiang J H, et al. Differential mechanisms regarding triclosan vs. bisphenol A and fluorene-9-bisphenol induced zebrafish lipid-metabolism disorders by RNA-Seq[J]. Chemosphere, 2020, 251:126318 李姣, 胡群, 罗佩, 等. 肝脏脂质代谢关键转录因子研究进展[J]. 动物医学进展, 2016, 37(4):90-93 Li J, Hu Q, Luo P, et al. Progress on key transcription factors in liver lipid metabolism[J]. Progress in Veterinary Medicine, 2016, 37(4):90-93(in Chinese)
Rosen E D, MacDougald O A. Adipocyte differentiation from the inside out[J]. Nature Reviews Molecular Cell Biology, 2006, 7(12):885-896 Tzameli I, Fang H, Ollero M, et al. Regulated production of a peroxisome proliferator-activated receptor-γ ligand during an early phase of adipocyte differentiation in 3T3-L1 adipocytes[J]. Journal of Biological Chemistry, 2004, 279(34):36093-36102 Perez-Diaz S, Johnson L A, DeKroon R M, et al. Polymerase I and transcript release factor (PTRF) regulates adipocyte differentiation and determines adipose tissue expandability[J]. FASEB Journal, 2014, 28(8):3769-3779 Matsushita K, Morello F, Zhang Z P, et al. Nuclear hormone receptor LXRα inhibits adipocyte differentiation of mesenchymal stem cells with Wnt/beta-catenin signaling[J]. Laboratory Investigation, 2016, 96(2):230-238 Manteiga S, Lee K. Monoethylhexyl phthalate elicits an inflammatory response in adipocytes characterized by alterations in lipid and cytokine pathways[J]. Environmental Health Perspectives, 2017, 125(4):615-622 Chen H, Zhang W, Rui B B, et al. Di(2-ethylhexyl) phthalate exacerbates non-alcoholic fatty liver in rats and its potential mechanisms[J]. Environmental Toxicology and Pharmacology, 2016, 42:38-44 Zhang H Y, Xue W Y, Li Y Y, et al. Perinatal exposure to 4-nonylphenol affects adipogenesis in first and second generation rats offspring[J]. Toxicology Letters, 2014, 225(2):325-332 Jin Y X, Lin X J, Miao W, et al. Oral exposure of pubertal male mice to endocrine-disrupting chemicals alters fat metabolism in adult livers[J]. Environmental Toxicology, 2015, 30(12):1434-1444 Cocci P, Mosconi G, Arukwe A, et al. Effects of diisodecyl phthalate on PPAR:RXR-dependent gene expression pathways in sea bream hepatocytes[J]. Chemical Research in Toxicology, 2015, 28(5):935-947 唐春奇, 刘畅. 生物时钟与脂肪组织代谢整合机制研究进展[J]. 生命科学, 2015, 27(11):1418-1426 Tang C Q, Liu C. Advances on the relationship between the circadian clock and metabolism in adipose tissue[J]. Chinese Bulletin of Life Sciences, 2015, 27(11):1418-1426(in Chinese)
Sato F, Kohsaka A, Bhawal U K, et al. Potential roles of dec and Bmal1 genes in interconnecting circadian clock and energy metabolism[J]. International Journal of Molecular Sciences, 2018, 19(3):E781 Oishi K, Shirai H, Ishida N. CLOCK is involved in the circadian transactivation of peroxisome-proliferator-activated receptor alpha (PPARalpha) in mice[J]. The Biochemical Journal, 2005, 386(Pt 3):575-581 Chen L H, Yang G R. PPARs integrate the mammalian clock and energy metabolism[J]. PPAR Research, 2014, 2014:653017 Grimaldi B, Bellet M M, Katada S, et al. PER2 controls lipid metabolism by direct regulation of PPARγ[J]. Cell Metabolism, 2010, 12(5):509-520 Weger M, Weger B D, Diotel N, et al. Real-time in vivo monitoring of circadian E-box enhancer activity:A robust and sensitive zebrafish reporter line for developmental, chemical and neural biology of the circadian clock[J]. Developmental Biology, 2013, 380(2):259-273 杨钦, 田倩倩, 王茹. 内源性大麻素系统在运动减控体重中的作用机制研究[J]. 