张瑞, 陈晓珍, 李丽萍, 朱粤, 李玲, 刘贺荣, 德小明. 邻苯二甲酸酯类化合物对大鼠脂代谢的影响及潜在机制[J]. 环境与职业医学, 2022, 39(7): 799-803, 814. DOI: 10.11836/JEOM21497
引用本文: 张瑞, 陈晓珍, 李丽萍, 朱粤, 李玲, 刘贺荣, 德小明. 邻苯二甲酸酯类化合物对大鼠脂代谢的影响及潜在机制[J]. 环境与职业医学, 2022, 39(7): 799-803, 814. DOI: 10.11836/JEOM21497
ZHANG Rui, CHEN Xiaozhen, LI Liping, ZHU Yue, LI Ling, LIU Herong, DE Xiaoming. Effects of typical phthalate esters on lipid metabolism in rats and its potential mechanism[J]. Journal of Environmental and Occupational Medicine, 2022, 39(7): 799-803, 814. DOI: 10.11836/JEOM21497
Citation: ZHANG Rui, CHEN Xiaozhen, LI Liping, ZHU Yue, LI Ling, LIU Herong, DE Xiaoming. Effects of typical phthalate esters on lipid metabolism in rats and its potential mechanism[J]. Journal of Environmental and Occupational Medicine, 2022, 39(7): 799-803, 814. DOI: 10.11836/JEOM21497

邻苯二甲酸酯类化合物对大鼠脂代谢的影响及潜在机制

Effects of typical phthalate esters on lipid metabolism in rats and its potential mechanism

  • 摘要: 背景 邻苯二甲酸二(2-乙基己基)酯(DEHP)和邻苯二甲酸二丁酯(DBP)是代表性的邻苯二甲酸酯类(PAEs)环境内分泌干扰物,研究表明PAEs暴露对机体脂代谢可能产生影响。

    目的 观察DEHP和/或DBP对大鼠脂代谢的影响,探讨其可能的作用机制。

    方法 初断乳健康的SD雄性3周龄大鼠36只,体重50~70 g,分为玉米油对照、DEHP(750 mg·kg−1)、DBP(500 mg·kg−1)、DEHP+DBP(750 mg·kg−1+500 mg·kg−1)四组,经口灌胃染毒8周,每周称量大鼠体重一次。末次染毒24 h后心尖取血处死大鼠。大鼠血液样本用于高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)、总胆固醇(TC)、甘油三酯(TG)四种脂代谢相关生化指标检测。采集大鼠肝脏组织、生殖器周围脂肪组织,称重后部分置于10%中性福尔马林中固定用于病理形态学观察。部分肝脏组织用于脂代谢相关基因酪氨酸蛋白激酶3(JAK3)、转录激活因子5b(STAT5b)和过氧化物酶体增殖物激活受体γ(PPARγ)mRNA水平检测。

    结果 在染毒期间,各组大鼠无死亡、受伤情况,自由进食饮水。与对照组相比:从第2周开始各个时间点DEHP+DBP组大鼠体重增长量均降低(P<0.05),DEHP、DEHP+DBP组大鼠的肝脏脏器系数升高(P<0.05),DEHP、DBP组大鼠血清LDL-C浓度升高(P<0.05)。与DEHP+DBP组相比:DEHP组大鼠体重增长量在第2、4、5、8周均升高(P<0.05),除第1周外其余各个时间点DBP组大鼠体重增长量均升高(P<0.05),DEHP、DBP组大鼠肝脏脏器系数均降低(P<0.05),DEHP组大鼠血清TG浓度升高(P<0.05),DEHP、DBP组大鼠血清LDL-C浓度升高(P<0.05)。肝组织的病理形态结果显示:DEHP、DBP和DEHP+DBP组大鼠肝细胞排列紊乱,条索状排列不明显,肝细胞增大,表现为细胞增殖的改变,另外可见肝细胞内胆色素颗粒沉着。生殖器周围脂肪组织的病理形态结果显示:DEHP、DBP和DEHP+DBP组大鼠生殖器周围脂肪组织脂肪细胞排列不整齐,形态呈现不规则状,大小不一。肝脏脂代谢相关基因mRNA水平检测结果显示:DEHP、DBP和DEHP+DBP组大鼠肝脏组织JAK3、STAT5b、PPARγ mRNA水平均低于对照组(P<0.05);且DEHP、DBP组大鼠肝脏组织PPARγ mRNA水平均低于DEHP+DBP组(P<0.05)。

