Organoids in environmental toxicology: Applications, advantages, and future prospects.

Recent advances in environmental toxicology: Exploring gene editing, organ-on-a-chip, chimeric animals, and in silico models

In the preface1 to this supplement, we pointed out that pediatricians and other clinicians have made major contributions to the discovery of environmental toxicants. Many acute illnesses that are caused by high exposures to some toxicants are clinically diagnosable or at least are commonly in the differential diagnosis, eg, organophosphate poisoning, infant botulism, acute lead encephalopathy, carbon monoxide poisoning, acrodynia, hypervitaminosis A and some cases of aplastic anemia, convulsions, asthma, respiratory distress, methemoglobinemia, Reyes syndrome, kernicterus, and many of the recognizable syndromes that result from exposures to teratogenic drugs and chemicals. In contrast to the obvious effects of high exposures to environmental toxicants, there is less information and less certainty concerning the magnitude of the contribution of many low exposures of environmental toxicants to morbidity, mortality, and subtle alterations in children as well as adults or how the effects of these exposures vary with age or chronicity of exposure. We also informed the readership that we were going to address the issue of environmental toxicology from both a clinical and a toxicologic viewpoint. Very low exposures to environmental toxicants may lead to diseases that resemble many common illnesses that have other causes, or they may lead to decrements in functioning that are subtle or nonspecific. It is an almost insurmountable task for individual practitioners to conclude a cause-and-effect relationship from low exposures to environmental toxicants among patients in the physician’s patient population. Only well-planned, sophisticated epidemiologic and animal studies can answer the questions that pertain to the toxicity of low-level exposures to environmental toxicants, given that not all individuals will be affected equally, if at all, at any particular level of exposure. Many of the previous multi-authored compendia that have been published by groups of scientists have been unified in their conclusions that environmental toxicants are a very serious … Reprint requests to (R.L.B.) Rm 308, R/A, Alfred I. duPont Hospital for Children, Box 269, Wilmington, DE 19899. E-mail rbrent{at}nemours.org

Environmental stress and pollution pose significant threats to bird populations by impacting their health and survival and this study provides a comprehensive examination of the histological changes in avian tissues caused by such stressors and pollutants. Analyzing 151 scientific documents published between 1975 and 2024, the study utilized source analysis to identify publication trends, keyword analysis to highlight key topics, Lotka analysis to assess scientific productivity among researchers, and thematic analysis to categorize the research into main clusters. The findings indicate a growing scientific interest in this field since 2000 and show that the highest number of publications was reached in 2023, even though the dataset includes articles published up to 2024. The United States leads in the number of publications (30.5%), followed by Canada (17.2%), China (13.2%), and Spain (11.3%) and most articles have appeared in leading environmental science journals such as Science of the Total Environment, Environmental Pollution, and Environmental Toxicology and Chemistry. The most prominent topics identified include “histological changes,” “heavy metal accumulation,” “oxidative stress,” and “plastic pollution.” Lotka analysis shows that scientific productivity is driven by a small number of highly productive researchers, while the majority of authors have published only one (n=551) or two (n=68) articles. Thematic analysis revealed four main research clusters: (i) heavy metal accumulation, (ii) plastic pollution, (iii) the effects of organic and inorganic minerals, and (iv) histological changes. Overall, this study underscores the importance of histological analysis in understanding the impact of environmental pollution on avian health and provides a bibliometric framework that can guide future research priorities and conservation strategies, particularly by highlighting emerging contaminants, underrepresented regions, and key themes for long-term histopathological monitoring.

A workshop titled "Using Sentinel Species Data to Address the Potential Human Health Effects of Chemicals in the Environment," sponsored by the U.S. Army Center for Environmental Health Research, the National Center for Environmental Assessment of the EPA, and the Agency for Toxic Substances and Disease Registry, was held to consider the use of sentinel and surrogate animal species data for evaluating the potential human health effects of chemicals in the environment. The workshop took a broad view of the sentinel species concept, and included mammalian and nonmammalian species, companion animals, food animals, fish, amphibians, and other wildlife. Sentinel species data included observations of wild animals in field situations as well as experimental animal data. Workshop participants identified potential applications for sentinel species data derived from monitoring programs or serendipitous observations and explored the potential use of such information in human health hazard and risk assessments and for evaluating causes or mechanisms of effect. Although it is unlikely that sentinel species data will be used as the sole determinative factor in evaluating human health concerns, such data can be useful as for additional weight of evidence in a risk assessment, for providing early warning of situations requiring further study, or for monitoring the course of remedial activities. Attention was given to the factors impeding the application of sentinel species approaches and their acceptance in the scientific and regulatory communities. Workshop participants identified a number of critical research needs and opportunities for interagency collaboration that could help advance the use of sentinel species approaches.

