A wide diversity of plant protection products (PPP) is used for crop protection leading to the contamination of soil, water, and air, which can hâve ecotoxicological impacts on living organisms. It is inconceivable to study the effects of each compound on each species from each compartment, experimental studies being time consuming and cost prohibitive, and animal testing having to be avoided. Therefore, numerous models are developed to assess PPP ecotoxicological effects. Our objective was to provide an overview of the modelling approaches enabling the assessment of PPP effects (inc.luding biopesticides) on the biota. Six categories of models were inventoried: QSAR, DR and TKTD, population, multi-species, landscape, and mixture models. They were developed for various species (terrestrial and aquatic vertebrates and invertebrates, primary producers, micro-organisms) belonging to diverse environmental compartments, and address different goals (e.g., species sensitivity or PPP bioaccumulation assessment, ecosystem ser vices protection). Among them, mechanistic models are increasingly recognized by EFSA for P P P regulatory risk assessment but, to date, remain not considered in notified guidance documents. The strengths and limits of the reviewed models are discussed together with improvement avenues (multi-generational effects, multiple biotic and abiotic stressors. ..). This review also underlines a lack of model testing by rneans of fleld data and of sensitivity and uncertainty analyses. Accurate and robust modelling of PPP effects and other stressors on living organisms, from their application in the ffeld to their functional consé quences on the ecosystems at different scales of time and space, would help going towards a more sustainable management of the environment. K e y w o r d s: Ecotoxicological m odels, ecological m odels, risk assessm ent, environm ent, ecotoxicity, m ulti-stressors, E u ro p ea n rég u latio n Review of models for ERA of plant protection products
Interactions between the different liver cell types are critical to the maintenance or induction of their function in vitro . In this work, human-induced Pluripotent Stem Cells (hiPSCs)-derived Liver Sinusoidal Endothelial Cells (LSECs) and Hepatocytes-Like Cells (HLCs) were cultured and matured in a microfluidic environment. Both cell populations were differentiated in Petri dishes, detached, and inoculated in microfluidic biochips. In cocultures of both cell types, the tissue has exhibited a higher production of albumin (3.19 vs 5.31 μ g/mL/10 6 cells in monocultures and cocultures) as well as a higher inducibility CYP450 over monocultures of HLCs. Tubular-like structures composed of LSECs and positive for the endothelial marker PECAM1, as well as a tissue more largely expressing Stabilin-2 were detected in cocultures only. In contrast, monocultures exhibited no network and less specific endothelial markers. The transcriptomic analysis did not reveal a marked difference between the profiles of both culture conditions. Nevertheless, the analysis allowed us to highlight different upstream regulators in cocultures (SP1, EBF1, and GATA3) and monocultures (PML, MECP2, and NRF1). In cocultures, the multi-omics dataset after 14 days of maturation in biochips has shown the activation of signaling related to hepatic maturation, angiogenesis, and tissue repair. In this condition, inflammatory signaling was also found to be reduced when compared to monocultures as illustrated by the activation of NFKB and by the detection of several cytokines involved in tissue injury in the latter. Finally, the extracted biological processes were discussed regarding the future development of a new generation of human in vitro hepatic models.
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