Healthy and diseased placental barrier on-a-chip models suitable for standardized studies.

Pathologies associated with uteroplacental hypoxia, such as preeclampsia are among the leading causes of maternal and perinatal morbidity in the world. Its fundamental mechanisms are yet poorly understood due to a lack of good experimental models. Here we report an in vitro model of the placental barrier, based on co-culture of trophoblasts and endothelial cells against a collagen extracellular matrix in a microfluidic platform. The model yields a functional syncytium with barrier properties, polarization, secretion of relevant extracellular membrane components, thinning of the materno-fetal space, hormone secretion, and transporter function. The model is exposed to low oxygen conditions and perfusion flow is modulated to induce a pathological environment. This results in reduced barrier function, hormone secretion, and microvilli as well as an increased nuclei count, characteristics of preeclamptic placentas. The model is implemented in a titer plate-based microfluidic platform fully amenable to high-throughput screening. We thus believe this model could aid mechanistic understanding of preeclampsia and other placental pathologies associated with hypoxia/ischemia, as well as support future development of effective therapies through target and compound screening campaigns. STATEMENT OF SIGNIFICANCE: The human placenta is a unique organ sustaining fetal growth but is also the source of severe pathologies, such as preeclampsia. Though leading cause of perinatal mortality in the world, preeclampsia remains untreatable due to a lack of relevant in vitro placenta models. To better understand the pathology, we have developed 3D placental barrier models in a microfluidic device. The platform allows parallel culture of 40 perfused physiological miniaturized placental barriers, comprising a differentiated syncytium and endothelium that have been validated for transporter functions. Exposure to a hypoxic and ischemic environment enabled the mimicking of preeclamptic characteristics in high-throughput, which we believe could lead to a better understanding of the pathology as well as support future effective therapies development.

Biopesticide spinosad induces transcriptional alterations in genes associated with energy production in honey bees (Apis mellifera) at sublethal concentrations.

Bees experience substantial colony losses, which are often associated with pesticides. Besides synthetic insecticides biological compounds such as spinosad are used in agriculture and organic farming against insect pests. However, potential adverse effect at sublethal concentrations to pollinators are poorly known. Here we aim to determine potential adverse outcome pathways of spinosad and to identify molecular effects by investigating transcriptional alterations in the brain of honey bees. We experimentally exposed bees to three sublethal concentrations of 0.05, 0.5 and 5 ng spinosad/bee, and assessed transcriptional alterations of target genes. Additionally, we evaluated whether spinosad-induced transcriptional alterations were influenced by the time of the year. In April, alterations were most pronounced after 24 h exposure, while in June alterations occurred mostly after 48 h. In July, expressional alterations were often lower but the pattern was more similar to that in June than that in April. Down-regulation of genes encoding acetylcholine receptors, enzymes involved in oxidative phosphorylation (cox5a, ndufb7 and cox17), cytochrome P450 dependent monooxygenases (cyp9q1, cyp9q2 and cyp9q3) and insulin-like peptide-1 were among the most significant transcriptional alterations. This suggests adverse effects of spinosad to energy production and metabolism and thus negative consequences on foraging. Together, our study indicates that spinosad causes adverse effects at environmentally realistic concentrations, which may pose a risk to bee populations.