The field of cancer research has long been driven by the pursuit of more physiologically relevant and predictive model systems. Traditional two-dimensional cell cultures and animal models, while invaluable, often fall short of recapitulating the complex heterogeneity, spatial architecture, and dynamic microenvironment of human tumors. This gap has propelled the emergence of three-dimensional organoid cultures as a transformative technology. This Research Topic, "Organoids as Advanced Model in Cancer Biology: The Drug Screening and Clinical Applications", was conceived to explore the rapidly evolving role of cancer organoids in refining drug discovery pipelines and bridging the daunting gap between preclinical findings and clinical utility. The articles published within this collection collectively underscore the significant potential of organoid technology while also acknowledging the challenges that remain on the path to its widespread standardization and application. This special issue significantly advances cancer organoid research by demonstrating their critical role in elucidating resistance mechanisms and enhancing drug screening. The study "Autophagy inhibition improves sensitivity to the multi-kinase inhibitor regorafenib in preclinical mouse colon tumoroids " utilizes mouse colon organoids to reveal that autophagy inhibition overcomes regorafenib resistance by suppressing EMT and Erk1/2 activation, providing a novel combinatorial strategy for colorectal cancer. The other article "Repurposing piroxicam enhances the antineoplastic effects of docetaxel and enzalutamide in prostate cancer cells using 2D and 3D in vitro culture models" employs prostate cancer organoids and 2D/3D models to show that repurposing piroxicam synergistically enhances the efficacy of conventional docetaxel and enzalutamide therapies, effectively reducing cell proliferation and organoid growth. The paper "Organoids technology in cancer research: from basic applications to advanced ex vivo models" reviews the broader utility of patient-derived organoids (PDOs), highlighting innovative techniques like decellularized ECM scaffolds to better recapitulate the tumor microenvironment (TME) for improved preclinical drug testing and personalized therapy prediction. Collectively, these contributions underscore organoids as physiologically relevant models that bridge basic research and clinical applications, offering powerful platforms for mechanistic discovery and therapeutic optimization in oncology. In a broader context, this Research Topic illustrates a field in a state of exciting maturation. The published articles move beyond simply extolling the virtues of organoids and instead present critical data and analyses that probe their practical applications and limitations. The collective findings affirm that organoids serve as a crucial intermediate model, offering a much-needed human-relevant system that sits between conventional cell lines and patient trials. However, the journey is far from complete. Future directions must address the need to incorporate non-epithelial components—such as immune cells, fibroblasts, and vasculature—to create more complex tumor microenvironments that can be used to study immunotherapy and stromal interactions. Standardization of protocols for organoid generation, biobanking, and drug screening assays is also paramount to ensure reproducibility and allow for multi-institutional comparisons. Moreover, the ethical considerations surrounding the use of patient-derived tissues and the potential for these living biobanks to guide patient care require ongoing dialogue. In conclusion, the work presented in this Topic solidifies the standing of organoids as an advanced and indispensable model in cancer biology, poised to make significant contributions to drug development and the realization of personalized cancer medicine.

