Biology subjects

Aleksunes, L. M.

Publications and source records attributed to Aleksunes, L. M..

3 recordsLinked to original sources

bioRxiv2026

Transporter-Mediated Uptake of Microcystin-LR in Human Trophoblasts: Regulation By Oxygen Concentration and Cell Fusion

BackgroundRising global temperatures and eutrophication are increasing the intensity and frequency of cyanobacterial harmful algal blooms that release toxins including microcystin-LR (MC-LR). MC-LR inhibits protein phosphatases in the human liver and brain, but its accumulation in the placenta is unclear. Placental transporter expression varies across pregnancy and is influenced by physiological cues, such as low oxygen concentrations which activate HIF1A, and trophoblast cell fusion forming syncytiotrophoblasts that engage CREB-driven transcription. This study examined whether MC-LR accumulates in placental cells, which transporters mediate uptake, and how these transporters are regulated by HIF1A and CREB. MethodsIntracellular accumulation of MC-LR (0.1-10 {micro}M, 3 hour) was measured in human cytotrophoblasts (JAR, BeWo) and extravillous trophoblasts (HTR-8/SVneo) by western blotting for MC-LR-adducted proteins. Organic anion transporting polypeptide (OATP) involvement was tested using cyclosporin A (10 {micro}M), an OATP inhibitor, before exposure to the OATP substrate or MC-LR. Cells were also cultured under 3%, 8%, or 20% O2 to induce hypoxic responses or treated with forskolin (a potent intracellular cAMP inducer) to stimulate cell fusion before MC-LR exposure. ResultsMC-LR accumulated in all three placenta cell lines in a concentration-dependent manner. Cyclosporin A reduced MC-LR uptake by 57% in JAR cells, confirming OATP-mediated transport. Low O2 increased OATP4A1 expression and function but reduced protein phosphatase expression, decreasing MC-LR-bound proteins by 52-72%. Forskolin increased OATP4A1 expression and enhanced MC-LR uptake >2.5-fold. ConclusionMC-LR enters placental trophoblasts via active OATP transport, likely OATP4A1, and uptake increases under hypoxia and trophoblast fusion.

pharmacology and toxicology↗

bioRxiv2026

vToxiNet: a biologically constrained deep learning framework for interpretable prediction of drug-induced hepatotoxicity

Hepatotoxicity remains a leading cause of drug attrition and post-marketing withdrawal, resulting from diverse and complex toxicity mechanisms. Traditional in vitro models can only capture a limited subset of toxicity pathways, and animal studies face translational and ethical limitations. Regulatory agencies have therefore promoted new approach methodologies, including human-relevant assays, omics technologies, and computational models to improve predictive toxicology and support evidence-based decision-making. However, most machine learning models for hepatotoxicity either rely solely on chemical structure or operate as black boxes, limiting mechanistic interpretability and broader applicability. Here, we introduce the virtual toxicity network (vToxiNet), a biologically constrained deep learning framework that embeds systems toxicology knowledge directly into neural network architecture for interpretable hepatotoxicity prediction. vToxiNet integrates chemical descriptors, high-throughput assay responses, transcriptomic signatures, and Reactome pathway hierarchy to construct a virtual adverse outcome pathway network. Across cross-validation and multiple external validation datasets, vToxiNet demonstrates robust predictive performance and generalizes to previously unseen chemicals. Importantly, interpretation of vToxiNet enables gene and pathway-level attribution, supporting mechanism-informed hazard characterization and chemical prioritization. These results demonstrate that encoding biological hierarchy as architectural constraints enables both predictive accuracy and mechanistic insight, establishing a generalizable framework for modeling complex biological outcomes.

pharmacology and toxicology↗

bioRxiv2024

A bioengineered model of human placental exposure to environmental metals during pregnancy

Exposure of pregnant women to toxic metals is an environmental health issue associated with various pregnancy complications. Efforts to advance our biological understanding of this problem and mitigate its adverse effects, however, have been challenged by ethical concerns of human subject research during pregnancy. Here, we present an alternative approach that leverages the design flexibility, controllability, and scalability of bioengineered human reproductive tissues to enable experimental simulation and in-depth investigation of placental exposure to environmental metals in maternal circulation. Central to this method is an in vitro analog of the maternal-fetal interface and its dynamic tissue-specific environment constructed using primary human placental cells grown in a micro-engineered device. Using cadmium as a representative toxicant, we demonstrate the proof-of-concept of emulating the human placental barrier subjected to the flow of cadmium-containing maternal blood to show how this model can be used to examine adverse biological responses and impaired tissue function on both the maternal and fetal sides. Moreover, we present a mechanistic study of maternal-to-fetal cadmium transport in this system to reveal that efflux membrane transporters expressed by trophoblasts may play an important protective role against cadmium-induced toxicity. Finally, we describe metabolomic analysis of our microphysiological system to demonstrate the feasibility of discovering metabolic biomarkers that may potentially be useful for detection and monitoring of cadmium-induced placental dysfunction.

bioengineering↗