生命早期双酚A暴露联合断乳后高脂饮食对小鼠糖脂代谢的影响及其机制  

Effects of early-life bisphenol A exposure combined with post-weaning high-fat diet on glucose and lipid metabolism in mice and their mechanisms

作　　者：陈福彬 黄海燕[2] 张慧红 刘建军[2] 朱伟[4] 谢易容 李洪娅 皮姝荣 钟婧怡 丁树仁 张珂 吴帆 张波 何云[1] CHEN Fubin;HUANG Haiyan;ZHANG Huihong;LIU Jianjun;ZHU Wei;XIE Yirong;LI Hongya;PI Shurong;ZHONG Jingyi;DING Shuren;ZHANG Ke;WU Fan;ZHANG Bo;HE Yun(Department of Toxicology,School of Public Health,Sun Yat-sen University,Guangzhou 510080;Key Laboratory of Modern Toxicology,Shenzhen Center for Disease Control and Prevention,Shenzhen Key Discipline of Health Toxicology,Shenzhen 518055;Center for Food Safety and Health Research,School of Public Health,Southern Medical University,Guangzhou 510515;Guangzhou Center for Disease Control and Prevention,Guangzhou 510440,Guangdong,China)

机构地区：[1]中山大学公共卫生学院毒理学系,广东广州510080 [2]深圳市疾病预防控制中心现代毒理学重点实验室,深圳市卫生毒理学医学重点学科,广东深圳518055 [3]南方医科大学公共卫生学院食物安全与健康研究中心,广东广州510515 [4]广州市疾病预防控制中心,广东广州510440

出　　处：《癌变．畸变．突变》2024年第6期421-430,共10页Carcinogenesis,Teratogenesis & Mutagenesis

基　　金：国家自然科学基金(81472998,81872661,81773403);中国广东省重点研发计划(2019B020210003);深圳医学三名工程(SZSM202211010);深圳市医学重点学科建设基金(SZXK069)。

摘　　要：目的:研究生命早期双酚A(BPA)暴露联合断乳后高脂饮食对小鼠糖脂代谢的影响,并探讨其发生机制。方法:在母鼠受孕第6天至子代小鼠断乳前按0.5 mg/(kg·d)对母鼠进行双酚A饮水染毒,分成未染毒组和BPA组,每组10只孕鼠。子代小鼠断乳后终止BPA染毒,并进行高脂饮食干预,分成普通饮食未染毒组、普通饮食BPA组、高脂饮食未染毒组和高脂饮食BPA组,每组10只,雌雄各半。在子代小鼠出生后第21天(PND21)和第91天(PND91)时处死小鼠并收集血液和胰腺组织样本,PND91小鼠在处死前进行葡萄糖耐量和胰岛素耐量试验,采用高分辨液质联用仪对小鼠胰腺进行非靶向脂质组学检测,实时荧光定量PCR法(qPCR)检测小鼠胰腺神经酰胺合成基因的mRNA表达水平,ELISA试剂盒检测小鼠血浆胰岛素和胰腺神经酰胺合成酶(Cers)活性,试剂盒检测小鼠胰腺丙二醛(MDA)含量和超氧化物歧化酶(SOD)活性。结果:PND21时,与未染毒组相比,BPA暴露组子代雄性和雌性小鼠均出现体质量增长加快。PND91时,与高脂饮食未染毒组相比,高脂饮食BPA组雄性小鼠体质量增加(P<0.05)。PND91小鼠的葡萄糖耐量和胰岛素耐量试验结果显示,与高脂饮食未染毒组相比,高脂饮食BPA组雄性和雌性小鼠血糖曲线下面积均显著增加(P<0.05)。计算小鼠胰岛素抵抗指数发现,与高脂饮食未染毒组相比,PND91高脂饮食BPA组雄性小鼠胰岛素抵抗指数升高(P<0.05)。胰腺的非靶向脂质组学检测结果表明,PND21小鼠中,与未染毒组相比,BPA组雄性和雌性小鼠神经酰胺(Cer)丰度显著升高(P<0.05);PND91小鼠中,与高脂饮食未染毒组相比,高脂饮食BPA组雄性小鼠神经酰胺(Cer)丰度显著升高(P<0.05)。胰腺qPCR检测结果发现,PND21小鼠中,与未染毒组相比,BPA组雄性小鼠Cers4和Cers6 mRNA的表达上调,雌性小鼠Cers4mRNA的表达上调(P<0.05);PND91小鼠中,与高脂饮食未染毒组相比,高脂饮食BPA组雄OBJECTIVE:To investigate the effects of early-life Bisphenol A(BPA)exposure on glucose and lipid metabolism in post-weaning mice fed a high-fat diet.METHODS:Pregnant mice were exposed to BPA through drinking water at a concentration of 0.5 mg/(kg·d)from gestational day 6 until weaning of offspring.Twenty pregnant mice were divided equally into control and BPA groups.The weaned offspring were organized into,four groups:normal diet control,normal diet BPA,high-fat diet control,and high-fat diet BPA,with 10 mice per group,balanced by sex.Mice were sacrificed at postnatal day 21(PND21)and postnatal day 91(PND91)for the collection of blood and pancreas samples.Before sacrificing the PND91 mice,they were tested for glucose and insulin tolerance.Non-targeted lipidomics of the pancreas was analyzed using high-resolution liquid chromatography-mass spectrometry.qPCR was employed to measure mRNA expression levels of ceramide synthesis genes in the pancreas.Plasma insulin and pancreatic ceramide synthase activity were assessed using ELISA kits.Malondialdehyde(MDA)and superoxide dismutase(SOD)activities in the pancreas were measured using specific assay kits.RESULTS:At PND21,both male and female offspring in the BPA exposure group exhibited accelerated weight gain compared to the control group.At PND91,male mice in the high-fat diet BPA group showed increased body weight compared to the high-fat diet control group(P<0.05).Results of glucose tolerance and insulin tolerance tests at PND91 indicated that,compared to the high-fat diet control group,both male and female mice in the high-fat diet BPA group had significantly increased areas under the blood glucose curve(P<0.05).Calculating the insulin resistance index in mice,it was found that,male mice in the PND91 high-fat diet BPA group had an elevated insulin resistance index(P<0.05).Non-targeted lipidomics of the pancreas revealed that at PND21,compared to the control group,male and female mice in the BPA group had significantly increased ceramide(Cer)abundance(P<0.05).At PND9

关 键 词：双酚A 高脂饮食 生命早期 糖脂代谢 神经酰胺 

分 类 号：R114[医药卫生—卫生毒理学]