Drug screening is traditionally based on the pharmacodynamic models from 2D cell culture or animal experiments. However, these models suffer from poor drug efficacy prediction due to their difference from human in vivo cell microenvironments. In recent years, advances in biotechnology and tissue engineering have enabled rapid growth of in vitro organoid culturing. These organoids cultured in matrigel can mimic human in vivo cell microenvironment and physiology more accurately than traditional 2D cell culture and animal models. Among them, tumor organoids, especially patient-derived tumour organoids, can be applied as effective cancer models for drug screening and personalized medicine. By integrating organoid culturing and microfluidics, organoid-on-a-chip platform has been developed to simulate the structure and function of human tissues or organs. In 2010, Ingber et al. reported a biomimetic microfluidic platform called lung-on-a-chip. Microscale engineering technologies were firstly utilized to create biomimetic microchips. Henceforth, increasing kinds of organ-on-a-chips were reported all over the world to mimic different organs, such as liver, kidney and brain. 2D planar cells were cultured in PDMS chambers in majority organ-on-a-chips. More and more studies focused on 3D cells or organoids instead recently due to their better biomimetic capability for drug screening and disease models. In 2018, Qin et al. reported a liver organoid from human iPSCs in a 3D perfusable chip system, which is the first study that uses human organoid in a microfluidic chip and executed drug testing successfully. The established liver organoid-on-a-chip system may provide a promising platform for engineering stem cell-based organoids with applications in regenerative medicine, disease modeling and drug testing. Conventionally, drug efficacy evaluation in organoid-on-a-chip was performed by cell staining. However, this approach only presents static results of live/dead cells, but cannot monitor the cells dynamically for long-term recording. Sensor integration with organoid-on-a-chips paves a new way for dynamic recording. Currently, Wang et al. developed a 3D electric cell/matrigel-substrate impedance sensing (3D-ECMIS) platform for real-time and non-invasive monitoring of 3D cell viability and drug susceptibility. This platform integrated impedance sensors to monitor the impedance changes during 3D cell culturing. Additionally, Wang et al. reported the 3D cardiomyocytes detection by combining microelectrode arrays (MEAs). Heart cells of neonatal rat were cultured on a tissue engineering scaffold, which was fabricated by 3D printing and electro-spinning. The experimental results demonstrated that extracellular field potential (spike amplitude and firing rate) of 3D cardiomyocytes can be recorded in real time. Moreover, non-invasive measurement of cellular metabolism is important to study the metabolism mechanism and drug efficacy. Thus, light-addressable potentiometric sensor (LAPS) was integrated with organoid-on-a-chip for chemical imaging of ions (H+, Na+, K+, Ca2+) induced by cellular metabolism, which enables accurate detection of different chemical parameters in organoid-on-a-chip. Multiple organoid chip linked by microfluidics, called human-on-a-chip is a newly emerging and frontier technology to mimic the interaction of multiple human organs in recent years. It can recapitulate the physiologically relevant structures and functions of the organs, as well as the interaction between multiple organs as in vivo , thereby offering alternative models for predicting human responses to various drugs and environmental stimulus. Organoid-on-a-chip demonstrates outstanding potential in drug screening, disease modeling and personalized precision medicine.

Environmental toxicology wars: Organ-on-a-chip for assessing the toxicity of environmental pollutants.

No one wants their bed, couch, chair, computer, or TV to catch on fire. “If an ordinary upholstered chair in your home gets ignited, it can essentially take your whole house down,” says Richard Gann, a senior research scientist at the U.S. National Institute of Standards and Technology’s (NIST) Building and Fire Research Laboratory. The most flammable part of a mattress or couch is its plastic polyurethane foam cushioning, he explains. Once a fire gets through a chair or mattress’s fabric covering and into this cushioning, it can start a catastrophic reaction that quickly leads to “flashover,” in which nearly everything combustible inside a room ignites simultaneously. Until very recently, brominated flame retardants, especially polybrominated diphenyl ethers (PBDEs), were one of the main materials used to reduce the speed with which the plastic components of consumer goods including beds, couches, chairs, and electronics could be consumed by fire. However, growing evidence shows that PBDE compounds are escaping from the products they protect and making their way into the products’ users. Moreover, the chemicals may disrupt human thyroid hormone functioning and cause other health effects, prompting many nations to ban or suspend their use in new consumer goods. [For more information on the health effects of PBDEs, see “Unwelcome Guest: PBDEs in Indoor Dust, p. A202 this issue.] Although bromine- and chlorine-containing flame retardants are still used in some products, the need for new alternatives is being driven by a confluence of policy, standards, and pressure from environmental groups. Europe banned the use of two formulations, PBDE pentaBDE and octaBDE, in 2004, the same year they were withdrawn from the North American market. A third compound, decaBDE, was banned 1 April 2008 by the European Court of Justice. Stateside, Maine has banned the use of decaBDE, the only PBDE still on the market in North America, in mattresses and residential upholstered furniture produced and sold in that state, and will extend the ban to electronics in 2010. Washington prohibits the use of decaBDE in mattresses and sets a process for a future ban in furniture and electronics if the state can identify a safer and feasible alternative that meets fire safety standards. Asian countries and other U.S. states have similar legislation in the works. “Instead of adding new fire retardant chemicals that ultimately may be shown to cause health problems, we should be asking whether we need to use these chemicals or if there are other ways to achieve equivalent fire safety,” contends Arlene Blum, a biophysical chemist and visiting scholar at the University of California, Berkeley. “So many of the chemicals we have banned in the past were flame retardants—think about asbestos, polychlorinated biphenyls, polybrominated biphenyls, tris(2,3-dibromopropyl) phosphate, PBDEs—[and] they all ended up in the environment and in people,” she points out. “We need to think carefully about adding these sorts of chemicals to consumer products before there is adequate health information.”

