Organoid-based platforms for investigating microplastic-induced human organ toxicity

Article information

Organoid. 2025;5.e5

Publication date (electronic) : 2025 May 13

doi : https://doi.org/10.51335/organoid.2025.5.e5

Yeongseon Cho¹, Hong Nam Kim^,1,2,3

¹Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul, Korea

²Division of Bio-Medical Science and Technology, KIST School, University of Science and Technology (UST), Seoul, Korea

³School of Mechanical Engineering, Yonsei-Korea Institute of Science and Technology Convergence Research Institute, Yonsei University, Seoul, Korea

Correspondence to: Hong Nam Kim, PhD Brain Science Institute, Korea Institute of Science and Technology (KIST), 5 Hwarang-ro 14-gil, Seongbuk-gu, Seoul 02792, Korea E-mail: hongnam.kim@kist.re.kr

Received 2025 April 1; Revised 2025 April 11; Accepted 2025 April 21.

Abstract

Introduction

Micro- and nano-plastics (MNPs) have become pervasive environmental contaminants, originating from the degradation of synthetic textiles, consumer products, and industrial waste [1,2]. These particles have been detected in diverse ecosystems, including marine and freshwater environments, soils, the atmosphere, and even polar regions [3]. More concerningly, recent studies have identified MNPs in human biological samples such as blood, lungs, placenta, breast milk, and feces, suggesting chronic and widespread exposure in modern populations [4–6]. Once MNPs are introduced into the body through ingestion, inhalation, or dermal absorption, they can traverse biological barriers, circulate throughout the body, and accumulate in organs, where they may trigger oxidative stress, inflammation, endocrine disruption, mitochondrial dysfunction, genotoxicity, and gut microbiota imbalance [7–9].

Despite increasing concerns, conventional toxicological models remain inadequate for assessing human-relevant MNP effects [10]. Two-dimensional cell cultures lack the structural complexity and cellular interactions present in human tissues, while animal models are limited by interspecies differences in physiology and metabolism [11]. These limitations are especially problematic when modeling chronic, low-dose, or multi-organ exposures that more accurately reflect real-world conditions [12]. Thus, alternative platforms capable of recapitulating human-specific responses to MNPs are urgently needed. Moreover, despite growing concerns regarding chronic, low-dose MNP exposure, most in vitro studies have utilized relatively high concentrations (often 10 to 200 μg/mL) to induce detectable responses [13,14]. In contrast, real-world exposure estimates indicate that indoor airborne microplastic concentrations typically range from 0.3 to 60 particles per cubic meter, resulting in much lower levels of human exposure [15–17]. This disparity highlights the need for experimental models that both reflect human tissue architecture and incorporate physiologically relevant dosing conditions.

Organoid technology has emerged as a promising solution. Organoids are 3-dimensional structures derived from pluripotent or adult stem cells that self-organize to mimic the architecture and function of native human organs [18,19]. These models reproduce the key features of in vivo tissues, including spatial organization, cellular diversity, and tissue-specific signaling pathways [20]. Moreover, organoids can be derived from patient-specific cells, enabling personalized toxicological assessments and the investigation of individual genetic or disease-related susceptibilities [21]. Their scalability and adaptability make them ideal for chronic exposure studies and for evaluating combinations of environmental stressors [22].

Organoid-based models have recently been employed to study MNP toxicity across multiple physiological systems, including the nervous, circulatory, respiratory, and metabolic systems (Table 1) [23–39]. These studies have begun to uncover organ-specific vulnerabilities and mechanistic pathways that were previously difficult to capture using traditional in vitro or animal models [40]. Notably, organoids have helped uncover subtle, organ-specific toxic responses and mechanistic pathways that conventional models often fail to capture [6,10,41]. In this review, we summarize recent findings on MNP-induced organ toxicity by using various organoid models. We also address the limitations of current organoid systems in assessing the toxicity of MNPs, including the need for vasculature, immune cells, mechanical cues, and inter-organ communication [42,43]. Organoid-based methodologies are envisioned to offer valuable insights for assessing the health risks associated with environmental contaminants. A summary of organoid-based MNP toxicity across different physiological systems is presented in Fig. 1.