    结论 DEHP和/或DBP染毒可不同程度抑制大鼠体重的增长,对大鼠肝脏组织具有炎性损伤作用,可引起大鼠脂代谢异常,其机制可能与抑制大鼠肝脏组织中JAK3/STAT5b/PPARγ信号通路的活化有关。

     

    Abstract: Background Di(2-ethylhexyl)phthalate (DEHP) and dibutyl phthalate (DBP) are representative environmental endocrine disruptors of phthalate esters (PAEs). Some studies have shown that PAEs exposure may have an impact on lipid metabolism.

    Objective To investigate the effects of DEHP and/or DBP on lipid metabolism in rats and their possible mechanisms of action.

    Methods Thirty-six weaned healthy SD male rats, 3 weeks old, weighing 50-70 g, were divided into four groups, i.e., a corn oil control group, a DEHP (750 mg·kg−1) group, a DBP (500 mg·kg−1) group, and a DEHP+DBP (750 mg·kg−1+500 mg·kg−1) group. The rats were exposed to DEHP and/or DBP by oral gavage for 8 weeks, and weighed once a week. The rats were anesthetized 24 h after the last dose, and blood was taken from the apical part of the heart. Serum high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), total cholesterol (TC), and triglyceride (TG) were detected. Liver tissues and perigenital adipose tissues were collected, weighed, and one portion of the tissues was fixed in 10% neutral formalin for pathomorphological observation, and another portion was used for mRNA detection of lipid metabolism-related genes such as Janus kinase 3 (JAK3), signal transducer and activator of transcription 5b (STAT5b), and peroxisome proliferator-activated receptor γ (PPARγ).

    Results During the DEHP and/or DBP exposure period, the rats in all groups were free to eat and drink without death or injury observed. Compared with the control group: The body weight gain in the DEHP+DBP group was lower at all time points from the 2nd week onwards (P<0.05); the liver organ coefficients of the DEHP and the DEHP+DBP groups were higher (P<0.05); the serum LDL-C levels in the DEHP and the DBP groups were higher (P<0.05). Compared with the DEHP+DBP group: The body weight gains in the DEHP group at the 2nd, 4th, 5th, and 8th weeks were higher (P<0.05), and the body weight gains in the DBP group were higher at all time points except the 1st week (P<0.05); the liver organ coefficients in the DEHP group and the DBP group were lower (P<0.05); the serum TG level in the DEHP group was higher(P<0.05), and the serum LDL-C levels in the DEHP and the DBP groups were higher (P<0.05). The pathomorphological results of liver tissues showed that the hepatocytes in the DEHP, DBP, and DEHP+DBP groups were disordered with loss of cord-like arrangement, swelling (suggesting change of cell proliferation), and presented bilirubin pigmentation. The pathomorphological results of rat perigenital adipose tissues showed had irregular alignment, sizes, and arrangement of adipocyte in the DEHP, DBP, and DEHP+DBP groups. The results of rat liver lipid metabolism-related gene mRNA levels showed that the liver JAK3, STAT5b, and PPARγ mRNA levels in the DEHP, DBP, and DEHP+DBP groups were lower than those in the control group (P<0.05); the rat liver PPARγ mRNA levels in the DEHP and DBP groups were lower than those in the DEHP+DBP group (P<0.05).

    Conclusion DEHP and/or DBP can inhibit the increase of body weight to varying degrees, induce inflammatory damage to liver tissues, and cause abnormal lipid metabolism in rats, and the associated mechanism may be related to inhibiting the activation of JAK3/STAT5b/PPARγ signaling pathway in rat liver tissues.

     

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