Interaction between dolutegravir and folate transporters and receptor in human and rodent placenta.
Interaction between dolutegravir and folate transporters and receptor in human and rodent placenta.
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DOI：
10.1016/j.ebiom.2021.103771
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发表时间：
2022-01
期刊：
影响因子：
11.1
通讯作者：
Bendayan R
中科院分区：
文献类型：
--
作者：
Gilmore JC;Hoque MT;Dai W;Mohan H;Dunk C;Serghides L;Bendayan R
由于叶酸在神经发育中的关键作用，了解妊娠期间使用的抗HIV药物与胎盘中叶酸递送途径之间的潜在相互作用非常重要。本研究探讨了度鲁特韦（DTG）暴露对胎盘中还原型叶酸载体（RFC）、质子偶联叶酸转运蛋白（PCFT）和叶酸受体-α（FR α）功能表达的影响。使用人胎盘细胞系、人胎盘外植体和经临床相关浓度DTG处理的妊娠小鼠模型。通过qPCR、免疫印迹和免疫组织化学测定评估基因和蛋白质表达。通过应用基于放射性同位素的转运测定来测量叶酸转运功能。在胎盘细胞中，临床相关的DTG暴露3小时或6小时与RFC和PCFT在mRNA和蛋白质水平上的表达适度但显著的降低相关，以及RFC和PCFT底物[3H]-甲氨蝶呤和[3H]-叶酸的摄取分别降低。在妊娠小鼠中，DTG给药与胎盘RFC和PCFT mRNA表达的增加相关，同时伴有叶酸缺乏饮食条件下胎盘FR α mRNA的减少。这些发现表明，DTG和叶酸转运途径之间的潜在相互作用在胎盘中，特别是在体内，在叶酸缺乏的条件下，可能影响叶酸递送到胎儿的背景下，DTG为基础的ART在怀孕期间。由安大略艾滋病毒治疗网络资助，赠款#506657;和尤妮斯肯尼迪施赖弗国家儿童健康与人类发展研究所的国家卫生研究院，奖#R01HD104553。
Due to the critical role of folates in neurodevelopment, it is important to understand potential interactions between anti-HIV drugs used during pregnancy, and folate delivery pathways in the placenta. This study investigates the effect of dolutegravir (DTG) exposure on the functional expression of the reduced folate carrier (RFC), proton-coupled folate transporter (PCFT), and folate receptor-α (FRα) in the placenta. Human placental cell lines, human placental explants, and a pregnant mouse model treated with clinically relevant concentrations of DTG were used. Gene and protein expression were assessed by qPCR, immunoblot and immunohistochemical assays. Folate transport function was measured by applying radioisotope-based transport assays. In placental cells, clinically relevant DTG exposure for 3h or 6h was associated with a modest but significant reduction in the expression of RFC and PCFT both at the mRNA and protein levels, as well as decreased uptake of RFC and PCFT substrates [3H]-methotrexate and [3H]-folic acid, respectively. In pregnant mice, DTG administration was associated with an increase in both placental RFC and PCFT mRNA expression, accompanied by a decrease in placental FRα mRNA under folate-deficient dietary conditions. These findings demonstrate a potential interaction between DTG and folate transport pathways in the placenta, particularly in vivo, under folate deficient conditions, potentially impacting folate delivery to the foetus in the context of DTG-based ART during pregnancy. Funded by Ontario HIV Treatment Network, grant #506657; and Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health, award #R01HD104553.
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影响因子：
4.7
作者：
Hoque MT;Shah A;More V;Miller DS;Bendayan R
通讯作者：
Bendayan R
影响因子：
4.8
作者：
Alam, Camille;Hoque, Md. Tozammel;Bendayan, Reina
通讯作者：
Bendayan, Reina
影响因子：
3.8
作者：
Cabrera, Robert M.;Souder, Jaclyn P.;Finnell, Richard H.
通讯作者：
Finnell, Richard H.
影响因子：
3.8
作者：
Halwachs, Sandra;Lakoma, Cathleen;Honscha, Walther
通讯作者：
Honscha, Walther
影响因子：
64.5
作者：
Qiu, Andong;Jansen, Michaela;Goldman, I. David
通讯作者：
Goldman, I. David