Table 1.

Graphical summary illustrating organoid-based evaluations of micro- and nanoplastic toxicity across various physiological systems

Fig. 1.

Graphical summary of organoid-based evaluation of micro-/nanoplastic toxicity across physiological systems. ROS, reactive oxygen species; TNF-α, tumor necrosis factor-α; IL, interleukin; ORO, oil red O staining.

Nervous system

Ethics statement: This study constituted a comprehensive analysis of previously released studies and thus, was not subject to the approval of the institutional review board.

The nervous system is particularly sensitive to environmental contaminants, especially during critical developmental periods [44]. Growing evidence indicates that MNPs can cross biological barriers, negatively impacting neural functions through mechanisms including neuroinflammation, oxidative stress, and impaired neurodevelopment [45]. Brain organoid models derived from human induced pluripotent stem cells (hiPSCs) have become valuable tools for studying MNP-induced neurotoxicity.

Hua et al. [24] investigated the impact of polystyrene microplastics (PS-MPs) on hiPSC-derived brain organoids, discovering a biphasic effect: short-term exposure stimulated proliferation in neural progenitors, while prolonged exposure decreased cell viability and neuronal differentiation marker expression. The effects varied by particle size and concentration, suggesting persistent microplastic exposure disrupts neuronal development (Fig. 2A).

Fig. 2.

Effects of microplastic and nanoplastic exposure on neural development in human brain organoids. From day 4 to 30, the spheroids were treated with 1 μm and 10 μm microplastics at a concentration of 100 μg/mL. Immunocytochemical analysis was performed for (A-i) Ki67 and (A-ii) SOD2, both co-localized with β-tubulin III. Nuclei were counterstained with Hoechst 33342 (blue). Scale bar=100 μm. Reproduced from Hua et al. J Hazard Mater 2022;435:128884, with permission from Elsevier [24]. (B-i) Bright-field images of cerebral organoids exposed to 0 and 200 ng/mL polystyrene nanoplastics. (B-ii) Cortical organoids derived from human induced pluripotent stem cells (hiPSCs) (ihtc-03) were analyzed on day 24 using immunostaining for Ki67 (green) and SOX2 (red), with subsequent quantification of Ki67-positive cells. (B-iii) Immunostaining was performed for PKC-λ (red) and DCX (green), followed by quantification of the ventral zone regions enclosed by PKC-λ and measurement of their thickness. (B-iv) On day 24, cortical organoids derived from hiPSCs (ihtc-03) were immunostained for TBR1 (green) and SOX2 (red), and TBR1-positive cells were subsequently quantified. Reproduced from Tao et al. Ecotoxicol Environ Saf 2024;285:117063, according to the Creative Commons license [25].

Tao et al. [25] investigated the subcellular effects of polystyrene nanoplastics (PS-NPs) in cerebral organoids. Immunostaining and transcriptomic analyses revealed mitochondrial damage characterized by structural and functional impairments, elevated apoptosis, and disrupted neural lineage commitment. These findings underscore mitochondria's critical role in nanoplastic-induced neurotoxicity (Fig. 2B).

Expanding on these findings, Chen et al. [26] showed that nanoplastic exposure significantly disrupted tissue architecture, decreased total neural cell populations, and downregulated Wnt signaling pathway components in brain organoids. Reduced expression of neural cadherin indicated impaired axon formation and synaptic connectivity, highlighting broad developmental risks associated with MNP exposure.

Circulatory system

MNPs have also been implicated in disrupting the development and function of the circulatory system, particularly affecting the kidneys and heart [46]. These organs, characterized by high metabolic activity and structural complexity, are especially sensitive to oxidative stress, apoptosis, and inflammation induced by plastic particles [47]. Recent advances using human organoid models have provided deeper insights into the mechanisms by which MNPs impair renal and cardiovascular systems.

