Placental P-glycoprotein inhibition enhances susceptibility to Di-(2-ethylhexyl)-phthalate induced cardiac malformations in mice: A possibly promising target for congenital heart defects prevention
Placental P-glycoprotein inhibition enhances susceptibility to Di-(2-ethylhexyl)-phthalate induced cardiac malformations in mice: A possibly promising target for congenital heart defects prevention
复制标题
胎盘 P-糖蛋白抑制增强小鼠对邻苯二甲酸二（2-乙基己基）酯诱导的心脏畸形的易感性：预防先天性心脏缺陷的一个可能有希望的目标
DOI：
10.1371/journal.pone.0214873
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发表时间：
2019
期刊：
影响因子：
3.7
通讯作者：
Wang Chuan
中科院分区：
文献类型：
--
作者：
Tang Changqing;Luo Chunyan;Hua Yimin;Zhou Kaiyu;Duan Hongyu;Ma Fan;Zhang Yi;Li Yifei;Qiu Dajian;Wang Chuan
研究背景降低有毒物质经胎盘的发生率有助于预防先天性心脏病。胎盘P-糖蛋白（P-gp）在胎儿毒物暴露中起着至关重要的作用，并随后影响毒物诱导的出生缺陷的风险。然而，关于胎盘P-gp在减少毒物诱导的心脏异常中的作用的数据非常有限。本研究旨在探讨胎盘P-gp在降低邻苯二甲酸二（2-乙基己基）酯（DEHP）所致小鼠心脏畸形风险中的保护作用。方法将C57 BL小鼠随机分为4组：对照组（玉米油）、DEHP 500 mg/Kg组（n = 15）、维拉帕米3 mg/Kg组（n = 10）、DEHP 500 mg/Kg+维拉帕米3 mg/Kg组（n = 20）。不同组中的妊娠母鼠从E6.5-14.5每天一次通过灌胃接受相应的干预。每天监测母体体重，并在E15.5采集样本。HE染色观察胎儿心脏畸形。采用实时荧光定量PCR（RT-qPCR）和Western-Blot方法分别检测Nkx 2. 5/Gata 4/Tbx 5/Mef 2c/Chf 1 mRNA和蛋白的表达。RT-qPCR法检测过氧化物酶体增殖物激活受体γ（PPARγ）mRNA的表达。结果与DEHP组、维拉帕米组和溶剂组相比，维拉帕米和DEHP联合给药显著增加了胎儿心脏畸形率。在DEHP组和DEHP+维拉帕米组中观察到不同的心脏异常表型，包括间隔缺损和心室肌致密化不全。DEHP和维拉帕米组的心肌致密化不全似乎更严重。DEHP+维拉帕米组胎心组织中PPARγ mRNA表达显著增加，Gata 4/Mef 2c/Chf 1表达显著降低。结论胎盘P-gp抑制可增加DEHP致小鼠心脏畸形的易感性。
Backgrounds Reducing toxicants transplacental rates could contribute to the prevention of congenital heart defects (CHDs). Placental P-glycoprotein (P-gp) plays a vital role in fetal toxicants exposure and subsequently affects the risk of toxicants-induced birth defects. However, data on the role of placental P-gp in decreasing toxicants-induced cardiac anomalies is extremely limited. This study aimed to explore the protective role of placental P-gp in reducing the risk of Di-(2-ethylhexyl)-phthalate (DEHP) induced cardiac anomalies in mice. Methods The C57BL mice were randomly divided into four groups: the vehicle group (corn oil, n = 10), 500mg/Kg DEHP group (n = 15), 3mg/Kg verapamil group (n = 10) and 500mg/Kg DEHP & 3mg/Kg verapamil group (n = 20). Pregnant dams in different group received respective intervention by gavage once daily from E6.5–14.5. Maternal weights were monitored every day and samples were collected at E15.5. HE staining was used to examine fetal cardiac malformations. Real-time quantitative PCR (RT-qPCR) and Western-Blot were applied to detect Nkx2.5/Gata4/Tbx5/Mef2c/Chf1 mRNA and protein expression, respectively. The mRNA expression of peroxisome proliferator-activated receptor γ (PPARγ) was also determined using RT-qPCR. Results Co-administration of verapamil and DEHP significantly elevated fetal cardiac malformation rates, in comparison with the DEHP group, the verapamil group and the vehicle group. Different phenotypes of cardiac anomalies, including septal defects and ventricular myocardium noncompaction, were noted both in the DEHP group and the DEHP & verapamil group. The ventricular myocardium noncompaction appeared to be more severe in the DEHP & verapamil group. Fetal cardiac PPARγ mRNA expression was notably increased and Gata4/Mef2c/Chf1 expression was markedly decreased in the DEHP & verapamil group. Conclusion Placental P-gp inhibition enhances susceptibility to DEHP induced cardiac malformations in mice.