RESUMEN
Concerns over Bisphenol A (BPA) and its substitute, Bisphenol S (BPS), have led to innovative exploration due to potential adverse health effects. BPS, replacing BPA in some regions to avoid toxic impacts, remains insufficiently studied. Besides this, the organ-on-a-chip technology emerges as a transformative solution in drug discovery and chemiclas toxicity testing, minimizing costs and aligning with ethical standards by reducing reliance on animal models, by integrating diverse tissues and dynamic cell environments enhances precision in predicting organ function. Here, we employ a 3-organ-on-a-chip microfluidic device with skin, intestine, and liver cultures to assess the effects of BPA and BPS via topical and oral administration. Our evaluation focused on gene markers associated with carcinogenicity, systemic toxicity, and endocrine disruption. BPA exhibited expected absorption profiles, causing liver injury and genetic modulation in related pathways. BPS, a safer alternative, induced adverse effects on gene expression, particularly in topical absorption, with distinct absorption patterns. Our findings underscore the urgency of addressing BPA and BPS toxicity concerns, highlighting the crucial role of organ-on-a-chip technology in understanding associated health risks. The study promotes the organ-on-a-chip methodology as a valuable tool for safe drug development and disease treatments, offering a novel liver toxicity screening alternative to traditional animal tests. This contributes to advancing comprehension of the biological effects of these compounds, fostering improved safety assessments in human health.
Asunto(s)
Compuestos de Bencidrilo , Dispositivos Laboratorio en un Chip , Hígado , Fenoles , Piel , Sulfonas , Fenoles/toxicidad , Compuestos de Bencidrilo/toxicidad , Hígado/efectos de los fármacos , Hígado/metabolismo , Sulfonas/toxicidad , Animales , Piel/efectos de los fármacos , Piel/metabolismo , Humanos , Intestinos/efectos de los fármacos , Disruptores Endocrinos/toxicidad , Pruebas de Toxicidad/métodos , Sistemas MicrofisiológicosRESUMEN
Animal testing for cosmetic ingredients and final products has been banned in Europe and is gaining legal force worldwide. However, the need for reliable testing methodologies remains for safety assessment of cosmetic ingredients. While new approach methodologies exist for many toxicological endpoints, some complex ones lack appropriate testing methods. Microphysiological systems (MPSs) have emerged as a promising tool to address this gap in pre-clinical testing, offering higher predictivity compared to animal models due to the phylogenetic distance between humans and animals. Moreover, they provide a more physiological approach than traditional in vitro testing by mimicking interconnections between different culture compartments as seen in complex organisms. This study presents a three-organ microfluidic MPS comprising skin, liver, and intestine equivalents. Combining this model with gene expression analysis, we evaluated toxicological endpoints of chemicals, demonstrating its potential for diverse applications. Our findings highlight the MPS model as a reliable and ethical method to be applied in an integrated approach for safety assessment in the cosmetic industry. It offers a promising strategy to evaluate toxicological endpoints for cosmetic ingredients and other chemicals, supporting the elimination of animal testing while ensuring consumer safety.
Asunto(s)
Seguridad de Productos para el Consumidor , Cosméticos , Humanos , Animales , Sistemas Microfisiológicos , Filogenia , Transcriptoma , Cosméticos/toxicidad , Perfilación de la Expresión GénicaRESUMEN
Particulate matter (PM) has been associated with adverse effects on human health, causing allergies, skin and eye irritation and corrosion, respiratory tract irritation, headaches, bronchoconstriction, cardiopulmonary diseases such as asthma, chronic obstructive pulmonary disease (COPD), lung cancer, reproductive problems, premature deaths, and epigenetic changes that lead to a wide variety of cancers, among other health conditions. The air quality in the Medellín - Colombia presents fluctuations that oscillate between the maximum permissible levels established at the national level and by the WHO, which represents a latent risk to people's health. Although important efforts have been made to quantify the different levels of pollution and administrative measures have been established to mitigate air pollution, little research work has been done to establish the relationship between these levels of pollutants and the effects on biological systems. The objective of the present research was to make a morphological and chemical characterization of particulate matter (PM) captured with a commercial air filter and a electrospun nanofiber membrane and evaluate the cytotoxicity of the each PM extracts in monolayer and co-culture models which recreate microphysiological systems of lung, skin and cornea and propose the possible cellular interactions that lead the cytotoxic response of the chemical compounds found in particulate matter in cities. The morphology and elemental chemical characterization were done with scanning electron microscopy