双酚A替代物对小鼠的心肌毒性研究  

Cardiovascular toxicity induced by bisphenol A alternatives

作　　者：武美琼 王新静 刘瑾[1] 李颖君 杨佳[2] 路上云 王莉[1] WU Meiqiong;WANG Xinjing;LIU Jin;LI Yingjun;YANG Jia;LU Shangyun;WANG Li(School of Public Health,Shanxi Medical University,Taiyuan 030001;Children’s Hospital of Shanxi,Taiyuan 030013)

机构地区：[1]山西医科大学公共卫生学院,太原030001 [2]山西省儿童医院,太原030013

出　　处：《环境科学学报》2023年第6期503-510,共8页Acta Scientiae Circumstantiae

基　　金：山西省自然科学基金(No.201901D211331,202103021223449);山西省博士启动基金(No.SD1919,SD2016);山西医科大学博士启动基金(No.XD1919);山西省高等学校科技创新项目(No.2021L219)。

摘　　要：当前,双酚A(Bisphenol A,BPA)替代物,如双酚B(Bisphenol B,BPB)、双酚S(Bisphenol S,BPS)和双酚AF(Bisphenol AF,BPAF),逐渐取代BPA被广泛应用于消费品中.已有研究证实,BPA替代物与心血管疾病发生密切相关.本研究旨在综合评估不同BPA替代物的心脏毒性差异,并探讨其可能的分子机制.采用10周龄ICR雄性小鼠作为动物模型,随机分为对照组、BPB组、BPS组和BPAF组.对实验小鼠进行为期4周的灌胃处理(600μg·kg^(-1),溶于玉米油),2 d一次,其中,对照组只灌胃玉米油.采用苏木精-伊红(Hematoxylin-Eosin,HE)和Masson染色观察小鼠心脏组织病理学改变和胶原沉积情况;分别使用2’,7’-二氯二氢荧光素二乙酸酯(2,7-Dichlorodihydrofluorescein diacetate,DCFHDA)探针和硫代巴比妥酸(Thiobarbituric acid,TBA)比色法检测心脏组织活性氧(Reactive oxygen species,ROS)和丙二醛(Malondialdehyde,MDA)水平,评估心肌细胞氧化损伤;采用荧光定量PCR技术测定炎症因子(白细胞介素10(Interleukin-10,Il-10)、肿瘤坏死因子α(Tumor necrosis factor-α,Tnf-α)和转化生长因子-β(Transforming growth factor-β,Tgf-β))、心肌纤维化标志物Ⅰ型胶原Α1(Collagen Type I Alpha 1,Col1a1)和心肌肥大标志物心房钠尿肽(Atrial natriuretic peptide,Anp)的mRNA表达水平.结果显示:BPB组、BPS组和BPAF组小鼠心脏核质比下降,而Anp表达在BPS组和BPAF组上调;BPS组和BPAF组心脏出现明显胶原沉积,纤维化标志物Col1a1在BPS组显著增加.此外,处理组均可诱导氧化应激标志物ROS和MDA含量增加,同时不同程度导致炎症因子(Il-10、Tnf-α、Tgf-β)表达的上调.提示BPA替代物可能诱发小鼠心脏氧化应激和炎症反应,引起心肌细胞纤维化和心肌肥大,进而导致心脏功能障碍.At present,bisphenol A(BPA)alternatives,such as bisphenol B(BPB),bisphenol S(BPS),and bisphenol AF(BPAF),have gradually replaced BPA in consumer products.It has been confirmed that BPA alternatives are closely related to the occurrence of cardiovascular diseases.The aim of this study was to evaluate comprehensively the cardiotoxicity differences of BPA alternatives and to explore the possible molecular mechanisms.The 10-week-old ICR male mice were randomly divided into control group and treatment groups(BPB,BPS,and BPAF).The mice in treatment groups were exposed to BPB,BPS,or BPAF through intragastric administration(600μg·kg^(-1),dissolved in corn oil)every other day for 4 weeks,while the mice in vehicle control were treated with corn oil.The histopathological changes and collagen deposition in mice hearts were observed by Hematoxylin-Eosin(HE)and Masson staining.The production of reactive oxygen species(ROS)and malondialdehyde(MDA)were detected to evaluate the oxidative damage through 2',7'-Dichlorodihydrofluorescein diacetate(DCFHDA)and thiobarbituric acid(TBA)colorimetric method,respectively.The mRNA expression of inflammatory cytokines(Il-10,Tnf-α,and Tgf-β),myocardial fibrosis markers(Col1a1),and myocardial hypertrophy markers(Anp)were analyzed by RT-PCR.The results demonstrated that BPB,BPS,and BPAF decreased nucleoplasmic ratio of cardiomyocytes in mice,and Anp expression were up-regulated in BPS and BPAF groups.Significant collagen deposition was observed in the mice hearts of BPS and BPAF groups,while Col1a1 expression was increased only in BPS group.The levels of ROS and MDA were elevated in treatment groups,and the BPA alternatives up-regulated the inflammatory factors(Il-10,Tnf-α,and Tgf-β)in different degrees.The above results suggest that BPA alternatives exposure induce oxidative stress and inflammation response in mice hearts,which were involved in the cardiac fibrosis and myocardial hypertrophy,resulting in cardiac dysfunction.

关 键 词：双酚A替代物 心肌毒性 氧化应激 炎症反应 心肌纤维化 心肌肥大 

分 类 号：X171.5[环境科学与工程—环境科学]