中国运动医学杂志, 2017, 36(2):169-175 Pagano C, Rossato M, Vettor R. Endocannabinoids, adipose tissue and lipid metabolism[J]. Journal of Neuroendocrinology, 2008, 20(Suppl 1):124-129 Matias I, Gonthier M P, Orlando P, et al. Regulation, function, and dysregulation of endocannabinoids in models of adipose and beta-pancreatic cells and in obesity and hyperglycemia[J]. The Journal of Clinical Endocrinology and Metabolism, 2006, 91(8):3171-3180 O'Sullivan S E. Cannabinoids go nuclear:Evidence for activation of peroxisome proliferator-activated receptors[J]. British Journal of Pharmacology, 2007, 152(5):576-582 张林, 胡茂清. 表观遗传和肥胖[J]. 中国糖尿病杂志, 2013, 21(4):376-378 Zhang L, Hu M Q. Epigenetics and obesity[J]. Chinese Journal of Diabetes, 2013, 21(4):376-378(in Chinese)
赵飞. 双酚A对斑马鱼(Danio rerio)雌激素效应的DNA甲基化机制研究[D]. 青岛:中国海洋大学, 2015:9-13 Zhao F. The DNA methylation mechanism underlying the estrogenic effects of bisphenol A on zebrafish (Danio rerio)[D]. Qingdao:Ocean University of China, 2015:9 -13(in Chinese)
Fujiki K, Kano F, Shiota K, et al. Expression of the peroxisome proliferator activated receptor gamma gene is repressed by DNA methylation in visceral adipose tissue of mouse models of diabetes[J]. BMC Biology, 2009, 7:38 Melzner I, Scott V, Dorsch K, et al. Leptin gene expression in human preadipocytes is switched on by maturation-induced demethylation of distinct CpGs in its proximal promoter[J]. The Journal of Biological Chemistry, 2002, 277(47):45420-45427 Noer A, Sørensen A L, Boquest A C, et al. Stable CpG hypomethylation of adipogenic promoters in freshly isolated, cultured, and differentiated mesenchymal stem cells from adipose tissue[J]. Molecular Biology of the Cell, 2006, 17(8):3543-3556 Wang L F, Jin Q H, Lee J E, et al. Histone H3K27 methyltransferase Ezh2 represses Wnt genes to facilitate adipogenesis[J]. PNAS, 2010, 107(16):7317-7322 Strelow J M, Xiao M, Cavitt R N, et al. The use of nucleosome substrates improves binding of SAM analogs to SETD8[J]. Journal of Biomolecular Screening, 2016, 21(8):786-794 Tateishi K, Okada Y, Kallin E M, et al. Role of Jhdm2a in regulating metabolic gene expression and obesity resistance[J]. Nature, 2009, 458(7239):757-761 Lee K H, Ju U I, Song J Y, et al. The histone demethylase PHF2 promotes fat cell differentiation as an epigenetic activator of both C/EBPα and C/EBPδ[J]. Molecules and Cells, 2014, 37(10):734-741 Miremadi A, Oestergaard M Z, Pharoah P D P, et al. Cancer genetics of epigenetic genes[J]. Human Molecular Genetics, 2007, 16(1):R28-R49 Ferrari A, Fiorino E, Giudici M, et al. Linking epigenetics to lipid metabolism:Focus on histone deacetylases[J]. Molecular Membrane Biology, 2012, 29(7):257-266 Feng D, Liu T, Sun Z, et al. A circadian rhythm orchestrated by histone deacetylase 3 controls hepatic lipid metabolism[J]. Science, 2011, 331(6022):1315-1319 朱磊, 路瑛丽, 冯连世, 等. microRNA调节脂代谢的研究进展[J]. 中国体育科技, 2016, 52(3):61-68 Zhu L, Lu Y L, Feng L S, et al. Research advancement of miRNA regulation effect on lipid metabolism[J]. China Sport Science and Technology, 2016, 52(3):61-68(in Chinese)
Yueh M F, Tukey R H. Triclosan:A widespread environmental toxicant with many biological effects[J]. Annual Review of Pharmacology and Toxicology, 2016, 56:251-272 Cocci P, Mosconi G, Palermo F A. Changes in expression of microRNA potentially targeting key regulators of lipid metabolism in primary gilthead sea bream hepatocytes exposed to phthalates or flame retardants[J]. Aquatic Toxicology, 2019, 209:81-90 Choi E M, Suh K S, Park S Y, et al. Orientin reduces the inhibitory effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on adipogenic differentiation and insulin signaling pathway in murine 3T3-L1 adipocytes[J]. Chemico-Biological Interactions, 2020, 318:108978 Kim J, Sun Q C, Yue Y R, et