Department of Oncology, KU Leuven, Herestraat 49, 3000 Leuven, Belgium; Department of Obstetrics and Gynecology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium.
Genomics Core, KU Leuven, Herestraat 49, 3000 Leuven, Belgium.
Placenta. 2018 Apr;64:61-70. doi: 10.1016/j.placenta.2018.03.002. Epub 2018 Mar 9.
Fetal growth restriction (FGR) carries an increased risk of perinatal mortality and morbidity. A major cause of FGR is placental insufficiency. After in utero chemotherapy-exposure, an increased incidence of FGR has been reported. In a prospective cohort study we aimed to explore which pathways may contribute to chemotherapy-associated FGR.
Placental biopsies were collected from 25 cancer patients treated with chemotherapy during pregnancy, and from 66 control patients. Differentially expressed pathways between chemotherapy-exposed patients and controls were examined by whole transcriptome shotgun sequencing (WTSS) and Ingenuity Pathway Analysis (IPA). Immunohistochemical studies for 8-OHdG and eNOS (oxidative DNA damage), proliferation (PCNA) and apoptosis (Cleaved Caspase 3) were performed. The expression level of eNOS, PCNA and IGFBP6 was verified by real-time quantitative Reverse Transcription Polymerase Chain Reaction (RT-qPCR).
Most differential expressed genes between chemotherapy-exposed patients and controls were related to growth, developmental processes, and radical scavenging networks. The duration of chemotherapy exposure had an additional impact on the expression of genes related to the superoxide radicals degeneration network. Immunohistochemical analyses showed a significantly increased expression of 8-OHdG (P = 0.003) and a decreased expression of eNOS (P=0.015) in the syncytiotrophoblast of the placenta of cancer patients. A decreased expression of PCNA was detected by immunohistochemistry as RT-qPCR (NS).
Chemotherapy exposure during pregnancy results in an increase of oxidative DNA damage and might impact the placental cellular growth and development, resulting in an increased incidence of FGR in this specific population. Further large prospective cohort studies and longitudinal statistical analyses are needed.
胎儿生长受限（FGR）会增加围产期死亡和发病的风险。FGR 的一个主要原因是胎盘功能不全。在宫内接受化疗后，报道了 FGR 的发生率增加。在一项前瞻性队列研究中，我们旨在探讨哪些途径可能导致与化疗相关的 FGR。
从 25 名接受孕期化疗的癌症患者和 66 名对照患者的胎盘组织中采集胎盘活检。通过全转录组鸟枪法测序（WTSS）和 Ingenuity 通路分析（IPA）检测化疗暴露患者与对照组之间差异表达的通路。进行 8-OHdG 和 eNOS（氧化 DNA 损伤）、增殖（PCNA）和凋亡（Cleaved Caspase 3）的免疫组织化学研究。通过实时定量逆转录聚合酶链反应（RT-qPCR）验证 eNOS、PCNA 和 IGFBP6 的表达水平。
化疗暴露患者与对照组之间差异表达的大多数基因与生长、发育过程和自由基清除网络有关。化疗暴露时间的长短对与超氧化物自由基降解网络相关的基因表达有额外的影响。免疫组织化学分析显示，癌症患者胎盘合体滋养层中 8-OHdG 的表达显著增加（P=0.003），eNOS 的表达显著降低（P=0.015）。免疫组织化学和 RT-qPCR 均显示 PCNA 的表达降低（NS）。
孕期化疗暴露会导致 DNA 氧化损伤增加，可能会影响胎盘细胞的生长和发育，导致该特定人群中 FGR 的发生率增加。需要进一步进行大型前瞻性队列研究和纵向统计分析。
