双酚A(BPA)暴露对WHHL家兔糖类和脂类代谢的影响The Effects of Bisphenol A( BPA) Exposure on the Glucose and Lipid Metabolism in WHHL Rabbit
方超;宁博;范江霖;董四君;
摘要(Abstract):
为利用和人类更为接近的动物模型来研究在高脂血症条件下,BPA暴露是否能促进脂类和糖类代谢异常,并探索潜在的毒性效应机制,选取渡边可遗传高脂血症家兔(WHHL)模型,通过灌胃的方式将其暴露于400μg·kg-1体重的BPA溶液长达12周。在持续暴露第8周,检测了在空腹状态下,家兔血浆中葡萄糖、胰岛素和脂肪含量的变化,并根据所得结果进行了静脉注射胰岛素耐受试验(IVTT)。在暴露第12周,同样对空腹状态下,家兔血浆中的葡萄糖,胰岛素和脂肪含量进行了检测,并测量了血压和心率。然后,将所有的家兔进行解剖,通过苏木精-伊红(HE)及糖原(PAS)染色分别对心脏和肝脏部位的脂肪及糖原蓄积情况进行了病理学切片分析。同时,检测了肝脏中与脂类和糖类代谢相关基因在m RNA水平上的表达变化。结果显示,BPA暴露8周后促使WHHL家兔发生了胰岛素抵抗现象,导致第12周血糖及胰岛素含量升高,同时也促进了高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)及游离脂肪酸(NEFA)含量的上升。BPA暴露第12周,暴露组WHHL家兔的冠状动脉粥样硬化损伤程度未发生明显增加,但心肌细胞发生了肿胀,胞质中出现了脂肪的蓄积,同时伴随着心律失常。肝脏重量发生增加,肝细胞中同时出现了脂肪和糖原的蓄积现象,相关基因的表达发生了显著上调。研究结果表明,BPA持续暴露可促进WHHL家兔发生脂类和糖类代谢异常,其毒性效应机制可能和胰岛素抵抗及相关基因的异常表达有关。
关键词(KeyWords): 双酚A(BPA);WHHL家兔;代谢异常;脂肪和糖原蓄积;胰岛素抵抗;基因表达
基金项目(Foundation): 国家自然科学基金(21207127,21277137,21477124,41390240);; 宁波市自然科学基金(2013A610179);; 中国科学院城市环境研究所城市环境与健康重点实验室基金(KLUEH-S-201303)
作者(Authors): 方超;宁博;范江霖;董四君;
参考文献(References):
- [1]Vandenberg L N,Chahoud I,Heindel J J,et al.Urinary,circulating,and tissue biomonitoring studies indicate widespread exposure to bisphenol A[J].Environmental Health Perspective,2010,118(8):1055-1070
- [2]Calafat A M,Ye X,Wong L Y,et al.Exposure of the US population to bisphenol A and 4-tertiary-octylphenol:2003-2004[J].Environmental Health Perspective,2008,116(1):39-44
- [3]He Y,Miao M,Herrinton L J,et al.Bisphenol A levels in blood and urine in a Chinese population and the personal factors affecting the levels[J].Environmental Research,2009,109(5):629-633
- [4]Walsh B.The perils of plastic[J].Time,2010,175(14):44-54
- [5]Melzer D,Osborne N J,Henley W E,et al.Urinary bisphenol A concentration and risk of future coronary artery disease in apparently healthy men and women[J].Circulation,2012,125(12):1482-1490
- [6]Bae S,Kim J H,Lim Y H,et al.Associations of bisphenol A exposure with heart rate variability and blood pressure novelty and significance[J].Hypertension,2012,60(3):786-793
- [7]Trasande L,Attina T M,Blustein J.Association between urinary bisphenol A concentration and obesity prevalence in children and adolescents[J].Journal of the American Medical Association,2012,308(11):1113-1121
- [8]Rochester J R.Bisphenol A and human health:A review of the literature[J].Reproductive Toxicology,2013,42:132-155
- [9]Alonso-Magdalena P,Vieira E,Soriano S,et al.Bisphenol A exposure during pregnancy disrupts glucose homeostasis in mothers and adult male offspring[J].Environmetal Health Perspective,2010,118(9):1243-1250
- [10]Wei J,Lin Y,Li Y,et al.Perinatal exposure to bisphenol A at reference dose predisposes offspring to metabolic syndrome in adult rats on a high-fat diet[J].Endocrinology,2011,152(8):3049-3061
- [11]Yan S,Song W,Chen Y,et al.Low-dose bisphenol A and estrogen increase ventricular arrhythmias following ischemia-reperfusion in female rat hearts[J].Food and Chemical Toxicology,2013,56:75-80
- [12]Fan J,Watanabe T.Transgenic rabbits as therapeutic protein bioreactors and human disease models[J].Pharmacology&Therapeutics,2003,99(3):261-282
- [13]Seok J,Warren H S,Cuenca A G,et al.Genomic responses in mouse models poorly mimic human inflammatory diseases[J].Proceedings of the National Academy of Sciences,2013,110(9):3507-3512
- [14]Hugo E R,Brandebourg T D,Woo J G,et al.Bisphenol A at environmentally relevant doses inhibits adiponectin release from human adipose tissue explants and adipocytes[J].Environmental Health Perspective,2008,116(12):1642-1647
- [15]Vassilopoulos S,Esk C,Hoshino S,et al.A role for the CHC22 clathrin heavy-chain isoform in human glucose metabolism[J].Science,2009,324(5931):1192-1196