al. 4,4'-dichlorodiphenyltrichloroethane (DDT) and 4, 4'-dichlorodiphenyldichloroethylene (DDE) promote adipogenesis in 3T3-L1 adipocyte cell culture[J]. Pesticide Biochemistry and Physiology, 2016, 131:40-45 Zhang L Y, Sun W J, Duan X Y, et al. Promoting differentiation and lipid metabolism are the primary effects for DINP exposure on 3T3-L1 preadipocytes[J]. Environmental Pollution, 2019, 255(Pt 1):113154 Wang Y X, Zhang J L, Pan M Q. Tributyltin targets hepatic transcriptional regulation of lipid metabolism in mice[J]. Toxicological & Environmental Chemistry, 2017, 99(3):492-504 Podratz P L, Merlo E, de Araújo J F P, et al. Disruption of fertility, placenta, pregnancy outcome, and multigenerational inheritance of hepatic steatosis by organotin exposure from contaminated seafood in rats[J]. Science of the Total Environment, 2020, 723:138000 Zhang Y Z, Zhang Z M, Zhou L T, et al. Di (2-ethylhexyl) phthalate disorders lipid metabolism via TYK2/STAT1 and autophagy in rats[J]. Biomedical and Environmental Sciences, 2019, 32(6):406-418 Baralić K, Buha Djordjevic A, Živančević K, et al. Toxic effects of the mixture of phthalates and bisphenol A-subacute oral toxicity study in Wistar rats[J]. International Journal of Environmental Research and Public Health, 2020, 17(3):E746 Shu L, Meng Q Y, Diamante G, et al. Prenatal bisphenol A exposure in mice induces multitissue multiomics disruptions linking to cardiometabolic disorders[J]. Endocrinology, 2019, 160(2):409-429 Li Y N, Zhang Q N, Fang J, et al. Hepatotoxicity study of combined exposure of DEHP and ethanol:A comprehensive analysis of transcriptomics and metabolomics[J]. Food and Chemical Toxicology, 2020, 141:111370 Doskey C M, Fader K A, Nault R, et al. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) alters hepatic polyunsaturated fatty acid metabolism and eicosanoid biosynthesis in female Sprague-Dawley rats[J]. Toxicology and Applied Pharmacology, 2020, 398:115034 Faheem M, Lone K P. Oxidative stress and histopathologic biomarkers of exposure to bisphenol-A in the freshwater fish, Ctenopharyngodon idella[J]. Brazilian Journal of Pharmaceutical Sciences, 2018, 53(3):DOI:10.1590/s2175-97902017000317003 Guan Y J, Gao J C, Zhang Y Y, et al. Effects of bisphenol A on lipid metabolism in rare minnow Gobiocypris rarus[J]. Comparative Biochemistry and Physiology Toxicology & Pharmacology:CBP, 2016, 179:144-149 Zhang J L, Zhang C N, Ma D D, et al. Lipid accumulation, oxidative stress and immune-related molecules affected by tributyltin exposure in muscle tissues of rare minnow (Gobiocypris rarus)[J]. Fish & Shellfish Immunology, 2017, 71:10-18 华江环, 史奇朋, 郭威, 等. 左炔诺孕酮对稀有鮈鲫脂质代谢的干扰效应[J]. 中国环境科学, 2020, 40(3):1345-1355 Hua J H, Shi Q P, Guo W, et al. Disrupting effects of levonorgestrel on lipid metabolism in Chinese rare minnow[J]. China Environmental Science, 2020, 40(3):1345-1355(in Chinese)
张林宝, 胡莹, 陈海刚, 等. 邻苯二甲酸二(2-乙基己基)酯对罗非鱼肝脏转录组影响研究[J]. 中国环境科学, 2019, 39(1):386-396 Zhang L B, Hu Y, Chen H G, et al. Transcriptome analysis in the liver of Nile tilapia(Oreochromis niloticus) after treated with di(2-ethylhexyl) phthalate[J]. China Environmental Science, 2019, 39(1):386-396(in Chinese)
Wang W W, Zhang X N, Wang Z H, et al. Bisphenol S induces obesogenic effects through deregulating lipid metabolism in zebrafish (Danio rerio) larvae[J]. Chemosphere, 2018, 199:286-296 Zhang J L, Sun P, Kong T, et al. Tributyltin promoted hepatic steatosis in zebrafish (Danio rerio) and the molecular pathogenesis involved[J]. Aquatic Toxicology, 2016, 170:208-215 -
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