Development of a TBXT-EGFP iPS cell model for screening the early developmental toxicity of typical environmental pollutants

Mercury concentrations in seawater, sediments and wild mussels from the coast of Galicia (NW Spain)

Emerging trends in the methodology of environmental toxicology: 3D cell culture and its applications

Organoids are 3D invitro models derived from human stem cells, capable of simulating the structure, function, and intercellular interactions of human organs to a high degree. In recent years, organoid research in toxicology has deepened, with applications spanning drug toxicity, environmental toxicity, and food toxicity. Current research focuses on elucidating molecular pathways of toxin action, establishing personalized toxicity assessment models, and optimizing detoxification treatment strategies. Concurrently, the integration of multi-organ chips with microfluidic technology has advanced the analysis of cross-organ interactions and dynamic toxicity. In the future, integrating organoid technology with artificial intelligence, multi-omics, and microphysiological systems holds promise for significantly enhancing toxicity prediction accuracy while advancing the standardization and automated application of organoid models. This review summarizes research development in organoids within toxicology, emphasizing their applications in drug, environmental, and food toxicity studies as well as personalized clinical treatment, and outlines future development directions.

Organoids, as 3D in vitro models derived from stem cells, have unparalleled advantages over traditional cell and animal models for studying organogenesis, disease mechanisms, drug screening, and personalized diagnosis and treatment. Despite the tremendous progress made in organoid technology, the translational application of organoids still presents enormous challenges due to the complex structure and function of human organs. In this review, the limitations of the translational application of traditional organoid technologies are first described. Next, we explore ways to address many of the limitations of traditional organoid cultures by engineering various dimensions of organoid systems. Finally, we discuss future directions in the field, including potential roles in drug screening, simulated microphysiology system and personalized diagnosis and treatment. We hope that this review inspires future research into organoids and microphysiology system.

Complications of vascular diseases, including atherosclerosis, are the number one cause of death in Western societies. Dysfunction of endothelial cells is a critical underlying cause of the pathology of atherosclerosis. Lipid rafts, and especially caveolae, are enriched in endothelial cells, and down-regulation of the caveolin-1 gene may provide protection against the development of atherosclerosis. There is substantial evidence that exposure to environmental pollution is linked to cardiovascular mortality, and that persistent organic pollutants can markedly contribute to endothelial cell dysfunction and an increase in vascular inflammation. Nutrition can modulate the toxicity of environmental pollutants, and evidence suggests that these affect health and disease outcome associated with chemical insults. Because caveolae can provide a regulatory platform for pro-inflammatory signalling associated with vascular diseases such as atherosclerosis, we suggest a link between atherogenic risk and functional changes of caveolae by environmental factors such as dietary lipids and organic pollutants. For example, we have evidence that endothelial caveolae play a role in uptake of persistent organic pollutants, an event associated with subsequent production of inflammatory mediators. Functional properties of caveolae can be modulated by nutrition, such as dietary lipids (e.g. fatty acids) and plant-derived polyphenols (e.g. flavonoids), which change activation of caveolae-associated signalling proteins. The following review will focus on caveolae providing a platform for pro-inflammatory signalling, and the role of caveolae in endothelial cell functional changes associated with environmental mediators such as nutrients and toxicants, which are known to modulate the pathology of vascular diseases.

BackgroundNutrition and lifestyle are well-defined modulators of chronic diseases. Poor dietary habits (such as high intake of processed foods rich in fat and low intake of fruits and vegetables), as well as a sedentary lifestyle clearly contribute to today’s compromised quality of life in the United States. It is becoming increasingly clear that nutrition can modulate the toxicity of environmental pollutants.ObjectivesOur goal in this commentary is to discuss the recommendation that nutrition should be considered a necessary variable in the study of human disease associated with exposure to environmental pollutants.DiscussionCertain diets can contribute to compromised health by being a source of exposure to environmental toxic pollutants. Many of these pollutants are fat soluble, and thus fatty foods often contain higher levels of persistent organics than does vegetable matter. Nutrition can dictate the lipid milieu, oxidative stress, and antioxidant status within cells. The modulation of these parameters by an individual’s nutritional status may have profound affects on biological processes, and in turn influence the effects of environmental pollutants to cause disease or dysfunction. For example, potential adverse health effects associated with exposure to polychlorinated biphenyls may increase as a result of ingestion of certain dietary fats, whereas ingestion of fruits and vegetables, rich in antioxidant and anti-inflammatory nutrients or bioactive compounds, may provide protection.ConclusionsWe recommend that future directions in environmental health research explore this nutritional paradigm that incorporates a consideration of the relationships between nutrition and lifestyle, exposure to environmental toxicants, and disease. Nutritional interventions may provide the most sensible means to develop primary prevention strategies of diseases associated with many environmental toxic insults.