coupled with energy dispersive X-ray spectroscopy (SEM - EDS). For the polycyclic aromatic hydrocarbons detection was made with a chromatographic method accoupled to mass spectrometer. Finally, the cytotoxicity was made in monolayers of A549, HEK001, and SIRC cell lines and microphysiological systems consisting of two-cell layer construct to resemble the interaction between fibroblast and epithelial cells that comprises naturally the corneal, skin and lung tissue. We performed three different cocultures models with BALB/3T3 clone A31 as a feeder layer, using porous Transwell® inserts in the in-contact and non-contact way. Monolayer and co-culture models were exposed to coarse and fine PM (1, 2, and 5 mg/mL) and the cell viability was evaluated at 24 h using an MTT assay. The electrospun nanofibers membranes demonstrates higher efficiency to capture PM with different sizes and high concentration of polycyclic aromatic hydrocarbons, heavy metals, and other chemical compounds responsible of many human diseases. Cytotoxic effects of MP were observed in all models at higher concentration; however, models exposed to fine PM exhibited a significant reduction in cell viability compared to those exposed to coarse PM. In addition, multilayer models are more resistant to PM exposure than monolayer models. Furthermore, the study indicated that, depending on the seeding strategy, different results might be observed: the non-contact model showed higher resistance to PM exposure than in-contact for SIRC and HEK001, but A549 monolayers showed the highest viability response. This study demonstrates the usefulness of applying co-culture models to assess environmental pollutant toxicity, in addition to being a potential alternative method to animal testing for risk assessment.
Asunto(s)
Contaminantes Atmosféricos , Contaminantes Ambientales , Hidrocarburos Policíclicos Aromáticos , Animales , Humanos , Material Particulado/toxicidad , Contaminantes Atmosféricos/toxicidad , Contaminantes Atmosféricos/análisis , Sistemas Microfisiológicos , Pulmón/metabolismo , Contaminantes Ambientales/análisis , Córnea , Hidrocarburos Policíclicos Aromáticos/toxicidadRESUMEN
Photodynamic therapy using Hypericin (Hy-PDT) is an alternative non-invasive treatment that enables selective tumor inhibition and angiogenesis derived from the differential recruitment of endothelial cells in the tumor microenvironment. Most PDT studies were performed on in vitro models without vascular biomechanical simulation. Our work strives to develop a microchip that generates a constant shear stress force to investigate the Hy-PDT efficiency on human umbilical vein endothelial cells (HUVECs). The microchip with a single straight microchannel was composed of the bottom layer (polystyrene), the middle layer (double-sided biocompatible adhesive tape), and the top layer (polyester film) and could produce shear stress in the range of 1.4 - 7.0 dyn cm-2. The quantification of vascular endothelial growth factor (VEGF), cell viability, and activities of caspases 3 and 7 were assayed to validate the microchip and Hy-PDT efficacy. After the endothelization, static and dynamic cell incubations with Hy were conducted in microchips. Compared to static systems, the shear stress displayed its effect on the increasing release of VEGF and promoted more cell damage and cell death via necrosis during Hy-PDT. In conclusion, the expressive shear stress-dependent manner during PDT treatments suggests that the microchip could be an essential approach in preclinical tests to evaluate the therapeutic outcome considering the endothelial shear stress microenvironment.
Asunto(s)
Perileno , Fotoquimioterapia , Humanos , Fármacos Fotosensibilizantes/farmacología , Factor A de Crecimiento Endotelial Vascular , Células Endoteliales , Sistemas Microfisiológicos , AntracenosRESUMEN
The blood brain barrier (BBB) is a multicellular microenvironment that plays an important role in regulating bidirectional transport to and from the central nervous system (CNS). Infections by many acutely infectious viruses such as alphaviruses and flaviviruses are known to impact the integrity of the endothelial lining of the BBB. Infection by Venezuelan Equine Encephalitis Virus (VEEV) through the aerosol route causes significant damage to the integrity of the BBB, which contributes to long-term neurological sequelae. An effective therapeutic intervention strategy should ideally not only control viral load in the host, but also prevent and/or reverse deleterious events at the BBB. Two dimensional monocultures, including trans-well models that use endothelial cells, do not recapitulate the intricate multicellular environment of the BBB. Complex in vitro organ-on-a-chip models (OOC) provide a great opportunity to introduce human-like experimental models to understand the mechanistic underpinnings of the disease state and evaluate the effectiveness of therapeutic candidates in a highly relevant manner. Here we demonstrate the utility of a neurovascular unit (NVU) in analyzing the dynamics of infection and proinflammatory response following VEEV infection and therapeutic effectiveness of omaveloxolone to preserve BBB integrity and decrease viral and inflammatory load.