Zhou et al. [27] exposed human kidney organoids to 1 μm PS-MPs during the nephron progenitor stage. They observed increased reactive oxygen species (ROS) production, elevated apoptosis, and reduced proliferation, accompanied by decreased organoid size. Notably, Notch signaling was downregulated, disrupting the segmentation of proximal and distal tubules and indicating interference with critical pathways involved in nephrogenesis (Fig. 3A).

Fig. 3.

Impact of microplastic exposure on kidney organoid development and renal injury markers. (A) Immunofluorescence analysis of distal tubular precursor markers, PAX2 and CDH1, in both NT and polystyrene microplastic (PS-MP)-treated groups. Reproduced from Zhou et al. Environ Pollut 2024;360:124645, with permission from Elsevier [27]. (B) Bright-field image and immunostaining of kidney organoids at the final time point following PS-MP exposure. Reproduced from Zhou et al. J Hazard Mater 2025;486:137002, with permission from Elsevier [28]. (C-i) Immunofluorescence staining of kidney organoids, highlighting KI67-positive proliferative cells and WT1-positive podocyte markers. (C-ii) Representative Western blot of mouse kidney tissue samples showing the expression levels of proteins associated with tubular injury across different groups. Reproduced from Chen et al. J Hazard Mater 2025;488:137393, with permission from Elsevier [29].

In a follow-up study, Zhou et al. [28] examined the metabolic consequences of PS-MP exposure. They reported reduced glycolysis resulting from the downregulation of glucose transporters and phosphofructokinase, alongside compensatory upregulation of the tricarboxylic acid cycle. This metabolic shift contributed to abnormal nephron patterning and organoid shrinkage (Fig. 3B), suggesting that MNP toxicity also manifests through disrupted energy metabolism.

Chen et al. [29] assessed the impact of PS-NPs on kidney organoids, finding that these nanoplastics were readily internalized. Exposure led to growth inhibition and increased expression of kidney injury markers, such as KIM-1. Compared to renal cell lines, organoids exhibited heightened sensitivity, highlighting their developmental vulnerability (Fig. 3C).

Cardiac organoids have similarly demonstrated susceptibility to MNP-induced toxicity. Zhou et al. [30] reported that exposure to PS-MPs disrupted mitochondrial function and calcium signaling, while Zhang et al. [31] showed that PS-NPs induced oxidative stress, inflammatory cytokine production, and structural disorganization. These adverse effects were further exacerbated under hypoxic or stress-mimicking conditions, resulting in increased fibrosis and reduced contractile function. Collectively, these studies indicate that MNPs can compromise cardiac development and performance through both molecular and structural perturbations. In summary, exposure to MNPs adversely impacts the circulatory system by impairing nephron formation, altering kidney energy metabolism, and weakening cardiac structure and function.

Respiratory system

As microplastics increasingly contaminate air in both indoor and outdoor environments, inhalation exposure has emerged as a potential threat to respiratory health [48]. The respiratory epithelium, serving as the first line of defense against airborne particles, is particularly susceptible to physical obstruction, inflammation, oxidative stress, and cellular damage [49]. To assess these risks in a physiologically relevant manner, recent studies have employed human airway organoids and lung epithelial models.

Using human airway organoids, Winkler et al. [32] investigated the effects of microplastic fibers (MPFs) collected from household dryer exhaust. Although exposure to MPFs at concentrations ranging from 1 to 50 μg/mL did not significantly affect organoid viability, the fibers were found embedded within organoid structures, redirecting epithelial cell growth along the fiber axis. Immunofluorescence imaging revealed fiber internalization and distortion of epithelial polarity. These morphological alterations were accompanied by reduced expression of SCGB1A1, a marker for club cells involved in epithelial repair, suggesting impaired regenerative capacity (Fig. 4A). Interestingly, despite structural alterations, markers of inflammation and oxidative stress remained unchanged, indicating subclinical or delayed toxicity mechanisms.

Fig. 4.

