Effects of chemotherapy on placental development and function using in vitro culture of human primary cytotrophoblasts.

Abstract

Introduction Cancers during pregnancy can be treated with chemotherapy after the first trimester but the treatment is associated with smaller placentas and an increased risk of stillbirth, fetal growth retardation and preterm delivery. We decided to assess the effect of several chemotherapeutic agents on placental development by using in vitro culture of human term cytotrophoblasts. Methods Cytotrophoblasts isolated from term placentas were cultured for 48h and treated for 24h with epirubicin, docetaxel, vinblastine, methotrexate, tamoxifen, 4-hydroxytamoxifen, and endoxifen. First, cell viability was assessed. Then, the effect of the treatment on trophoblast differentiation and placental angiogenesis was assessed by quantifying hCG and PlGF mRNA and protein expression. Finally, the expression of two efflux transporters, BCRP and MDR1 was investigated. Results Epirubicin only strongly decreased cell viability. Epirubicin, docetaxel, and vinblastine inhibited HCGB and PlGF expression while methotrexate, tamoxifen and its two metabolites increased it. BCRP was essentially expressed in syncytiotrophoblasts and MDR1 in undifferentiated cytotrophoblasts. Their expression was not affected by the drugs but vinblastine increased BCRP mRNA expression by 2.8-fold. Discussion The most commonly used chemotherapeutic drugs are well supported in vitro by syncytiotrophoblasts, except for epirubicin, which was very cytotoxic. Chemotherapy perturbed the expression of genes normally upregulated during placental differentiation and angiogenesis but not the expression of the drug transporters. Further studies looking at the effect of combination therapy and the transporter capacities to reject the drugs will be needed to better define the effects of chemotherapy on placental development and function.