- [16]Marrie R A,Yu B N,Leung S,et al.Rising prevalence of vascular comorbidities in multiple sclerosis:Validation of administrative definitions for diabetes,hypertension,and hyperlipidemia[J].Multiple Sclerosis(Houndmills,Basingstoke,England),2012,18(9):1310-1319
- [17]Repas T B,Tanner J R.Preventing early cardiovascular death in patients with familial hypercholesterolemia[J].The Journal of the American Osteopathic Association,2014,114(2):99-108
- [18]Gan S I,Edwards A L,Symonds C J,et al.Hypertriglyceridemia-induced pancreatitis:A case-based review[J].World Journal of Gastroenterology,2006,12(44):7197-7202
- [19]Arnold S V,Rich M.Hyperlipidemia in older adults[J].Clinics in Geriatric Medicine,2009,25:591-606
- [20]Vandentorren S,Zeman F,Morin L,et al.Bisphenol-A and phthalates contamination of urine samples by catheters in the Elfe pilot study:Implications for large-scale biomonitoring studies[J].Environmental Research,2011,111(6):761-764
- [21]Shiomi M,Fan J.Unstable coronary plaques and cardiac events in myocardial infarction-prone Watanabe heritable hyperlipidemic rabbits:Questions and quandaries[J].Current Opinion in Lipidology,2008,19(6):631-636
- [22]Waqar A B,Koike T,Yu Y,et al.High-fat diet without excess calories induces metabolic disorders and enhances atherosclerosis in rabbits[J].Atherosclerosis,2010,213(1):148-155
- [23]Fang C,Wu X,Huang Q,et al.PFOS elicits transcriptional responses of the ER,AHR and PPAR pathways in Oryzias melastigma in a stage-specific manner[J].Aquatic Toxicology,2012,106:9-19
- [24]Taylor J A,Vom Saal F S,Welshons W V,et al.Similarity of bisphenol A pharmacokinetics in rhesus monkeys and mice:Relevance for human exposure[J].Environmental Health Perspective,2011,119(4):422-430
- [25]Vandenberg L N,Hauser R,Marcus M,et al.Human exposure to bisphenol A(BPA)[J].Reproductive Toxicology,2007,24(2):139-177
- [26]Fang C,Ning B,Waqar A B,et al.Bisphenol A exposure enhances atherosclerosis in WHHL rabbits[J].PLOS One,2014,9(10):e110977
- [27]Bornfeldt K E,Tabas I.Insulin resistance,hyperglycemia,and atherosclerosis[J].Cell Metabolism,2011,14(5):575-585
- [28]Samuel V T,Shulman G I.Mechanisms for insulin resistance:Common threads and missing links[J].Cell,2012,148(5):852-871
- [29]Miksztowicz V,Lucero D,Zago V,et al.Hepatic lipase activity is increased in non-alcoholic fatty liver disease beyond insulin resistance[J].Diabetes/Metabolism Research and Reviews,2012,28(6):535-541
- [30]Barter P,Gotto A M,La Rosa J C,et al.HDL cholesterol,very low levels of LDL cholesterol,and cardiovascular events[J].The New England Journal of Medicine,2007,357(13):1301-1310
- [31]Carlsson M,Wessman Y,Almgren P,et al.High levels of nonesterified fatty acids are associated with increased familial risk of cardiovascular disease[J].Arteriosclerosis,Thrombosis,and Vascular Biology,2000,20(6):1588-1594
- [32]Kim M J,Moon M K,Kang G H,et al.Chronic exposure to bisphenol A can accelerate atherosclerosis in high-fat-fed apolipoprotein E knockout mice[J].Cardiovascular Toxicology,2013:1-9
- [33]van Herpen N A,Schrauwen-Hinderling V B.Lipid accumulation in non-adipose tissue and lipotoxicity[J].Physiology&Behavior,2008,94(2):231-241
- [34]Gribble F M,Ashcroft F M.Sulfonylurea sensitivity of adenosine triphosphate-sensitive potassium channels fromcells and extrapancreatic tissues[J].Metabolism,2000,49(10):3-6
- [35]Tao L,Wang W,Li L,et al.Effect of dibromoacetic acid on DNA methylation,glycogen accumulation,and peroxisome proliferation in mouse and rat liver[J].Toxicological Sciences,2004,82(1):62-69
- [36]Bugianesi E,Moscatiello S,Ciaravella M F,et al.Insulin resistance in nonalcoholic fatty liver disease[J].Current Pharmaceutical Design,2010,16(17):1941-1951
- [37]Marmugi A,Ducheix S,Lasserre F,et al.Low doses of bisphenol A induce gene expression related to lipid synthesis and trigger triglyceride accumulation in adult mouse liver[J].Hepatology,2012,55(2):395-407