Representative imaging of respiratory organoids exposed to microplastic. (A-i and ii) Surface views and (A-iii) cross-section of an immunostained organoid (treated with 50 μg/mL MPFs), highlighting cellular organization. Ciliated cells were marked with anti-acetylated tubulin (green), F-actin was visualized using phalloidin 565 (red), and nuclei were counterstained with Hoechst 33342 (blue). A synthetic fiber, also stained blue, is visible. Reproduced from Winkler et al. Environ Int 2022;163:107200, according to the Creative Commons license [32]. (B) Representative light microscopy images of human airway organoids under control and nylon-treated conditions. Yellow arrows indicate airway organoids. Reproduced from Song et al. Am J Respir Crit Care Med 2024;209:427–43, with permission from the American Thoracic Society [33].

In a related study, Song et al. [33] demonstrated that nylon MPFs impaired differentiation in both airway and alveolar organoids. Instead of direct cytotoxicity, the observed effects resulted from chemical leachates released from the fibers. Mechanistically, exposure led to upregulation of Hoxa5, a transcription factor involved in epithelial lineage specification. Inhibition of Hoxa5 restored normal development, indicating that transcriptional dysregulation was central to nylon-induced toxicity. Structural abnormalities—including reduced organoid size, loss of epithelial integrity, and altered expression of differentiation markers—were also observed, suggesting compromised maturation and alveolar specification (Fig. 4B).

Metabolic system

MNPs are emerging as metabolic disruptors that impair mitochondrial function, disturb redox homeostasis, and alter energy metabolism [50]. In liver organoids, aged polypropylene microplastics induced significant mitochondrial dysfunction, including increased NADH/NAD⁺ ratios and ATP depletion, with toxicity severity positively correlating with the carbonyl index [34]. Similarly, Cheng et al. [35] reported that exposure to PS-MPs elevated ROS production, activating oxidative stress and inflammatory signaling pathways. Upregulation of hepatic markers such as HNF4A and CYP2E1 indicated early stages of hepatic steatosis and fibrosis (Fig. 5A). Furthermore, exposure to PS-MPs in liver and kidney cells caused ROS accumulation, decreased cell proliferation, and downregulated crucial antioxidant enzymes, including GAPDH and SOD2 [51].

Fig. 5.

Hepatic and intestinal organoid-based models reveal cellular responses to microplastic and co-exposure toxicity. (A) Immunofluorescence staining revealed increased expression of hepatic markers HNF4A (red) and CYP2E1 (red) in the polystyrene microplastic (PS-MP) group compared to the CTRL group in liver organoids (LOs) sections, indicating similar trends in hepatic marker expression. In contrast, the hepatic cytosolic marker CK18 (green) appeared well-defined in the CTRL group but was reduced and less distinct in the PS-MP group. Reproduced from Cheng et al. Sci Total Environ 2022;806(Pt 1):150328, with permission from Elsevier [35]. (B) Immunofluorescent staining of sliced LOs showing HNF4A (green) and cleaved caspase-3 (red) after 72-hour exposure to PS (50 ng/mL), bisphenol A (BPA) (10 ng/mL), or their combination. LOs were sectioned at a thickness of 12 μm; scale bar=50 μm. Reproduced from Cheng et al. Sci Total Environ 2023;854:158585, with permission from Elsevier [36]. (C) Following exposure to polystyrene nanoplastics, intestinal organoids showed enhanced nuclear translocation of NF-κB p65. Reproduced from Hou et al. Sci Total Environ 2022;838(Pt 2):155811, with permission from Elsevier [37]. (D) Aged polystyrene microplastics (aPS)-induced hepatocytotoxicity was exacerbated by ferric ammonium citrate (FAC) but mitigated by nacetylcysteine (NAC). LOs were treated with aPS, FAC, and NAC individually and in combination, followed by calcein and propidium iodide staining to assess cell viability. Reproduced from Cheng et al. Sci Total Environ 2024;906:167529, with permission from Elsevier [39].

In a co-exposure model, Cheng et al. [36] showed that simultaneous treatment with PS-MPs and bisphenol A intensified metabolic toxicity, leading to enhanced hepatotoxicity, increased lipid accumulation, and estrogen receptor alpha activation (Fig. 5B). Additionally, benzo[a]pyrene-loaded aged PS-MPs impaired mitochondrial function and intestinal barrier integrity through excessive ROS generation and activation of Notch signaling [52]. Chronic co-exposure to PS-NPs and ionizing radiation further exacerbated inflammation in intestinal organoids by suppressing TGF-β1/p-Smad3 signaling [53].

