Abstract
BackgroundsReducing 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.MethodsThe 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.ResultsCo-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.ConclusionPlacental P-gp inhibition enhances susceptibility to DEHP induced cardiac malformations in mice.
Highlights
Worldwide congenital heart defect (CHD) is one of the most common birth defects, occurring in 7 to 8 per 1000 live births in China
The ventricular myocardium noncompaction appeared to be more severe in the DEHP & verapamil group
Fetal cardiac peroxisome proliferator-activated receptor γ (PPARγ) mRNA expression was notably increased and Gata4/Mef2c/ Chf1 expression was markedly decreased in the DEHP & verapamil group
Summary
Worldwide congenital heart defect (CHD) is one of the most common birth defects, occurring in 7 to 8 per 1000 live births in China. Thereafter, our animal study further proved that maternal exposure to di-(2-ethylhexyl)-phthalate (DEHP), which accounts for 80% of phthalate production in China, could result in various types of fetal cardiac anomalies in mice [6]. Localizing at maternal-facing apical membrane of the syncytiotrophoblast, placental P-gp has the capacity to actively extrude a wide range of toxicants back to the maternal circulation, thereby prevent potentially harmful compounds from entering fetal compartment [7, 8, 13, 15, 16]. Studies in Abcb knockout mice have verified that Pgp deficiency could result in many-fold higher concentrations of substrates in fetal compartment and could enhance susceptibility to chemicals induced birth defects [15, 17, 18]. Association between the interindividual variability in placental P-gp expression and fetal susceptibility to toxicants induced CHD has rarely been explored
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