The gastrointestinal tract, as the primary portal for ingested MNPs, is particularly susceptible to metabolic damage [54]. Using human intestinal organoids, Hou et al. [37] showed that PS-NPs selectively accumulated in goblet, Paneth, and enteroendocrine cells, leading to inflammation and apoptosis via clathrin-mediated endocytosis (Fig. 5C). Another study reported that exposure to small-sized PS-MPs reduced colon organoid viability and increased the expression of immune-metabolic genes. Moreover, microplastics translocated to distant metabolic organs such as the liver and pancreas, indicating systemic dissemination potential [38]. Notably, intestinal organoids incorporating M cells exhibited heightened inflammatory cytokine secretion upon high-dose MNP exposure, highlighting immune-metabolic interactions as central to MNP toxicity [55].

Ferroptosis, a regulated cell death pathway characterized by iron accumulation and lipid peroxidation, has also emerged as a key mechanism underlying MNP-induced liver toxicity. Cheng et al. [39] reported that aged PS-MPs triggered ferroptosis in liver organoids through mechanisms involving iron overload, glutathione peroxidase inhibition, and lipid peroxidation, accompanied by dysregulated expression of critical markers such as FTL, FTH1, and TFRC (Fig. 5D). Co-treatment with ferric ammonium citrate intensified these adverse effects, whereas the antioxidant N-acetylcysteine partially restored redox balance but failed to fully prevent cytotoxicity, underscoring the persistent oxidative burden imposed by MNP exposure.

Conclusion and future perspectives

Organoid technology has emerged as a physiologically relevant and versatile platform for elucidating the toxicological effects of MNPs across various human organ systems [26,40]. Findings from neural, circulatory, respiratory, and metabolic organoid models have demonstrated that MNPs induce diverse and organ-specific toxicities, including oxidative stress, apoptosis, metabolic dysregulation, and impaired cellular differentiation [10,56,57]. These studies underscore the ability of organoids to model complex, human-specific responses that are often inadequately represented by conventional in vitro and animal models.

Despite these promising advances, several critical limitations remain. Many current organoid systems lack essential physiological components such as vascularization, immune cell integration, and mechanical cues, restricting their capacity to accurately simulate systemic interactions and chronic exposure scenarios [58,59]. Additionally, a significant portion of existing studies employ simplified plastic compositions and predominantly focus on acute exposure paradigms, which fail to capture the heterogeneous and cumulative nature of real-world MNP exposure [60]. Consequently, the long-term developmental and physiological impacts of MNPs—particularly in vulnerable populations such as fetuses, children, or individuals with pre-existing conditions—remain largely unexplored [61].

Future research efforts should focus on enhancing organoid complexity by incorporating immune cells, vascular structures, and multi-organ connectivity to more faithfully replicate in vivo conditions. The use of patient-derived and genetically diverse organoid models will further enhance the translational applicability of research findings. Additionally, longitudinal studies utilizing environmentally realistic concentrations and chronic exposure timelines are essential to fully characterize the spectrum of MNP-induced pathophysiological changes. Moreover, given the increasing recognition of the endocrine-disrupting effects of MNP, incorporating endocrine-related organoid models—such as those derived from thyroid, pituitary, or reproductive tissues—represents a promising yet currently underexplored area for future research [62,63]. Furthermore, the development of co-exposure models, which include commonly co-occurring environmental toxicants such as endocrine-disrupting chemicals or heavy metals, will be critical for approximating real-life exposure scenarios.

As microplastic pollution continues to intensify, organoid-based toxicological models are poised to play a pivotal role in bridging the knowledge gap between environmental exposure and human health outcomes. Enhancing the fidelity and scope of these models will not only provide deeper mechanistic insights into MNP toxicity but also inform more accurate risk assessment frameworks.

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